Treatment of Women with Heavy Menstrual Bleeding with a Combination Therapy of Agnus Castus and Tranexamic Acid - Experiences of a German Single Centre

Abstract Background: Heavy menstrual bleeding (HMB) is a common gynaecological problem and is the reason for 18-30% of gynaecological visits. In a European study in 4,502 women, 27.2% were diagnosed with HMB (Fraser et al., 2015). On the other hand, HMB is often associated with bleeding disorders (Shankar et al., 2004). The definition of HMB has different perspectives; from a subjective perspective HMB is defined as e excessive menstrual blood loss impacting on women's physical, social, emotional and/or mental quality of life, whereas from an objective perspective it is defined as excessive blood loss >80 ml per cycle (Munro et al., 2012). There are different approaches for treating HMB such as the administration of non-steroidal drugs, Desmopressin, herbal Vitex Agnus Castus (VAC), Tranexamic acid (TXA) or a hormonal therapy; moreover, HMB can also be treated surgically. The aim of this study was to test the efficacy of the specific HMB management used in our center: Women with HMB are treated usually with VAC, which optimizes the relation of estrogen to progesterone in the female body (Yavarikia et al., 2013). VAC can be used without using any hormones (Shahnazi et al, 2016), providing a treatment with a low impact on women's bodies. Additionally, TXA is given during the menstruation due to its antifibrinolytic effect. Furthermore, the "Pictural Blood-Loss-Assessment- Chart" (PBAC Score) is administered to analyze the menstrual blood loss. Methods: Two ad hoc patient-reported questionnaires were developed to test the efficacy of the HMB management in our center The baseline questionnaire includes the following aspects: menarche, duration, regularity, number of sanitary products, pain level, medical background and family history. During the first visit in our center women with HMB filled in the baseline questionnaire. In addition, laboratory tests are done including a comprehensive coagulation test and the examination of iron and hemoglobin levels. Moreover, we presented an application called "My Flow Score" to the patients, which calculates the PBAC score as a result of all entered sanitary products women use during their period. Women are prescribed VAC and/or TXA for the management of their HMB. After four months patients are scheduled for a follow up appointment. At that time they complete the follow-up questionnaire including the following aspects: compliance with the medication or the reason for the non-compliance, health complaints due to the medication, duration of the period, improvement, pain level, PBAC score if the patient did use the APP "My Flow Score" or if not the number of sanitary products. A blood test was taken and the HMB management was adapted to the patients' needs. Results: So far, 100 women with HMB with a median age of 14 years (range 9-50) were enrolled in our study. They had their menarche with a median age of 12 years (range 8-17). Diagnosis of women ranged from iron or folic acid deficiency to different forms of bleeding disorders; with the majority suffering from von Willebrand disease (43/100) followed by iron deficiency (14/100). One fifth of the patients had more than one diagnosis. 1/3 of patients received a treatment for the HMB previously, mainly contraceptives, TXA or VAC. 49% reported anomalies with regard to previous other bleeding; 25.8% had increased hematomas and 19.6% recurrent epistaxis. Most of them reported anomalies already in the family (60.2%). Before treatment women had a median PBAC Score of 169 (range 77-800) and reported a median pain level of 6.5 during menstruation on a scale ranging from 1 (low pain) to 10 (extreme pain). 87/100 women received VCA, of these 75.4% regularly and 85/100 women received TXA, of these 84.6% regularly. 81% of them received a combination of both medicines. Compared to before 28.8% of patients reported shorter duration of menstruation and reduced bleeding with treatment, 11.9% did not experience any improvement; the PBAC score decreased significantly (p<.0001). Conclusions: Although the type of diagnosis in women suffering from HMB had a great variation, these patients had a high disease burden with a relatively high level of pain and a high loss of blood assessed with the PBAC score. Thanks to a combination of VAC and TXA the disease burden in these women could be reduced, especially for the time of menstruation and amount of bleeding. VAC proved to be highly accepted by women due to its low treatment burden. Disclosures Von Mackensen: University Medical Centre Hamburg-Eppendorf: Current Employment; Sobi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy; Novo Nordisk: Consultancy; Biomarin: Speakers Bureau; CSL Behring: Speakers Bureau; Chugai/Roche: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Evaluation of Disease Burden and Response to Treatment in Adults with Type 1 Gaucher Disase Using a Validated DS3 Severity Score Index

Blood ◽

10.1182/blood.v124.21.4957.4957 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4957-4957

Author(s):

Neal J. Weinreb ◽

Eleanor Feingold ◽

Suma Shankar ◽

Barry E. Rosenbloom ◽

David Finegold

Keyword(s):

Board Of Directors ◽

Disease Burden ◽

Fellowship Training ◽

Age At Diagnosis ◽

Advisory Committees ◽

Important Improvement ◽

Lytic Lesions ◽

History Of ◽

Pre Treatment

Abstract BACKGROUND: DS3 scoring is a method of expressing an integrated assessment of disease burden in a given patient based on bone, hematologic and visceral domains. A DS3 severity score index for adult patients with type 1 Gaucher disease (GD1) was developed and tested for validity, reliability and feasibility (Weinreb NJ et al. Genet Med 2009; 12:1-8). However, the DS3 score has not yet been applied to large numbers of patients across different clinics. We developed a consortium of five geographically separated North American GD treatment centers to further investigate the DS3 score as a tool for initial assessment, long term follow up and evaluation of treatment responses. METHODS: 133 adult patients with a history of IV enzyme treatment (ERT) for GD1 were recruited under informed consent. All patients agreed to allow International Collaborative Gaucher Registry (ICGG, supported by Genzyme) data with additional clinical phenotyping to be used to calculate DS3 and annotate longitudinal changes. An ICGG independent data center collated the information. Baseline DS3 scores were calculated around the date of initial treatment. Follow up scores were calculated annually with a ±3 month window. Because the calculation of DS3 scores is sensitive to missing data, some values were imputed. RESULTS: Patient characteristics: 68 patients (51%) identified all grandparents as Ashkenazi Jews. 48 of 52 N370S/N370S patients had complete or partial Ashkenazi Jewish ethnicity. N370S/L444P was the most common genotype among non-Jewish patients. 118 patients had at least one N370S allele. Median age at the time of GD1 diagnosis was 28 (0-85) y. 38 patients (26.6%) had a history of splenectomy. Treatment commenced at a median age of 45 (6-87) y with a median follow up on treatment of 14 (1-23) y. Baseline DS3 scores: In 58 patients, pre-treatment scores 6.0-14.9 (median 7.84) signified marked disease severity. 31 patients (53%) had a history of pre-treatment splenectomy. Median age at diagnosis was 18 (0-68) y. Median age at first treatment was 44 (7-69) y. Only 11 patients (19%) were N370S homozygous. 44 patients (76%) had major bone pathology (avascular necrosis, fractures, lytic lesions) pre-treatment. Fifty-three patients had moderate disease severity (DS3 3.00-5.93; median 4.33). Splenectomy prevalence was 15.1%. Median age at diagnosis was 32 (4-85) y; median age at first treatment was 50 (6-87) y. 26 patients (49%) were N370S/N370S. 9 patients (17%) had major pre-treatment bone disease. Twenty-two patients had mild severity disease (DS3 0.40-2.93; median 2.40). Median age at diagnosis was 40 (1-71) y; median age at first treatment was 44 (9-73) y. None had splenectomy or major pre-treatment bone disease. 15 patients (68%) were N370s/N370S. Response to treatment: Health-state transitions occurred primarily during the first 5 treatment years. Of 58 patients with marked pre-treatment disease, 33% remained so after Y1. At Y5, 14% were “marked,” 50% “moderate,” 19% “mild,“ 17% not evaluable (NE). Of 53 “moderate” patients, 38% continued so after Y1. At Y5, 30% were “moderate,” 49% “mild,” 21% NE. No patient worsened in severity category. Of 22 “mild” patients, all remained so at Y1, At Y5, 2 patients had transitioned to “moderate” (DS3 scores 3.07 and 3.17); 64% remained “mild” and 27% were NE. Among evaluable marked severity patients, 76% had clinically important improvement (defined as a -3.1 ΔDS3 from baseline) at Y5. In “moderate” patients with initial DS3 scores 4.58-5.93, 41% had clinically important improvement at Y5. No patients with baseline DS3 scores <4.50 had a clinically important response. CONCLUSIONS: DS3 is an effective tool for assessing pre-treatment disease burden in GD1 and for monitoring response to therapy. It is consistent with indirect indicators of GD1severity such as genotype and early age of diagnosis and symptom onset. ERT is associated with clinically important improvement in DS3 scores in patients with high severity scores. Nevertheless, even with sustained improvement in DS3 scores, GD1 patients on ERT, especially those with risk factors such as splenectomy and pre-treatment bone pathology are at continual risk for emerging major bone complications (Fig 1,2). SUPPORT: Independent Investigator Grant from Genzyme. DS3 score Figure 1. “Marked” severity patients: change in mean (+/-) SD DS3 scores with ERT Figure 1. “Marked” severity patients: change in mean (+/-) SD DS3 scores with ERT Years Figure 2. Major (AVN, fractures, lytic lesions) bone event-free survival Figure 2. Major (AVN, fractures, lytic lesions) bone event-free survival Disclosures Weinreb: Genzyme, a Sanofi Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Shire HGT: Honoraria, Speakers Bureau; Pfizer Corporation: Consultancy, Honoraria, Speakers Bureau. Shankar:Genzyme, a Sanofi Company: Consultancy, Honoraria, Travel reimbursement, received funds for fellowship training, for educational and patient meetings Other; Shire: Consultancy, Honoraria, Travel reimbursement, received funds for fellowship training, for educational and patient meetings, Travel reimbursement, received funds for fellowship training, for educational and patient meetings Other; Protalix-Pfizer: Consultancy, Honoraria, Travel reimbursement, received funds for fellowship training, for educational and patient meetings, Travel reimbursement, received funds for fellowship training, for educational and patient meetings Other; Biomarin: Consultancy, received funds for fellowship training, for educational and patient meetings, received funds for fellowship training, for educational and patient meetings Other; Actelion: Consultancy, received funds for fellowship training, for educational and patient meetings Other. Rosenbloom:Genzyme, a Sanofi Company: Consultancy, Honoraria, Travel reimbursement Other. Finegold:Genzyme, a Sanofi Company: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire HGT: Honoraria, Membership on an entity's Board of Directors or advisory committees; Protalix Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Prospective, Multicenter Study of the MTOR Inhibitor Everolimus (RAD001) As Primary Therapy in Waldenstrom's Macroglobulinemia

Blood ◽

10.1182/blood.v118.21.2951.2951 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2951-2951 ◽

Cited By ~ 7

Author(s):

Steven P Treon ◽

Christina K Tripsas ◽

Leukothea Ioakimidis ◽

Diane Warren ◽

Christopher Patterson ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Research Funding ◽

Disease Burden ◽

Response Assessment ◽

Primary Therapy ◽

Advisory Committees ◽

Bone Marrow Disease ◽

Unacceptable Toxicity

Abstract Abstract 2951 Introduction: Everolimus (RAD001) is an inhibitor of MTORC1, a component of the Akt-MTOR pathway which regulates growth and survival of lymphoplasmacytic cells in Waldenstrom's Macroglobulinemia (WM). Everolimus also exhibits activity in WM patients with relapsed/refractory disease (Ghobrial et al, JCO 2010; 28 :1408–14). We therefore initiated this multicenter, prospective study to delineate the efficacy and tolerability of Everolimus as primary therapy in WM. Patients and Methods: WM patients with symptomatic disease, adequate organ function, who were not previously treated, and who did not have symptomatic hyperviscosity were eligible for this study. Intended therapy consisted of 10 mg of oral Everolimus administered daily, with sequential dose de-escalation to 7.5 mg daily, 5 mg daily, and 5 mg every other day permitted for toxicity. Patients were treated until progression or unacceptable toxicity. Patients were encouraged to use 5 mL of an oral dexamethasone solution (0.5 mg/5mL) to swish and spit up to 4 times daily for prevention of oral ulcerations associated with Everolimus. Study participants were assessed monthly for the first 3 months, and thereafter every 3 months which included a physical examination, complete blood counts, chemistries, and serum IgM monitoring. Bone marrow biopsies and aspirations were performed at baseline, at months 6 and 12, and as required for response assessment. Results: Thirty-three patients were enrolled on this prospective, multicenter study and are evaluable for response. Median baseline characteristics for all patients are as follows: Age 62 (range 41–80 years); Hematocrit 31.3% (range 24.5–45.7%); Hemoglobin 10.8 (range 7.8–15.7 g/dL); serum IgM 4, 440 (range 959–10, 256 mg/dL), with 23 (69.7%) patients demonstrating an IgM level ≥3, 000 mg/dL; serum M-protein 2.60 g/dL (range 0.31–5.31 g/dL), B2M 3.0 mg/L (1.6–6.7 mg/L). The median baseline bone marrow disease burden was 70% (range 7.5–95%), and 21 patients (63.6%) demonstrated adenopathy or splenomegaly by CT scans at baseline. At best response, serum IgM levels declined from 4, 440 to 1, 925 (p<0.0001), and serum M-protein decreased from 2.60 to 1.50 g/dL (p<0.0001). The median time to best serum IgM response was 3 months (range 0.6–15 months). Median hematocrit and hemoglobin levels declined modestly from 31.3% to 30.6% (p=0.057) and 10.8 to 10.4 g/dL (p= 0.1059), respectively. Twenty-two patients are evaluable for response by both bone marrow biopsy and IgM level at 6 months, at which time bone marrow disease burden remained unchanged with a median of 65% involvement (range 10–95%; p=0.3595). The best overall response rate utilizing consensus criteria was 66.7% (14 Partial Responses, 8 Minor Responses, and 11 Stable Disease), for a major response rate of 42.4%. However, discordance between serum IgM levels upon which consensus criteria for response are based, and bone marrow disease response were common and complicated response assessment. At 6 month assessments, 10 of 22 (45.5%) patients for whom both serum IgM and bone marrow assessments were performed, discordance between serum IgM levels and bone marrow disease involvement were observed. Among these patients, 2 had no change, and 8 had increased bone marrow disease involvement despite decreases in serum IgM levels. Grade ≥2 hematologic and non-hematologic toxicities possibly, probably or definitively associated with Everolimus included anemia (n=8, 24%), thrombocytopenia (n=5, 15%), neutropenia (n=5, 15%), hyperglycemia (n=2, 6%), oral ulcerations (n=7, 21%), pneumonitis (n=5, 15%), fatigue (n=4, 12%), rash (n=2, 6%), and cellulitis (n=2, 6%). With a median follow-up of 9 months (range 0–18 months), 15 patients remain on study. Reasons for study discontinuation included non-response or disease progression (n=11), unacceptable toxicity (n=6, including 5 for pneumonitis and 1 for neutropenia), and loss of follow-up (n=1). Conclusions: Everolimus is active in the primary therapy of WM, with rapid reductions observed in serum IgM levels in most patients. Serum IgM discordance to underlying bone marrow disease burden is common, and serial bone marrow assessments are important for response monitoring in WM patients receiving Everolimus. Disclosures: Treon: Millennium: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Genentech: Honoraria. Eradat:Millennium: Speakers Bureau; Genentech, A Roche Company: Speakers Bureau. Matous:Seattle Genetics, Inc.: Research Funding; Celgene: Speakers Bureau; Cephalon: Speakers Bureau; Millennium: Speakers Bureau. Anderson:Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Acetylon: Equity Ownership. Ghobrial:Noxxon: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Population Based Observational Study Demonstrates Significant Increase in Watch-and-Wait for Newly Diagnosed Mantle Cell Lymphoma

Blood ◽

10.1182/blood-2018-99-114528 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2877-2877 ◽

Cited By ~ 1

Author(s):

Rory McCulloch ◽

Margie Berrow ◽

Brian Wainman ◽

Nicola Crosbie ◽

Andrew Pettitt ◽

...

Keyword(s):

United Kingdom ◽

Board Of Directors ◽

Systemic Therapy ◽

Research Funding ◽

Disease Burden ◽

Cell Lymphoma ◽

Advisory Committees ◽

The United Kingdom ◽

Mantle Cell

Abstract Background: Mantle cell lymphoma (MCL) is associated with a poor prognosis relative to other indolent B-cell lymphomas where clinicians have traditionally been reluctant to adopt watch-and-wait (W+W) strategies. US registry data from 2004 to 2011 demonstrated 6% of new diagnoses were observed beyond 3 months from diagnosis (Cancer 2016; 122: 2356-63), although other studies have demonstrated higher rates of W+W with no detriment to patient survival. Currently no consensus exists on how to determine suitability for W+W. The MCL Biobank Observational Study was set up to capture clinical behaviour across the United Kingdom and to characterise patients enrolled to W+W compared to those who receive upfront systemic therapy. The study remains open to recruitment. Method: From January 2015 to April 2017 222 patients from 49 centres in the United Kingdom enrolled to the study. All new MCL diagnoses compatible with WHO diagnostic criteria were eligible, with no specific exclusion criteria. Baseline data was recorded at entry including investigator decision to start systemic therapy or enter W+W. Clinical updates were provided at 6 month intervals. In contrast to previous studies W+W was defined as a period lasting at least 1 year from date of diagnosis. Results: All patients were followed-up for a minimum of 1 year. The median age was 70 (range 32-90), 69.4% were male and 47.1% were MIPI high risk. At 1 year follow-up 60 patients (27.0%) were on W+W, 141 (63.5%) received systemic therapy, 16 (7.2%) received isolated radiotherapy and 5 (2.3%) received palliative care. At 2 year follow-up 16 of 85 patients (18.9%) remained on W+W. There were no deaths recorded in patients on W+W. Estimated 2-year survival of the whole population was 80.6%. Univariate analysis comparing baseline characteristics of patients on W+W with those receiving systemic therapy showed no significant difference in age (median age 71.7 vs 69.0; p=0.48), baseline WCC (median 8.0 x 109/L vs 8.9 x 109/L; p=0.09) or performance status (ECOG >1 OR 0.7; p=0.51) meaning the MIPI was not predictive of suitability for W+W (MIPI high risk OR 1.18; p=0.61). Positive predictors for W+W included measures of low disease proliferation: LDH ratio <1.0 (p=<0.001), Beta-2-microglobulin < 3.5 mcg/ml (p=0.011) and Ki67 <30% (p=0.001). In addition, female sex (p=0.010) predicted for indolent behaviour. Measures of high disease burden were generally negative predictors including presence of B symptoms (p=0.001), haemoglobin <100 g/L (p=0.014) and stage IV disease (p=<0.001). The absence of measurable disease on CT was predictive of W+W (p=0.009), although measurable disease was identified in the majority of cases (70.2%) illustrating most patients on W+W were not the leukaemic, non-nodal subtype. Conclusion: This study demonstrates that adoption of W+W in the United Kingdom significantly exceeds use in previous observational studies and highlights a fundamental shift in clinical approach. The results show that conservative management can be reasonably adopted in a significant proportion of patients. Patients with low disease burden appear best candidates and markers of cell turnover may aid clinical judgement. The MIPI does not have a role in this setting. Longer follow-up will establish if W+W confers survival benefit. Disclosures Pettitt: Celgene: Research Funding; AstraZeneca: Research Funding; Roche: Research Funding; Gilead: Research Funding; Napp: Research Funding; GSK/Novartis: Research Funding; Chugai: Research Funding. Rule:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Sickle Cell Disease Burden in North Lebanon

Blood ◽

10.1182/blood-2019-128311 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1022-1022

Author(s):

Adlette Inati ◽

Chadi Al Alam ◽

Cristel El Ojaimi ◽

Taghrid Hamad ◽

Hemanth Kanakamedala ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Disease Burden ◽

Leg Ulcers ◽

Newly Diagnosed ◽

Advisory Committees ◽

Study Population ◽

The Mean ◽

Diagnosis Date

Background: Sickle cell disease (SCD) is one of the most prevalent hemoglobinopathies in Lebanon, where 0.1% of the population are affected by the disease, with the highest prevalence in North Lebanon. SCD burden has not been well characterized in this patient population. Moreover, there is limited understanding of the factors associated with complications of SCD. We hereby report on characteristics, complications, treatments and survival of a SCD cohort treated at a comprehensive SCD referral clinic in North Lebanon. Methods: Data were extracted from the health records and electronic registry of 335 SCD patients treated at the comprehensive SCD clinic of Nini hospital, Tripoli, North Lebanon between 2009 and 2019. The study population consisted of referred and newly diagnosed patients. Patients were considered to be newly diagnosed with SCD if there was a gap of ≤ 60 days between SCD diagnosis date and their first clinic visit date. Patients were regularly seen in the clinic at intervals ranging from every 2 months to 1 year depending on their age and disease severity. Patient characteristics, complications, treatment choices, and mortality were evaluated during follow-up. Follow-up was defined as the time between SCD diagnosis and last visit to the clinic. Complications included vaso-occlusive crisis (VOC), acute splenic sequestration (ASS), stroke, dactylitis, joint necrosis, priapism, leg ulcers, sepsis, iron overload and mortality. VOC events, defined as the composite of pain and/or acute chest syndrome (ACS), were only reported if they resulted in a hospitalization. Since history of VOC events was not well documented among referred patients, VOC events were assessed among patients newly diagnosed at the clinic. Results: The mean age of the study population at SCD diagnosis was 2.9 years (standard deviation [SD]: 4.3), with 73.1% of patients diagnosed within 3 years of age. Mean age at first visit to the clinic was 8.6 years (SD 10.0). 159 (47.5%) patients were female. The most common genotypes were Hemoglobin SS (233 [69.6%]), Hemoglobin Beta-0 Thalassemia (62 [18.5%]), and Hemoglobin Beta + thalassemia (27 [8.1%]). The mean number of follow up years between SCD diagnosis date and latest visit date to the clinic was 13.7 (SD: 10.5). 132 (39.4%) patients were newly diagnosed at the time of their first visit to the clinic. The most frequently encountered SCD clinical events were pain (189 [56.4%]) followed by ACS (135 [40.3%]), ASS (115 [34.3%]) and joint necrosis (55 [16.4%]). The incidence of stroke, pulmonary hypertension, priapism, leg ulcers and sepsis was low (3.3%, 4.2%, 6.0%, 3.0% and 3.9%). Persistent splenomegaly beyond 6 years was seen in 57 (17%) patients, 36 (63.2%) of these patients were of SS genotype. 276 (82.4%) patients required at least one hospitalization during their follow-up. Among newly diagnosed patients, 63% experienced at least one VOC event that led to a hospitalization with a mean of 0.4 (SD: 0.6) hospitalized VOC events per patient per year. 15 (4.5%) patients died during follow-up. The most common cause of death was stroke (3 [20%]). 84 (25.1%) and 76 (22.7%) patients underwent a cholecystectomy and surgical splenectomy respectively, and 30 (9.0%) patients underwent both. 236 (70.5%) patients were treated with Hydroxyurea. The mean age at introduction of Hydroxyurea was 11.5 years (SD: 10.1) and median starting dose was 15.2 mgs/kg/day. 281 (84%) patients received at least one blood transfusion during their follow-up. 37 (11.0%) patients received iron chelation during their follow up. 3 (0.9%) patients underwent bone marrow transplant and were cured of their disease. Conclusion: This first SCD study from North Lebanon demonstrates that SCD burden in North Lebanon is significant. Despite the high disease burden and the low community resources in this region, survival rate of this SCD patient population is relatively high. This can be attributed to the young age at diagnosis, the close comprehensive follow-up and the regular parent/patient education. The low rate of stroke, priapism and leg ulcers in this population warrants further investigation via disease associated markers and genetic determinants. As for priapism, it may be underreported due to social stigma in a conservative country as Lebanon. Noteworthy, Iron overload is under recognized and sub optimally treated. The association between specific risk factors and disease complications will be further addressed. Disclosures Inati: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novonordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Global Blood Therapeutics: Research Funding. Kanakamedala:Novartis: Consultancy; Genesis Research: Employment. Pilipovic:Novartis Pharma AG: Employment, Equity Ownership. Sabah:Novartis: Employment.

Download Full-text

Disease Burden Impacts Outcomes in Pediatric and Young Adult B-Cell Acute Lymphoblastic Leukemia after Commercial Tisagenlecleucel: Results from the Pediatric Real World CAR Consortium (PRWCC)

Blood ◽

10.1182/blood-2020-134472 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 14-15

Author(s):

Liora M. Schultz ◽

Christina Baggott ◽

Snehit Prabhu ◽

Holly Pacenta ◽

Christine L Phillips ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

Board Of Directors ◽

Real World ◽

Research Funding ◽

Disease Burden ◽

Publicly Traded ◽

Advisory Committees ◽

Car T

Introduction: Chimeric Antigen Receptor (CAR) T cell therapy targeting CD19 has shifted our treatment approach for relapsed and refractory (r/r) pediatric B cell acute lymphoblastic leukemia (ALL). The landmark ELIANA pediatric trial studying tisagenlecleucel, CD19-specific CAR T cells, demonstrated a complete response (CR) rate of 81% in 75 infused patients and 12 month overall survival (OS) and event-free survival (EFS) rates of 76% and 50% respectively. Cytokine release syndrome (CRS) and neurotoxicity rates of 77% and 40% were respectively reported. In August 2017, the FDA approved tisagenlecleucel for B-cell ALL that is refractory or in second or greater relapse in patients up to age 25. With CAR commercialization, institutions deliver tisagenlecleucel without the regulation of a clinical study and practices relating to CAR delivery and reporting remain heterogeneous. Here, we report real world clinical outcomes using commercially available tisagenlecleucel for pediatric r/r B-ALL. Methods and Results: Retrospective data were collected from PRWCC member institutions (n=15) and included 200 patients. This includes 15 (7.5%) patients not infused due to manufacturing failure (n=6), death from disease progression and/or toxicity (n=7), or physician discretion following disease remission from prior therapy(n=2). The remaining 185 patients (92.5%) were infused with tisagenlecleucel, including 87% (161) receiving standard-of-care CAR T cell products meeting manufacturing release criteria and 13% (24) receiving CD19-CAR T cells manufactured by Novartis and provided on the managed access program (NCT03601442; n=14) or with single-patient IND approval (n=10). At time of CAR T cell infusion, median age was 12 years (range 0-26) with 40% females and 60% males. Median duration of follow-up at time of analysis was 11.2 months (range 0.2-28.8). The CR rate at 1 month follow up was 79% (156/198) on an intent-to-treat basis and 85% (156/184) among evaluable infused patients. Of infused patients achieving morphologic CR with available testing, 97% (148/153) were negative for MRD by flow cytometry. Duration of remission at 6 and 12 months among patients who achieved CR was 75% and 63% respectively, with 35% (55/156) of responders experiencing relapse. At time of relapse, 41% (21/51) of evaluable patients had relapse with CD19- disease and 59% (30/51) had continued CD19 expression. OS and EFS rates were 85% and 64% at 6 months and 72% and 51% at 12 months, respectively. CRS and neurotoxicity of any grade were seen in 60% (111/184) and 22% (39/181) of evaluable patients with ≥ grade 3 CRS and neurotoxicity rates of 19% (35/184) and 7% (12/181) respectively. One grade 5 CRS and 1 grade 5 neurotoxicity (intracranial hemorrhage) were reported. Post infusion toxicity management included tocilizumab in 26% (47/184) and systemic steroids in 14% (25/184) of patients. Among 181 infused patients with documented disease burden, 51% (95) had high burden (HB) disease , as defined by >5% bone marrow lymphoblasts, peripheral blood lymphoblasts, CNS3 status or non-CNS extramedullary (EM) site of disease; 22% (40) had low burden (LB) disease, defined by detectable disease not meeting the HB criteria; and 25% (46) had no detectable disease (NDD) at time of last evaluation prior to CAR infusion. The morphologic CR rate was lower at day 28 in HB vs. LB and NDD (74% vs. 98% and 96%) and the OS and EFS were lower among patients with HB at 6 mo [OS; 75% (HB), 94%(LB), 98% (NDD), EFS; 50% (HB), 86% (LB), 75%(NDD), p<0.0001] and 12 mo [OS; 58% (HB), 85% (LB), 95% (NDD), EFS; 34% (HB), 69%(LB), 72%(NDD), p<0.0001]. Multivariate analysis will be presented at the meeting. Conclusions: This retrospective, multi-institutional analysis describes real world outcomes using tisagenlecleucel to treat pediatric r/r B-ALL. Early responses at 1 month and OS and EFS at 6 and 12 months are comparable to reported ELIANA trial outcomes. Safety is demonstrated in this cohort with lower rates or CRS and neurotoxicity, likely related to a lower disease burden cohort. Continued relapse and decrease in OS without evident plateau is seen following 6 months post-infusion warranting expanded follow up. Comparative analysis of outcomes in patient cohorts with varying disease burden demonstrate decreased CR, EFS and OS in patients with high disease burden as compared to patients with lower disease burden or no detectable disease at last evaluation prior to CAR infusion. Disclosures Phillips: Novartis: Membership on an entity's Board of Directors or advisory committees. Stefanski:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Margossian:Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Verneris:Fate Therapeutics: Consultancy, Current equity holder in publicly-traded company; Novartis: Membership on an entity's Board of Directors or advisory committees; Bmogen: Consultancy, Current equity holder in publicly-traded company; Uptodate: Consultancy. Myers:Novartis: Consultancy, Honoraria, Other: ELIANA trial Steering Committee, Speakers Bureau. Brown:Jazz: Honoraria; Servier: Honoraria; Janssen: Consultancy; Novartis: Consultancy. Qayed:Novartis: Consultancy; Mesoblast: Consultancy. Hermiston:Novartis: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees. Satwani:Takeda: Consultancy; Mesoblast: Consultancy. Curran:Novartis: Consultancy, Research Funding; Mesoblast: Consultancy; Celgene: Research Funding. Mackall:Lyell Immunopharma: Consultancy, Current equity holder in private company; Nektar Therapeutics: Consultancy; NeoImmune Tech: Consultancy; Apricity Health: Consultancy, Current equity holder in private company; BMS: Consultancy; Allogene: Current equity holder in publicly-traded company. Laetsch:Cellectis: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Research Funding; Bayer: Consultancy, Research Funding.

Download Full-text

The Clinical Relevance of Residual, Persistent and Elongated Abnormal Sized Nodes By Longest Diameter (LDi) in Patients (pts) with Chronic Lymphocytic Leukemia (CLL), Otherwise in a Complete Remission (CR)

Blood ◽

10.1182/blood-2020-136731 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 34-35

Author(s):

Jayant Narang ◽

Surabhi Bajpai ◽

Rudresh Rajnikant Jarecha ◽

Christiana Caplan ◽

Dana Macdonald ◽

...

Keyword(s):

Bone Marrow ◽

Lymph Nodes ◽

Board Of Directors ◽

Research Funding ◽

Disease Burden ◽

Residual Disease ◽

Short Axis ◽

Advisory Committees ◽

Clinical Imaging

Background: IWCLL 2008 and 2018 criteria require that all lymph nodes/nodal masses be ≤ 15mm in longest diameter (LDi) to be consistent with a CR. Lymph nodes or nodal masses >15mm in the LDi are considered abnormal. However, it has been observed that some bulky nodes may become thin and streak-like on follow-up timepoints (Figure 1) and may be normal by clinical and imaging standards (<10mm in short axis diameter) (Cheson et al Journal of Clinical Oncology, 17:1244, 1999) however, they continue to be >15mm in LDi (LDi Positive nodes- LDi+) and, hence, categorized as abnormal per iwCLL criteria. In lymphoma studies, FDG-PET negativity is the driver of CR, and residual disease on CT scan is allowed for CR. However, in the iwCLL response assessment, LDi+ nodes may prevent a true CR. Methods: 1168 patients across multiple phase III CLL clinical trials with targeted agents were analyzed, which were independently reviewed using iwCLL 2008 and 2018 criteria. To assess the impact of LDi+ nodes, we filtered our response to finding pts who had at least one lymph node with LDi >15mm (range 15.1 to 30mm) and, thus, a PR by imaging, but all other identified nodes either resolved or <10mm in short axis and the rest of the disease burden normalized. We also evaluated clinical information on all pts (e.g., bone marrow biopsy, complete blood count (CBC), Absolute Lymphocyte Count (ALC), and other confounding factors, when available). Figure 1: A large right axillary node at baseline (image on left), is reduced in size and is thin, streak like (image on right) but is abnormal as per iwCLL criteria by LDi definition. Results: Of 1168 pts, 161 (13.8%) had an overall response of PR because of these abnormal LDi+ nodes on imaging per iwCLL criteria, even though the rest of the disease burden had normalized and showed CR. Laboratory data (CBC and ALC) were available in all of these 161 patients and were normalized/CR. Bone marrow was available for 31 patients and was negative/CR in all of those patients in at least one follow-up assessment by both cellularity and CLL infiltration assessments (by either morphology, flow cytometry or immuno-histochemistry (IHC)). These pts continued to have a sustained response of CR for all other parameters for multiple follow up visits with a median follow up of about 6 months. Conclusion: Based on these data, approximately 13.8 % of pts with LDi+ nodes normal by clinical/imaging standards, clinical/laboratory parameters normalized and some with a normal bone marrow evaluation, but were labeled PR in overall assessment and denied a CR. These pts likely had achieved a CR as bone marrow is considered a gold standard for normalization of disease burden. These LDi+ lymph nodes by iwCLL criteria which are normal by clinical/imaging standards, likely represent scar tissue and not active disease based on normalization of the rest of the disease. These assessments made by stringent application of iwCLL criteria in assessing lymph nodes may result in underestimating the CR rate in a clinical trial. We propose an adaptation of the iwCLL criteria to allow hematologists/oncologists to update/override the radiology overall assessment from PR to CR if all other components for the oncology review (e.g., blood counts, bone marrow, target lesions, organ assessments) meet CR criteria, based on clinical judgment. This approach is being used universally in daily clinical practice (as well as by the site investigators) when assessing CLL patients and these abnormal LDi+ nodes by iwCLL criteria, do not prevent a CR. This proposed approach may help to reduce site-central discordance in a clinical trial setting. Further studies to correlate these findings with minimal residual disease in bone marrow/blood will help validate our findings. Figure 1 Disclosures Cheson: Trillium: Research Funding; Abbvie: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Jannsen: Consultancy; TG Therapeutics: Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees; Parexel: Consultancy; Kite: Consultancy; Symbio: Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Prognostic Factors for Developing Thrombosis in Polycytemia Vera: A Retrospective Analysis of 331 Patients with Long-Term Follow-up Highlights the Importance of White Blood Cells Levels

Blood ◽

10.1182/blood-2020-139431 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 48-49

Author(s):

Samantha Ferrari ◽

Chiara Pagani ◽

Mariella D'Adda ◽

Nicola Bianchetti ◽

Annamaria Pelizzari ◽

...

Keyword(s):

Risk Factors ◽

Multivariate Analysis ◽

High Risk ◽

Board Of Directors ◽

Advisory Board ◽

Advisory Committees ◽

Risk Status ◽

History Of ◽

Wbc Count

Polycythemia Vera (PV) is a chronic myeloproliferative neoplasm characterized by erythrocytosis, constitutively active mutations in JAK2 and an increased susceptibility to thrombotic events (TEs). There is still controversy about the role of increased hematocrit and of other variables including elevated white blood cell count as risk factors for the occurrence of TEs. A better definition of the relative prognostic importance of hematologic parameters would help us to better tailor the therapeutic approach to PV patients (pts), which is currently mainly based on the use of acetilsalycilic acid (ASA), venesection and hydroxyurea . The aim of our study was to analyze if any clinical or laboratory variables were significantly associated to the occurrence of TEs both at PV diagnosis and during the course of the disease in a large series of PV pts uniformly followed at a single Center over a period of 29.5 years from January 1986 to June 2019. Clinical and laboratory data were obtained from the time of diagnosis until death, progression to acute leukemia or last follow-up. Hematocrit (Hct), hemoglobin (Hb), white blood cell (WBC) and platelet (PLT) levels were recorded for each patient at least every 6 months. Among a total of 331 pts, the median age was 65 years (range 30-92 years), and 56% were male. "High risk" features (age ≥ 60 years and/or history of prior thrombosis) were present in 221 pts (66.7%). The incidence of cardiovascular risk factors was: hypertension 64%, diabetes 15%, hyperlipidemia 28%, history of active or remote smoking 41%. Patients on ASA were 279 (84%), 19 (6%) were on oral anticoagulation, while 27 (8%) were on ASA+oral anticoagulant. At PV diagnosis 54 pts (16%) presented with thrombosis, arterial in 32 (59%) and venous in 22 (41%). A previous TE was recorded in 57 pts (17%): in 43 (75%) arterial, in 12 (22%) venous and in 2 (3%) mixed (arterial+venous). Previous thrombosis was the only variable significantly associated with the presence of a TE at PV diagnosis (P=0.02). After PV diagnosis, with a median follow-up of 81 months (range 1-374 months), 63 pts (19%) experienced a TE and 11 of them a further episode, for a total of 74 TEs. The incidence rate (pts/year) of TEs was 2.7%. Forty-two events were arterial (57%), 31 were venous (42%) and 1 (1%) was mixed. It was the first TE for 37 pts. Cerebrovascular accidents and deep-venous thrombosis were the most frequent arterial and venous TEs both at PV diagnosis and throughout the disease course, with a relative incidence of 50% and 32% respectively. The table compares the characteristics of patients who did or did not develop a TE after PV diagnosis. At univariate analysis, PV high risk status, a previous TE and hyperlipidemia at PV diagnosis were significantly associated with a subsequent TE. Among hematologic variables an elevated WBC count at the time of thrombosis, but not Hct or PLT levels, was highly significantly associated with the development of a TE. At multivariate analysis, WBC count ≥10.4 x 10^9/L and hyperlipidemia maintained their independent prognostic value, while high risk status and a previous TE lost their prognostic significance. Both at univariate and multivariate analysis, hyperlipidemia at diagnosis (P=0.009 and P=0.002) and high WBC count at thrombosis (P=0.001 and P=<0.0001) predicted for arterial thromboses, while only a history of prior thrombosis (P=0.03) predicted for venous ones. In conclusion, our analysis confirms that elevated WBC count at the moment of the event more than increased hematocrit is associated to the development of thrombosis in PV pts. We also found that hyperlipidemia was an independent risk factor for arterial thrombosis, calling for an accurate management of increased lipid levels. Whether a reduction of the WBC count during the course of PV may reduce the frequency of TE remains to be demonstrated by prospective studies. Table Disclosures D'Adda: Novartis: Other: Advisory board; Incyte: Other: Advisory board; Pfizer: Other: Advisory board. Rossi:Daiichi Sankyo: Consultancy, Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Advisory board; Alexion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Evolving Unmet Need in Patients Refractory to Lenalidomide: Overview of the Clinical Trials in Relapsed/Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2020-142642 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 22-23

Author(s):

Maria-Victoria Mateos ◽

Rohan Medhekar ◽

Istvan Majer ◽

Mehmet Turgut

Keyword(s):

Multiple Myeloma ◽

Clinical Trials ◽

Literature Review ◽

Board Of Directors ◽

Unmet Need ◽

Publicly Traded ◽

First Line ◽

Advisory Committees ◽

Line Of Therapy

Introduction: The majority of newly diagnosed multiple myeloma (NDMM) patients are currently treated with lenalidomide-based regimens as their first line of therapy. This trend is likely to continue in the coming years. Typically, lenalidomide is administered until disease progression and has significantly contributed to better outcomes in these patients. However, most patients relapse, and prognosis worsens with each relapse. The choice of optimal treatment for patients who relapse while receiving lenalidomide as first line of therapy is unclear. Moreau et al (Blood Cancer J. 9, 38 [2019]) concluded that there is limited data on approved combinations for treating these patients and are restricted by the low number of lenalidomide-refractory patients enrolled in the pivotal trials. Results from the ongoing clinical trials of the combination of carfilzomib and anti-CD38 antibodies were not available at the time of the Moreau et al publication. The aim of this targeted literature review was to include this new data and to summarize currently available evidence on progression-free survival (PFS) for the treatment of RRMM patients who progressed on lenalidomide-based regimens. Methods: A targeted literature review was conducted to identify registrational clinical trials in patients with RRMM reporting PFS outcomes. PubMed, congress proceedings, and product labels were searched between Jan 2014 to July 2020. In addition to PFS, demographic, disease characteristics and treatment history were extracted for the trial populations to contextualize potential variations in study outcomes. The regimens studied in these trials were classified as lenalidomide-based, proteasome inhibitor (PI)-based and pomalidomide-based. Number of prior lines of therapy, prior exposure and refractoriness to lenalidomide and bortezomib were reported. Results: Twelve registrational trials were identified based on the search criteria (Table 1). Most pivotal trials assessing lenalidomide-based regimens (POLLUX, ELOQUENT-II, TOURMALINE-MM1) except the ASPIRE trial excluded patients who were refractory to lenalidomide. Trials evaluating PI-based regimens (e.g., CANDOR) or pomalidomide-based regimens (e.g., OPTIMISMM) included these patients, with more recent studies enrolling a larger proportion. Percentage of lenalidomide-exposed (and lenalidomide refractory) ranged from 40% (32%) in CANDOR to 98% (90%) in ELOQUENT III. These studies also enrolled a larger proportion of patients who were bortezomib-exposed, although most of these patients were at first relapse, with the exception of ELOQUENT III and ICARIA where most patients were at third relapse. Among lenalidomide-refractory patients, the median-PFS (mPFS) observed for the pomalidomide-based regimens ranged from 9.5 to 10.1 months and that observed for PI-based regimens ranged from 4.9 to 25.7 months. PFS in the lenalidomide-refractory subgroup was considerably shorter than in the ITT population. The mPFS for patients receiving carfilzomib/daratumumab/dexamethasone (KDd; CANDOR) and isatuximab/carfilzomib/dexamethasone (IsaKd; IKEMA) was not reached at median follow-up of 16.9 and 20.7 months respectively. While the mPFS for (KDd) for lenalidomide-refractory patients in CANDOR trial was not yet reached at median follow up of 16.9 months; the mPFS of 25.7 months for KDd in the MMY-1001 trial appears to be the longest among the assessed regimens. Conclusion: Patients refractory to lenalidomide have shorter PFS and represent a population with high unmet need. This targeted literature review suggests that the PI-based KDd regimen provides longer PFS compared to other lenalidomide-sparing regimens in lenalidomide-refractory populations. Heterogeneity across trial populations may limit the comparability of these treatments. Disclosures Mateos: Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; PharmaMar-Zeltia: Consultancy; GlaxoSmithKline: Consultancy. Medhekar:Amgen Inc.: Current Employment, Current equity holder in publicly-traded company. Majer:Amgen (Europe) GmbH: Current Employment, Current equity holder in publicly-traded company.

Download Full-text

Comparable Outcomes between Unrelated Donor (8/8 or 7/8 matched) and Haploidentical Donor for Allogeneic Stem Cell Transplantation in Adult Patients with Severe Aplastic Anemia

Blood ◽

10.1182/blood-2019-130419 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4619-4619

Author(s):

Jee Yon Shin ◽

Sung-Soo Park ◽

Gi June Min ◽

Silvia Park ◽

Sung-Eun Lee ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Advisory Committees ◽

Sibling Donor ◽

Alternative Donor ◽

Matched Sibling ◽

Grade Ii

Background Either allogeneic hematopoietic stem cell transplantation (SCT) from HLA-matched sibling donor or immunosuppressive therapy (IST) has been recommended as one of the standard treatments for severe aplastic anemia (SAA). Regarding only 30% of chance finding HLA‐matched sibling donor, SCT from an alternative donor including unrelated (URD) or haplo-identical related donor (HAPLO) is considered to be a treatment option after failure to IST in patients who lack of a HLA-matched sibling donor. The aim of this study was to compare the outcomes of URD SCT and HAPLO SCT for SAA patients. Method Consecutive 152 adult patients with SAA who received first SCT between March 2002 and May 2018 were included: 73 of HLA-well-matched (8/8) URD (WM-URD), 34 of HLA-mismatched URD (MM-URD), and 45 of HAPLO. With the intention to have a follow-up period at least 1 year, data were analyzed at May 2019. A conditioning regimen with total body irradiation (TBI) and cyclophosphamide was used for URD-SCT, whereas that with TBI and fludarabine was administered for HAPLO-SCT (Lee et al, BBMT 2011;17:101, Park et al, BBMT 2017;23:1498, Lee et al, Am J Hematol 2018;93:1368). The combination of tacrolimus and methotrexate were used as graft-versus-host disease (GVHD) prophylaxis. Results The median follow-up was 53.4 (range, 0.2-174.1) months. The median age of URD and HAPLO cohort was 30 (range 18-59) and 34 (range 18-59) years, respectively. Except for one and three patients who failed respective a neutrophil and platelet engraftment, other patients achieved neutrophil and platelet engraftments with median 11 and 15 days for WM-URD, 13 and 16.5 days for MM-URD, and 12 and 14 days for HAPLO, respectively. The five-years overall survival (OS), failure-free survival (FFS), and cumulative incidences (CIs) of graft-failure and transplant-related mortality were similar among three groups: 88.3%, 85.5%, 2.7%, and 11.7% for WM-URD; 81.7%, 81.7%, 0%, and 18.3% for MM-URD, and 86.3%, 84.1%, 6.7%, and 9.2% for HAPLO. The 180-days CI of grade II-IV acute GVHD in WM-URD, MM-URD and HAPLO were 35.6%, 52.9%, and 28.9%, respectively; and moderate to severe chronic GVHD were 28.7%, 38.7% and 11.8% in respective cohort. The CI of grade II-IV acute GVHD and moderate to severe chronic GVHD were significantly higher in MM-URD than those in HAPLO (both, p=0.026). ATG is the only factor affecting both grade II-IV acute GVHD (Hazard ratio 0.511, p=0.01) and moderate to severe chronic GVHD (Hazard ratio 0.378, p=0.003) in multivariate analysis. Other complications including CMV DNAemia, hemorrhagic cystitis, invasive fungal disease, secondary malignancy, and sinusoidal obstruction syndrome were similar among three groups. Survival outcomes of a subgroup of ≥ 2 allele MM-URD (n=16) extracted form MM-URD were inferior that of other donor types (n=136): 75.0% vs. 86.9% (p=0.163) for 5-year OS and 75.0% vs. 84.7% (p=0.272) for 5-year FFS. Conclusion This study shows that there were no significant differences between alternative donor sources in the absence of suitable matched sibling donor. Host/donor features and urgency of transplant should drive physician towards the best choice among alternative donor sources for SAA patients treated with SCT. However, selection of ≥ 2 allele MM-URD should not be recommended due to high incidence of GVHD and inferior outcomes. Figure Disclosures Kim: Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Amgen: Honoraria; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; BL & H: Research Funding; Otsuka: Honoraria. Lee:Alexion: Consultancy, Honoraria, Research Funding; Achillion: Research Funding.

Download Full-text

Clinical and Biological Characteristics and Outcomes of Richter Transformation : A French Multicenter Study from the Filo Group

Blood ◽

10.1182/blood-2019-128053 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4112-4112

Author(s):

Charline Moulin ◽

Romain Morizot ◽

Thomas Remen ◽

Hélène Augé ◽

Florian Bouclet ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Intermediate Risk ◽

Line Treatment ◽

First Line ◽

Advisory Committees ◽

Long Term Survivors ◽

First Line Treatment

Introduction: About 2 to 10% of patients (pts) diagnosed with Chronic Lymphocytic Leukemia (CLL) develop diffuse large B-cell lymphoma (DLBCL, so-called Richter transformation (RT)) over long-term follow-up. The outcomes of pts with RT are variable and poorly understood and there is no consensus on the best therapeutic approach. The aim of this study was to analyze the clinical characteristics, outcomes and factors predictive of survival in a large series of RT from the French Innovative Leukemia Organization (FILO). Methods: Biopsy-confirmed RT (limited to DLBCL and excluding Hodgkin lymphoma) diagnosed from 2001 to 2018 were identified from eight FILO centers. Clinical and biological characteristics of CLL and RT at diagnosis, including cytogenetics, clonal relation with the pre-existing CLL, Epstein-Barr virus (EBV) status, cell of origin (COO) analyzed by immunohistochemistry and RT score (Tsimberidou AM et al, J Clin Oncol, 2006) were analyzed as well as treatment and outcomes. Overall survivals (OS) were defined as time from CLL and RT diagnosis to death from any cause and analyzed using the Kaplan-Meier method. Statistical analyses were performed with SAS version 9.4. Results: A total of 70 CLL pts who developed RT were identified. The median age at CLL diagnosis was 62 years old (range 35-82), and 50 (71.4 %) were male. The median time to transformation was 5.5 years (range 0 to 22 years), with 12 simultaneous diagnosis of CLL and RT. Prior to RT, 20 (29%) pts had not been treated for CLL, 50 received one (n=21) or more (n= 29) line of treatment ; 6 pts had received a novel agent (ibrutinib, idelalisib or venetoclax). The median age at RT diagnosis was 68 years old (range 42-88). All biopsies were centrally reviewed; 38/58 pts (66%) had elevated LDH (>1.5N) ; 35/65 pts (54 %) had bulky disease (≥ 5 cm); 10/54 (18.5%) pts had del(17p) or TP53 mutation ; 9/42 pts (21%) had a complex karyotype (at least 3 abnormalities). The CLL and RT were clonally related in 27/27 (100%) tested pts. COO by Hans algorithm was non germinal center B cell-like (GCB) in 26/28 pts (93%). EBV was positive or detected in 5/40 (12.5%) pts. The median of Ki67 positivity was 70% (range 30% to 100%). The RT score (based at RT diagnosis on ECOG performance status 2-4, LDH >1.5 x normal, platelets<100 x 109/L, tumor size >5 cm and >1 prior therapy for CLL) was : low risk in 17 pts (31%), low-intermediate risk in 10 pts (19%), high-intermediate risk in 14 pts (25%) and high risk in 14 pts (25%). The most common first-line treatment of RT was immunochemotherapy (n=57, 87%) including R-CHOP-like regimen (n=48, 73%). Autologous or allogeneic transplantation was performed for 7 pts (11%). Response to first-line treatment was complete or partial response in 26 pts (40%), and stable disease or progression in 39 pts (60%). After a median follow-up of 8 years, 51/64 pts (80%) have died. The main causes of death were progressive DLBCL (n=36, 71%), infection (n=8, 16%) or progressive CLL (n=2, 4%). The median OS of the cohort from CLL and RT diagnosis (Figure 1) were 7.8 years and 9.5 months, respectively. In univariate analysis, patients with TP53 disruption at CLL stage, low platelets count, elevated LDH, elevated beta2-microglobulin, high ECOG score, high RT score, EBV positivity and absence of response to first-line RT treatment had worse OS. The ECOG score, platelets count and TP53 disruption remain significant in multivariate Cox-regression. Last, we compared the clinical and biological parameters of two Richter groups defined as: (i) short-term survivors (<12 months, n = 34) and (ii) long-term survivors (>48 months, n = 18). Long survival was significantly associated with elevated platelets count, low LDH, low ECOG, low RT score and response to RT first-line treatment. Discussion: The clinical outcomes of RT patients is poor and novel treatment options are needed. However, a group of long-term survivors was identified, characterized by elevated platelets count, low LDH, low ECOG, low RT score and response to immunochemotherapy. Disclosures Leblond: Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Cymbalista:Janssen: Honoraria; Gilead: Honoraria; AstraZeneca: Honoraria; Sunesis: Research Funding; Roche: Research Funding; Abbvie: Honoraria. Guièze:Abbvie: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Roche: Honoraria. Broseus:Janssen: Honoraria; Gilead: Honoraria; Novartis: Research Funding. Feugier:gilead: Honoraria, Research Funding, Speakers Bureau; janssen: Honoraria, Research Funding, Speakers Bureau; abbvie: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau.

Download Full-text