scholarly journals Effective Treatment of Cold Agglutinin Disease/Cold Agglutinin Syndrome with Ibrutinib: An International Case Series

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 29-30
Author(s):  
Marit Jalink ◽  
Sigbjørn Berentsen ◽  
Jorge J. Castillo ◽  
Steven Treon ◽  
Bruno Fattizzo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cell ◽  
Hemolytic Anemia ◽  
Median Duration ◽  
Autoimmune Hemolytic Anemia ◽  
Research Funding ◽  
Cold Agglutinin ◽  
Cold Agglutinin Disease ◽  
Btk Inhibitor

Background In cold agglutinin mediated autoimmune hemolytic anemia (cAIHA), anti-red blood cell autoantibodies lead to complement-mediated hemolysis with or without symptoms of acrocyanosis after exposure at low temperatures. cAIHA can be divided into cold agglutinin disease (primary CAD) and cold agglutinin syndrome (CAS). The latter is secondary to diseases such as B-cell malignancies including CLL, infections or autoimmune disorders. In primary CAD, more than 90% of patients have a monoclonal IgM (mostly low level) and often a small bone marrow B-cell clone. There is no approved treatment. For patients with significant hemolytic anemia or acrocyanosis despite thermal protection, rituximab is the most accepted first line treatment with an overall response rate of 50% and median duration of response <1 year. Cytotoxic combinations such as rituximab-bendamustine produce more sustained remissions, although with concerns for long-term adverse effects and stem cell toxicity. Studies involving complement inhibitors are showing promising results on hemolysis, although cold induced peripheral symptoms (IgM mediated rather than complement-mediated) will not improve. Recent international guidelines on cAIHA suggest treatment with the Bruton tyrosine kinase (BTK)-inhibitor ibrutinib in refractory patients with cAIHA (Jäger et al Blood Rev 2020). Indeed, the underlying pathophysiology of cAIHA suggest that BTK inhibition could be effective. Aims To evaluate the efficacy of ibrutinib on anemia, hemolysis and acrocyanosis in patients with cold agglutinin-mediated AIHA (CAD/CAS). Methods An international retrospective study was undertaken of cAIHA patients (CAD/CAS) treated with BTK inhibition using a preformed questionnaire. For eligible patients, laboratory and clinical data regarding underlying disease, bone marrow pathology, hemolytic parameters and patient-reported acrocyanosis were collected at diagnosis, 30 days, 3 months, 6 months and 12 months and last date of follow up. Hemoglobin (Hb) response was considered none (NR), partial (PR, >2 g/dL Hb increase or >10g/dL) or complete (CR, >12g/dL). Adverse events were graded according to the Common Terminology Criteria, version-5.0 (2017). Results So far, 10 patients with cAIHA treated with a BTK-inhibitor (all involving ibrutinib) could be included in the study. Patients were followed from April 2014 until June 2020 at 5 centers (Italy (2), Norway, The United Kingdom and The United States). Median duration of follow up was 20 months (1-74 months). The main findings are summarized in table 1. The indication to start treatment was cAIHA based in all but 1 case (CLL). Median previous number of therapies was 2. All patients had a complement-mediated hemolytic anemia, 7 were transfusion-dependent, and 7 reported symptoms of acrocyanosis at the initiation of ibrutinib. After initiation of ibrutinib, all patients showed an improvement in hemoglobin (Median rise: 4.4 g/dL) resulting in 1 PR and 9 CR. All 7 transfusion-dependent patients became transfusion independent (5 within 30 days). In all but 1 patient, markers of hemolysis (LDH, bilirubin) improved after initiation of ibrutinib (see Figure 1). All 7 patients with acrocyanosis reported clear clinical improvement, with complete resolution of symptoms in 5. There was 1 adverse event (grade 1 bleeding). Data collection is still ongoing and future updates are expected. Conclusion Data show that ibrutinib is effective in the treatment of cAIHA with a notable and brisk improvement of both the hemolytic anemia as well as the cold induced peripheral symptoms. Although preliminary, these promising data support further research of BTK-inhibitor based treatment of cAIHA (CAD/CAS) in a prospective study. Disclosures Berentsen: Alexion, Apellis, Bioverativ and Janssen-Cilag: Other: Travel grants ; Alexion, Apellis, Bioverativ, Janssen-Cilag, True North Therapeutics: Honoraria; Apellis, Bioverativ, Momenta Pharmaceuticals and True North Therapeutics: Consultancy; Mundipharma: Research Funding. Castillo:TG Therapeutics: Research Funding; Pharmacyclics: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Kymera: Consultancy; Abbvie: Research Funding; Janssen: Consultancy, Research Funding. Treon:Bristol-Meyer-Squibb: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding. D'Sa:Sanofi: Honoraria; BeiGene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. OffLabel Disclosure: BTK-inhibitors (ibrutinib/acalabrutinib) are not yet indicated for the use in (primairy) cold autoimmune hemolytic anemia (cAIHA). However it is indicated for use in Waldenstrom macroglobulinemia (WM) and chronic lymphatic leukemia (CLL). Here we report retrospective data on a cohort of cases treated with ibrutinib for cAIHA mostly secondary to WM or CLL.

The Spectrum Of Cold Agglutinin Disease At The Era Of Rituximab: A Retrospective Study On 48 Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2193-2193 ◽  
Author(s):  
Mathilde Lamarque ◽  
Véronique Leblond ◽  
Bruno R. Varet ◽  
Sylvain Choquet ◽  
Jean Paul Vernant ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cell ◽  
Lymphoproliferative Disorder ◽  
B Cell Lymphoma ◽  
Cold Agglutinin ◽  
Cold Agglutinin Disease ◽  
Cold Agglutinins ◽  
Treatment Line ◽  
Positive Direct

Abstract Introduction To better describe the baseline characteristics, the management and the outcome of patients diagnosed with cold agglutinin disease (CAD) in the “real life”, a retrospective multicentre study was performed. Methods All patients diagnosed with CAD in one of the 3 participating university centers in Paris area over a 20-year period were included. The diagnosis of CAD was based on features of active hemolysis (with or without anemia) with a positive direct antiglobulin test (C3 ± IgG pattern) and the presence of cold agglutinins in the serum at a significant titer (>1/32), in the absence of any other cause of inherited or acquired hemolytic anemia. All patients’ characteristics were collected and retrospectively analyzed by the same investigator (ML) using a standardized study form. Results Forty eight patients (64.5 % of females, median age at diagnosis = 65.5 years [range: 30-93 years]) were included. The main symptom or biological abnormality leading to the diagnosis was: unexplained anemia (31%), acrocyanosis (25%), unusual fatigue (20%), hemoglobinuria (10%), neuropathy (8%), jaundice (8%), venous thrombosis (4%) or persistent lymphocytosis (4%). Of note, the diagnosis was incidental in 15% of the cases. The median hemoglobin (Hb) level at diagnosis was 9.3 g/dl [4-16.2 g/dl] and the titer of cold agglutinins varied from 1/32 to 1/64,000 with no obvious correlation with disease activity. Thirty-eight patients (77%) had a monoclonal IgM detected in the serum (kappa light chain in 92% of the cases). At time of diagnosis, a bone marrow aspirate (n= 19) or biopsy (n=11) was performed in 62.5% of the cases, an immunophenotyping of B-cell lymphocytes in the peripheral blood and/or in the bone marrow in 32 patients (66%), and a diagnostic imaging of chest and abdomen in 75% of the cases. Based on these tests, an underlying lymphoproliferative disorder (beyond the sole presence of monoclonal IgM) was found concomitantly in only 40% of the cases: unclassified clonal B cell- lymphoproliferative disorder (21%), chronic lymphocytic leukemia (11%), Waldenström macroglobulinemia (6%), and B-cell prolymphocytic leukemia (2%). The diagnosis of CAD was made after the diagnosis of lymphoma (1 follicular lymphoma and 1 case of marginal zone lymphoma) in 2 cases and before the onset of a diffuse large B-cell lymphoma in 1 case. After a median follow-up of 5 years [0.6-25 years], 12 patients (25%) did not require any other measures than folic acid supplementation and cold avoidance. At least one transfusion of packed-red blood cells (PRBCs) was required in 23 patients (48%), with a median of 10.5 PRBCs [2-40]. Thirty patients (62.5%) were given at least one treatment-line including rituximab (RTX, n=19), corticosteroids(n=14), alkylating agents (n=5), RTX + chemotherapy (n=7) or others (danazol: n=3, azathioprine: n=1, or intravenous immunoglobulin: n=3) The main treatment indication was an active haemolytic anemia (73%), marked cold-induced circulatory manifestations (7%) including 2 cases of cutaneous necrosis or both (13%), or tumor progression (7%). Of note, 15 patients (31%) were treated at least transiently with an erythropoietic-stimulating agent (ESA), mainly darbepoietin alpha, at various doses (ranging from 80µg to 300 µg/week) with a clear benefit observed in at least 8/15 cases (53%). In 5 patients, the use of ESA as a single agent was helpful to overcome one or several hemolytic episodes without the need of transfusion. Four patients (8%) have died during the follow-up period: CLL progression with sepsis (n = 1), myelodysplatic syndrome and sepsis (n =1), unknown cause in 2 elderly patients). Conclusion The initial workup and the management was highly heterogeneous and the observed rate of underlying lymphoproliferative disease was lower then previously reported in the literature. Whereas CAD has a relatively good long-term prognosis, a transfusion was required in almost 50% of the cases during follow-up and up to 65% of the patients received at least one treatment-line. The use of ESA off-label seems promising must needs to be better assessed prospectively. In the last decade, the use of rituximab alone or in combination with chemotherapy has emerged but its indications are still far from being consensual. There is definitely a need for international guidelines in order to harmonize the initial workup and treatment’s indications in patients with CAD. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Development of Multiple Myeloma of the IgA Type in a Patient with Cold Agglutinin Disease: Transformation or Coincidence?

2019 ◽  
Vol 2019 ◽  
pp. 1-6 ◽  
Author(s):  
Øystein Sefland ◽  
Ulla Randen ◽  
Sigbjørn Berentsen
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
B Cell ◽  
Hemolytic Anemia ◽  
Lymphoproliferative Disorder ◽  
Cold Agglutinin ◽  
Cold Agglutinin Disease ◽  
Monoclonal Immunoglobulin ◽  
Cold Agglutinins ◽  
Cell Clones

Cold agglutinin disease (CAD) is an autoimmune hemolytic anemia and a distinct, clonal bone marrow lymphoproliferative disorder, characterized in most cases by a monoclonal IgMκ serum protein. We describe a CAD patient presenting with a monoclonal immunoglobulin of the IgAλclass. For years, she remained asymptomatic apart from the hemolytic anemia until eventually she developed multiple myeloma (MM) of the IgAλphenotype. Prior to the development of MM, her hemolytic anemia responded to rituximab monotherapy. After she was diagnosed with MM, both conditions responded well to bortezomib-based therapy. We performed further investigations to determine whether her MM represented a progression/transformation of CAD or an independent disease. Flow cytometry and biopsy findings convincingly confirmed two unrelated clonal B-cell disorders. On this background, we also discuss previously published reports on cold agglutinin activity in patients with IgA gammopathy. In conclusion, cold agglutinins of the IgA class do probably not result in CAD. If a monoclonal immunoglobulin other than IgMκ is found in a patient with CAD, the coexistence of two unrelated B-cell clones should be suspected.

90Y-Ibritumomab Tiuxetan Followed by Rituximab Is a Safe Treatment Option for Relapsed or Refractory Diffuse Large B-Cell Non-Hodgkin s Lymphoma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2866-2866
Author(s):  
Katarina Luptakova ◽  
Michelle Kim ◽  
Pamela Ely ◽  
Barbara Grant ◽  
John Anthony Parker ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cell ◽  
Research Funding ◽  
Bone Marrow Involvement ◽  
B Cell Lymphoma ◽  
First Line ◽  
Ibritumomab Tiuxetan ◽  
Baseline Platelet Count ◽  
Large B Cell

Abstract Abstract 2866 Introduction: Diffuse large B cell lymphoma (DLBCL) is the most common lymphoid malignancy and is generally responsive to anthracycline-containing chemotherapy. However, 60% of patients (pts) will relapse after their first line treatment. At the time of relapse the only curative approach includes the use of a stem cell transplant (SCT). The incidence of DLBCL increases with age which creates a subset of pts who are not candidates for first line anthracycline-based chemotherapy, and a large subset of pts who are not candidates for SCT due to advanced age and/or co-morbidities. Thus, there is a significant unmet need for therapies with a low toxicity profile in elderly or medically unfit pts with DLBCL. 90Y-ibritumomab tiuxetan (90Y-IT) is an anti-CD20 murine antibody linked with a beta-emitting isotope approved for use in indolent lymphoma. Maintenance rituximab (R) has been reported to increase response rates and prolong remission duration in some lymphomas. We performed a phase II multicenter clinical trial to examine the efficacy of 90Y-IT induction followed by maintenance R in pts with DLBCL. Patients and Methods: Eligible pts were either intolerant of anthracycline-based chemotherapy or had relapsed or refractory CD20+ DLBCL with measurable disease. Pts had to be ineligible for SCT for reasons other than failure to harvest stem cells. Bone marrow involvement by lymphoma of less than 25% based on bilateral bone marrow aspirate and biopsy was required. R 250 mg/m2 was administered IV immediately followed by 111In-ibritumomab tiuxetan. Nuclear scans were performed at 24 and 48 hours to insure there was no altered biodistribution. On day 8 a second infusion of R 250 mg/m2 followed by 0.4 mCi/kg (for pts with a baseline platelet count >150,000/mm3) or 0.3 mCi/kg 90Y-IT (for pts with a baseline platelet count 100,000-149,000/mm3) was given. Pts with multiple extranodal sites or prior bone marrow involvement received CNS prophylaxis with intrathecal methotrexate or cytarabine. Maintenance R 375 mg/m2 was given on weeks 3–6, then weekly × 4 every 6 months × 4 cycles or until progression. Results: Between 10/2003 and 9/2009, 25 pts have been treated. During the course of the study, the ownership of the therapeutic agent changed three times and therefore enrollment was interrupted on two occasions. The median age of pts was 79 (range 45–91), 36% pts had a sIPI score 3 or more. The median number of prior regimens is 2 [0-5]. The 90Y-IT treatment regimen produced an overall response rate of 36% [9 pts] with 28% CR [7 pts]. To date, the mean OS is 18 months (median 8.1 months) with a median follow-up of 11.2 months. Among responding pts, the median OS has not been reached with a median follow-up of over 26.2 [0.1-71.4] months. Thirteen pts died within the first year, 6 patients (24%) continue to be in remission greater than 18 months, and 4 patients (16%) remain in long-term remission [39.9-71.4 months]. The most frequently observed toxicity was hematologic. Eleven percent of pts had grade 4 neutropenia with only one patient experiencing febrile neutropenia, and 16% of pts experienced grade 4 thrombocytopenia. There were no unexpected non-hematologic toxicities except for 1 patient that experienced extravasation. One late-occurring case of MDS/AML was reported that is possibly related to the study regimen, and one case of adenocarcinoma of the GI tract that is likely unrelated. Of note, none of the pts that progressed on the chemotherapy preceding this study achieved a response to the study regimen. Conclusions: The 90Y-IT treatment regimen has an acceptable toxicity profile in elderly or heavily pretreated pts with DLBCL. The two week outpatient 90Y-IT infusion produces response rates and durations similar to that of more prolonged cytotoxic chemotherapy regimens. Progression on previous chemotherapy predicts for poor response to 90Y-IT. Treatment with 90Y-IT can provide durable remission to a select subset of pts who are not candidates for SCT, or intensive anthracycline based chemotherapy. Disclosures: Off Label Use: We are describing a phase II study of the use of 90Y-Ibritumomab Tiuxetan for treatment of diffuse large B-cell lymphoma. Current FDA approved use of 90Y-Ibritumomab Tiuxetan includes relapsed or refractory, low-grade or follicular B-cell non-Hodgkin's lymphoma (NHL) or previously untreated follicular NHL who achieve a partial or complete response to first-line chemotherapy. Joyce:Spectrum Pharmaceuticals, Inc.: Research Funding; Cell Therapeutics Inc: Research Funding; Biogen Idec: Research Funding.

scholarly journals Predictors of Response to Erythropoietin in Autoimmune Hemolytic Anemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3516-3516 ◽  
Author(s):  
Bruno Fattizzo ◽  
Marc Michel ◽  
Laetitia Languille ◽  
Juri Giannotta ◽  
Henrik Frederiksen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Research Funding ◽  
Specific Treatment ◽  
Advisory Board ◽  
Recombinant Erythropoietin ◽  
Severe Anemia ◽  
Predictors Of Response ◽  
Small Series

BACKGROUND AND AIM Bone marrow compensation in autoimmune hemolytic anemia (AIHA) is an emerging predictor of clinical outcome. It is measured by reticulocytosis that may be inadequate in a proportion of cases, particularly in chronic refractory ones. Moreover, reticulocytosis may be masked by constant destruction, particularly in cold forms. Recombinant erythropoietin (EPO), has been anecdotally used off-label in AIHA to improve anemia, but only case reports and small series have been described. Here we evaluate EPO efficacy and predictors of response in a multicentric cohort of primary and secondary AIHA patients. METHODS Hematological data, hemolytic markers (LDH, reticulocytes), and concomitant treatments were retrospectively and prospectively collected. Efficacy was evaluated at 15 and 30 days, and then at 3,6 and 12 months after EPO start. Response was considered as partial (PR, >2 g/dL Hb increase or >10 g/dL) or complete (CR, >12g/dL and normalization of hemolytic markers). Forty-six AIHA cases followed from June 2007 to June 2019 at 9 centers in Italy, France, Norway, Austria, Denmark, and UK were included. RESULTS Table 1 shows patients characteristics: all AIHA types (warm, cold, mixed, and DAT negative) were present, and 5 cases were secondary to a lymphoproliferative disorder (not active and without specific treatment at the time of EPO start). Bone marrow evaluation pre-EPO (N=24) showed hypercellularity in 14 cases, dyserythropoiesis in 11, and reticulin fibrosis in 3; a lymphoid infiltrate was found in 19 patients (T-cell in 6, B-cell in 10, mixed in 3), greater than 10% in the 5 secondary cases only. Forty-one cases (89%) had been previously treated, with a mean of 1.8+1 lines of therapy including steroids, rituximab, splenectomy, immunosuppressors and sutimlimab (1 case, where the drug completely abolished hemolysis). The majority (67%) started EPO due to non-response to ongoing treatment (18 steroids, 6 immunosuppressors, 1 sutimlimab) or within 3 months from rituximab course (7). At EPO initiation, 30% of cases displayed severe anemia, 71% had inadequate reticulocytosis (bone marrow responsiveness index<121), and 73% showed inappropriately low endogenous EPO levels. Of note, 2 patients had concomitant renal impairment, possibly contributing to this finding. Most cases received epoetin alpha 40,000 UI/week (45%), followed by darbopoetin alpha (34% of cases, median dose 102 mcg/week) and epoetin zeta (14% of cases, 30,000 UI/week). EPO was administered for a median of 6 months and responses were observed in 68% and 70% of cases at month+1 and +3. Comparable response rates were recorded at month+6 (70%, 13 CR and 1 PR, N=20) and +12 (72%, 8 CR and 5 PR, N=18), although evaluable cases were fewer. Median Hb increase from baseline was 2.5 g/dL (0.2-7.6) at month+1 (p<0.001), and 3.1 g/dL (0-9.4) at month+3 (p<0.001). Consistently, reticulocytes increased by 23 x109/L (0-217) at month+1, and 33 x109/L (0-353) at month+3. No EPO-related adverse events occurred (particularly no thrombosis). At last follow up, 23 cases had discontinued EPO: 13 for long lasting CR and 10 because of NR. Considering predictors of response, a better efficacy was observed in primary versus secondary AIHA (71 vs 40%) and in patients with shorter time from diagnosis to EPO treatment (52% of responders started EPO within 1 year from diagnosis vs 8% of NR, p=0.01). Moreover, responders had received a lower number of previous treatments (p=0.04), particularly rituximab (p=0.05) and immunosuppressors (p=0.08). Remarkably, responders more frequently showed severe anemia (86% vs 62%) and lower endogenous EPO (91% vs 50% with a cut-off of <60 UI/L, p=0.05) at baseline. CONCLUSIONS EPO is effective in roughly 70% of chronic refractory AIHA cases, independently from antibody thermal characteristics/isotype and underlying disease. Concomitant treatments may partially affect response evaluation, although EPO treatment has been introduced because of their partial or complete inefficacy. Further limitations are the retrospective nature of the study and a possible selection bias (i.e. most of patients had inadequate reticulocytosis). Predictors of response were severe anemia and low levels of endogenous EPO, as well as, shorter disease duration and a lower burden of previous treatments. These data suggest an early use of EPO in this setting in order to overcome inadequate bone marrow compensatory ability. Table Disclosures Fattizzo: Apellis: Consultancy. Michel:Novartis: Consultancy; Amgen: Consultancy; Rigel: Consultancy. Frederiksen:Novartis: Research Funding; Janssen Pharmaceuticals: Research Funding; Abbvie: Research Funding; Alexion: Research Funding; Gilead: Research Funding. Mauro:Gilead: Consultancy, Research Funding; Shire: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Jannsen: Consultancy, Research Funding; Roche: Consultancy, Research Funding. Jilma:TrueNorth a Bioverativ company, a Sanofi company: Consultancy, Research Funding. Hill:Regeneron: Honoraria; Roche: Honoraria; Ra Pharma: Honoraria; Bioverativ: Honoraria; Novartis: Honoraria; Akari: Honoraria; Alexion: Honoraria; Apellis: Honoraria. Berentsen:Mundipharma: Research Funding; Apellis, Bioverativ (a Sanofi company), Momenta Pharmaceuticals, and True North Therapeutics: Consultancy; Alexion, Apellis, and Janssen-Cilag: Honoraria. Barcellini:Agios: Other: Advisory board; Bioverativ: Other: Advisory board; Alexion: Other: Invited Speaker, Research Funding; Novartis: Other: Invited Speaker, Research Funding; Incyte: Other: Advisory board. OffLabel Disclosure: Erythropoietin (EPO) is not yet indicated for the use in autoimmune hemolytic anemia. Here we report retrospective data on a large cohort of cases treated with EPO as a support to bone marrow compensation.

scholarly journals Cold Agglutinin Disease Transfusion Practices in the United States: An Electronic Medical Record-Based Analysis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3690-3690
Author(s):  
Jun Su ◽  
Rajeshwari Punekar ◽  
Jaime Morales Arias ◽  
Nisha Jain
Keyword(s):  
Medical Record ◽  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Index Date ◽  
Cold Agglutinin ◽  
Cold Agglutinin Disease ◽  
Employment Equity ◽  
Medical Activity ◽  
Equity Ownership ◽  
Rbc Transfusion

Introduction Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia (AIHA) accounting for 20% of all cases, with no approved therapies and limited management options for patients. CAD is characterized by immunoglobulin M-mediated erythrocyte agglutination, which triggers activation of the classical complement pathway leading to hemolysis and subsequent anemia. Red blood cell (RBC) transfusions are used as a supportive treatment in CAD to temporarily alleviate anemia, although the transfusion practices are variable among providers treating patients with CAD. Recent RBC transfusion guidelines from the AABB (formerly the American Association of Blood Banks) recommend that transfusions be administered with a restrictive threshold in most clinical scenarios (ie, transfusion is not indicated until hemoglobin [Hb] reaches 7-8 g/dL and/or patients exhibit anemia-related symptoms) to avoid associated complications such as acute reactions, alloantibody development, and hemochromatosis (Carson et al, JAMA, 2016; Carson et al, N Engl J Med, 2017). Because of the dearth of information available regarding trends in RBC transfusion practices among US hematologists, the objective of this longitudinal, retrospective, observational assessment of an electronic medical record database was to evaluate transfusion practices applied to patients with CAD in the US. Methods Patients were retrospectively identified from Optum® de-identified Electronic Health Record (EHR) dataset. Adult patients with ≥1 AIHA-related medical encounter between January 2007 and September 2018 (study period) and ≥3 mentions of CAD-related terms from physician notes ("cold agglutinin disease," "cold autoimmune hemolytic anemia," or "cold agglutinin hemoglobinuria") were included (Broome et al, Blood, 2017). The index date for each patient was the date of first mention of CAD during the study period. The baseline period was defined as the interval from the start of medical activity in the EHR database or study period (whichever occurred later) to the index date, and the follow-up period was defined as the interval from the index date to the end of the study period, end of medical activity, or death (whichever occurred earlier). The study sample was categorized into 2 study groups, the transfusion group (patients with CAD with ≥1 RBC transfusion after the index date) and the non-transfusion group (patients with CAD without any transfusions during the study period). Patients were further grouped based on the following Hb levels (g/dL): <8, ≥8 to ≤10, and >10 to ≤12. The closest Hb level prior to the most recent transfusion (within the prior 15 days and the lowest level) was used for the transfusion group and the lowest Hb level during the study period was used for the non-transfusion group. Descriptive statistics included mean, standard deviation, and median values for continuous variables and frequency (n and percent) for categorical variables. No adjustment was made for this descriptive analysis. Results A total of 903 patients with CAD were identified from the Optum EHR database; most patients were white (n=760 [84%]) and female (n=560 [62%]). Baseline demographics and clinical characteristics of each group can be found in the Table. Of the patients with CAD, 548 (61%) did not receive transfusions and 355 (39%) received ≥1 RBC transfusion. Among patients with CAD who received transfusions, 84% (n=297) had ≥2 RBC transfusions. Out of the 903 patients with CAD, 864 had Hb levels reported and 752 had Hb levels ≤12 g/dL. Forty-four percent (n=329/752) of those CAD patients received ≥1 RBC transfusion. When separated by Hb levels, 18% of patients with Hb >10 to ≤12 g/dL (n=19/108); 41% (n=88/216) of patients with Hb ≥8 to ≤10 g/dL; and 52% (n=222/428) of patients with Hb <8 g/dL received ≥1 RBC transfusion. Of the 423 (56%) patients with CAD and Hb levels ≤12 g/dL who did not receive RBC transfusions, 21% (n=89/423) had Hb levels >10 to ≤12 g/dL; 30% (n=128/423) had Hb levels ≥8 to ≤10 g/dL; and 49% (n=206/423) had Hb levels <8 g/dL. Conclusions Overall, patients with CAD are not a heavily transfused population. Even in those with a significantly decreased Hb (<8 g/dL), approximately half of them (49%) did not receive RBC transfusions. This suggests that the use of transfusions in patients with CAD may not reflect disease severity. Further prospective studies are needed to fully understand the impact of transfusions on patients with CAD. Disclosures Su: Sanofi Genzyme: Employment, Equity Ownership. Punekar:Sanofi: Employment, Equity Ownership. Morales Arias:Sanofi: Employment, Equity Ownership. Jain:Sanofi Genzyme: Employment, Equity Ownership.

scholarly journals Outcomes of Patients with Relapsed/Refractory (R/R) B-Cell Acute Lymphocytic Leukemia (ALL) Post Blinatumomab Failure

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1335-1335 ◽  
Author(s):  
Jenny Dahl ◽  
Hagop M. Kantarjian ◽  
Musa Yilmaz ◽  
Tapan Kadia ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
B Cell ◽  
Median Survival ◽  
Median Duration ◽  
Salvage Therapy ◽  
Research Funding ◽  
Clinical Characteristics ◽  
Complete Response ◽  
Best Response ◽  
Duration Of Response

Abstract Introduction: Blinatumomab is a first-in-class Bispecific T-cell engaging (BiTE) antibody targeting CD19-positive malignant cells and CD3-positive T cells. It has shown activity in both R/R B-cell ALL and with persistent minimal residual disease (MRD). However, despite a 50% response rate with blinatumomab, the duration of response is very short with many pts experiencing relapse. The goal of this study is to assess the outcome of patients with R/R B-cell ALL post blinatumomab failure. Methods: We reviewed 40 patients with R/R ALL treated with blinatumomab at our institution between 1/2012 and 1/2015. Of the 40 patients treated, 30 were either refractory (n=18) or lost their response (n=12) after initially achieving a complete response or complete response with incomplete count recovery (CRi). We analyzed the clinical characteristics and survival of these 30 patients who failed blinatumomab. Results: Clinical characteristics of the 30 patients with blinatumomab failure are summarized in Table 1. Best response to blinatumomab was CR in 9 pts and CRi in 3 with a median duration of response of 3 months (range, 1-8 months). After a median follow-up of 6.8 months (range 4.8- 31 months) from blinatumomab failure, 8 patients (27%) remain alive. The median overall survival was 6.4 months and the estimated 12-month survival rate was 36%. The median survival was 3 and 11 months for patients refractory to blinatumomab and those who relapsed after a previous response, respectively (p=0.179). Furthermore, there was a trend for better outcome post blinatumomab failure if the drug was administered as first, second, or third and beyond salvage therapy with a median survival of 19, 11, and 5 months, respectively (p= 0.248). Following blinatumomab failure, 11 patients received inotuzumab ozogamicin salvage therapy as a single agent in 5 or in combination with mini-hyper-CVD in 6 [Jabbour E et al; EHA 2015]. Eight patients responded for an overall response rate of 73% for a median duration of 6 months (range, 1.2-30 months). Overall, 9 patients underwent allogeneic stem cell transplant (allo-SCT), 5 of them post salvage therapy with inotuzumab. Seven of them remain alive in CR at the last follow-up. The 1-year survival rates were 83% and 11% for patients who received an allo-SCT and those who did not, respectively (p<0.001). Conclusions: Overall, the outcome of patients with R/R ALL post blinatumomab failure is poor with a median survival of 6.4 months. Inotuzumab ozogamicin is a good salvage therapy option allowing patients with refractory disease to proceed with allo-SCT that remains the only curative approach for these patients. Table 1. Clinical Characteristics of Patients with Blinatumomab Failure N=30 Parameter N (%)/Median [Range] Age (years) 29 [19-76] Sex (Male) 23 (77) Performance Status 1 [0-2] Cytogenetics Diploid 9 (30) t(4;11) 1 (3) Miscellaneous 15 (50) t(9;22) 1 (3) Insufficient Metaphase 4 (14) WBC at start (x 109/L) 2.75 [0.4-24] % PB blasts at start 8 [0-98] % BM Blasts at start 80 [10-98] WBC at failure (x 109/L) 3.4 [0-224] % BM Blasts at failure 69 [2-98] # Prior therapies, median 3 [1-6] # Blinatumomab courses 2 [1-5] Best response to blinatumomab CR 9 (30) CRi 3 (10) Median duration of response (months) 3 [1-8] Follow up, median (months) 6.8 [4.8-31] Disclosures Cortes: Teva: Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; BerGenBio AS: Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.

The Bruton's Tyrosine Kinase (BTK) Inhibitor PCI-32765 Induces Durable Responses in Relapsed or Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): Follow-up of a Phase Ib/II Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 983-983 ◽  
Author(s):  
Susan O'Brien ◽  
Jan A. Burger ◽  
Kristie A. Blum ◽  
Richard R. Furman ◽  
Steven E. Coutre ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Objective Response ◽  
Cellular Migration ◽  
Phase Iii ◽  
Employment Equity ◽  
Phase Ib ◽  
Btk Inhibitor ◽  
Equity Ownership

Abstract Abstract 983 Introduction: Btk is a central mediator of B-cell receptor signaling which is essential for normal B-cell development. PCI-32765 is an orally-administered irreversible inhibitor of Btk which induces apoptosis and inhibits cellular migration and adhesion in malignant B-cells. An early analysis of the phase Ib/II study PCYC-1102 showed PCI-32765 to be highly active and tolerable in patients with CLL (Byrd, ASCO 2011). Here we report longer-term follow-up of this multicenter phase Ib/II trial. Methods and Patients: Two cohorts of CLL patients (previously untreated ≥65 years old and relapsed/refractory [R/R] disease following at least 2 prior therapies, including fludarabine) were treated with oral PCI-32765 administered daily for 28-day cycles until progression of disease. Doses of 420mg (previously untreated and R/R) and 840mg daily (R/R) were examined. The patients with R/R disease are the subject of this report. Results: Sixty-one R/R CLL/SLL patients were enrolled (420mg cohort n=27, 840mg cohort n=34). The median follow-up time for the 420mg cohort is 10.2 months and for the 840mg cohort is 6.5 months. The median number of prior treatment regimens for the 420mg cohort was 3 (2–10) and for the 840mg cohort was 5 (1–12). Seventy-two percent of patients had at least one poor-risk molecular feature: del(17p) 31%, del(11q) 33%, IgVH un-mutated 57%. Treatment has been well tolerated. Two patients have discontinued for adverse events (AE); 6 patients have required reduction of PCI-32765 dose (420mg cohort 2/27, 840mg cohort 4/34). Grade 1 or 2 diarrhea, fatigue, nausea, and ecchymosis have been the most frequently reported AEs. Serious AEs (SAEs) have occurred in 38% of patients; SAEs considered potentially related to PCI-32765 have occurred in 10% of patients. Grade ≥3 AEs considered potentially related to PCI-32765 occurred in 21% of patients. A characteristic pattern of response, with a transient phase of lymphocytosis typically peaking within the first 2 months of Rx, followed by resolution over time, has been observed in the majority of patients. Objective response (ORR; PR + CR) by IWCLL criteria in the 420mg cohort cohort, previously reported as 48% with 6.2 months median follow-up (Byrd, et al ASCO 2011), is now 70% with 10.2 months median follow-up. ORR in the 840mg cohort is 44% at 6.5 months median follow-up. An additional 19%, and 35% of patients in these cohorts, respectively, have a nodal PR (>50% reduction in aggregate lymph node size) with residual lymphocytosis. ORR appears to be independent of molecular risk features. Eighty-two percent of patients (50/61; 420mg cohort 22/27, 840mg cohort 28/34) remain on PCI-32765. Only 8% (5/61) of patients have had progressive disease (PD); 6-month PFS is 92% in the 420mg cohort and 90% in the 840mg cohort. Treatment cessation not related to PD or AE includes: death (n=2) or investigator discretion (n=3). Conclusions: The potent Btk inhibitor PCI-32765 is well tolerated and is associated with high rates of 6-month PFS in R/R CLL/SLL. Phase III trials of PCI-32765 in CLL/SLL are planned. Disclosures: O'Brien: Pharmacyclics, Inc: Research Funding. Burger:Pharmacyclics, Inc: Research Funding. Blum:Pharmacyclics: Research Funding. Furman:Pharmacyclics, Inc: Research Funding. Coutre:Pharmacyclics, Inc: Research Funding. Sharman:Pharmacyclics, Inc: Research Funding. Flinn:Pharmacyclics, Inc: Research Funding. Grant:Pharmacyclics, Inc: Research Funding. Heerema:Pharmacyclics, Inc: Research Funding. Johnson:Pharmacyclics, Inc: Research Funding. Navarro:Pharmacyclics, Inc: Employment, Equity Ownership. Holmgren:Pharmacyclics, Inc: Consultancy. Hedrick:Pharmacyclics: Employment, Equity Ownership. Byrd:Pharmacyclics, Inc: Research Funding.

scholarly journals The Immunomodulatory Effect and Clinical Efficacy of Daratumumab in a Patient With Cold Agglutinin Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Anna Zaninoni ◽  
Juri A. Giannotta ◽  
Anna Gallì ◽  
Rosangela Artuso ◽  
Paola Bianchi ◽  
...  
Keyword(s):  
Hemolytic Anemia ◽  
Plasma Cell ◽  
Clinical Efficacy ◽  
Lupus Erythematosus ◽  
Autoimmune Hemolytic Anemia ◽  
Plasma Cells ◽  
Proteasome Inhibitors ◽  
Immunomodulatory Effect ◽  
Cold Agglutinin ◽  
Cold Agglutinin Disease

Daratumumab is a monoclonal antibody directed against the transmembrane glycoprotein CD38 expressed on plasma cells and lymphoplasmocytes, with a proven efficacy in multiple myeloma. Here we show its clinical efficacy in a patient with cold agglutinin disease (CAD) relapsed after multiple lines of therapy. CAD is caused by cold reactive autoantibodies that induce complement mediated hemolysis and peripheral circulatory symptoms. The disease is also characterized by the presence of monoclonal IgM gammopathy and of a lymphoid bone marrow infiltration that benefits from B-cell targeting therapies (i.e., rituximab) but also from plasma cell directed therapies, such as proteasome inhibitors. In the patient described, we also show that daratumumab therapy influenced the dynamics of several immunoregulatory cytokine levels (IL-6, IL-10, IL-17, IFN-γ, TNF-α, TGF-β) indicating an immunomodulatory effect of the drug beyond plasma cell depletion. In addition, we provide a literature review on the use of daratumumab in autoimmune conditions, including multi-treated and refractory patients with autoimmune hemolytic anemia (both CAD and warm forms), Evans syndrome (association of autoimmune hemolytic anemia and immune thrombocytopenia) and non-hematologic autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis.

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