The Incidence of Mastocytosis in Patients with Unclear Cytopenia and/or Leucocytosis: The Hryd Study

Systemic mastocytosis (SM) is reported to be a rare myeloid disease. The true incidence is unknown as the diagnosis is often missed due to the diversity of symptoms and signs. In the HRYD study, we hypothesized that the reported incidence of around 1/100000/year is too low and the assumed underdiagnosis could be reduced if serum tryptase, although only a minor criterion for the diagnosis of SM, would be measured in patients (pts) with cytopenia and/or leukocytosis. Methods: HRYD was a prospective single-center trial. The protocol was approved by the local ethics committee. The primary endpoint was the incidence of SM in a consecutive cohort of 100 unselected pts with unclear cytopenia and/or leukocytosis at the University Hospital Halle. Pts with suspected or known SM or cutaneous mastocytosis were excluded. Serum tryptase levels were measured at initial presentation (normal < 11 ng/ml). The diagnosis and classification of SM were based on the 2016 WHO classification where a baseline tryptase level > 20 ng/mL is considered as a minor criterion for SM. Routine diagnostic work-up included medical history, physical examination, blood analyses (blood picture, differential count, liver and renal function, albumin, and further tests as needed), and if indicated a bone marrow biopsy and aspiration for cytology, immunophenotyping, karyotyping, and molecular diagnostics as appropriate. Mutational profiling from a peripheral blood sample with next-generation sequencing (NGS) was done if required. All pts gave informed consent. Results: 100 pts (51% males) > 18 years (y) were recruited between February, 2019 and June, 2020. Median age was 64.5 (range 18-88) y. Based on the final diagnosis, pts were allocated to five subgroups (group A: SM, group B: non-SM malignant hematological diseases, group C: benign hematological diseases, group D: non-hematological diseases, group E: unclear diagnosis at data-cut-off) (table 1). For the entire cohort, fatigue (n=46), weight loss (n=25), and dyspnea (n=15) were the most frequent symptoms at presentation. A non-SM malignant disease (group B) was most frequently diagnosed (n=49) followed by a non-hematological cause (n=24) (figure1). With a median age of 70 (31-88) y, pts in group B tended to be older compared to those in groups C and D. Serum tryptase > 20 ng/ml was detected in 9 pts (median level 53.4, range 21.6-200) ng/ml. SM was diagnosed in 4 (4%) pts (group A). The remaining 5 pts belonged to group B, n=4 and group D, n=1. A history of allergies, skin lesions, hepatomegaly, and/or splenomegaly were not predictive for the diagnosis of SM. The median tryptase level in SM pts was 163 (range 32.1-200) ng/ml. All pts in group A suffered from SM with associated hematologic neoplasm (SM-AHN). The AHN were MDS, n=1; MPN, n=1; AML, n=2. A KIT point mutation at codon 816 was detected in one of the SM-AHN pts. Overall, a diagnosis of SM could be excluded with a probability of 85.4% and a specificity of 95% if the tryptase level was < 20 ng/ml. On the other hand and although sensitivity was 100%, the positive predictive value of a serum tryptase > 20 ng/ml for SM was only 44.4%. WBC, Hb, and platelets did not correlate with tryptase levels or the final diagnosis in all groups. In group B, three pts with BCR-ABL positive CML were diagnosed. In contrast to SM-AHN pts, marked leukocytosis with a WBC >100x109/L was present in the CML pts. NGS was performed in 27 pts. A median of 3 (range 0-8) somatic mutations were detected. From a diagnostic point of view, the added value of NGS was met in 8/27 (30%) pts. Conclusions: In an unselected cohort of pts with undiagnosed cytopenia and/or leucocytosis, the incidence of SM-AHN was higher than that for BCR-ABL positive CML. Our data question the low reported epidemiological data to SM. Because of the prognostic and therapeutic consequences of a correct diagnosis and despite the low positive predictive value of an elevated tryptase for the diagnosis of SM, including the cheap serum tryptase test in the work-up of pts with unclear clinical scenarios and abnormal hematological parameters is a simple tool to increase awareness of physicians to SM as a differential diagnosis. SM is highly unlikely if the tryptase level is below 20 ng/ml. Disclosures Niederwieser: Amgen: Speakers Bureau; Daiichi: Research Funding; Cellectis: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau. Al-Ali:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

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A COMPARISON BETWEEN SYNTHETIC AND BIOSYNTHETIC MESHES IN THE SURGICAL TREATMENT OF SEVERE GENITAL PROLAPSE: RESULTS AND COMPLICATIONS

Urogynaecologia ◽

10.4081/uij.2009.3.21 ◽

2010 ◽

Vol 23 (3) ◽

pp. 21

Author(s):

S. Dati ◽

V. De Lellis ◽

P. Palermo ◽

G. Carta

Keyword(s):

Genital Prolapse ◽

Pelvic Organ ◽

Wilcoxon Test ◽

Type I ◽

Replacement Surgery ◽

Group A ◽

Group B ◽

Work Up

The effectiveness, tolerability and complications of two surgical procedures using prosthetic materials with different physical and structural properties were assessed with a full Urogynecology work-up, through a retrospective study of 158 patients with severe genital prolapse (POP-Q staging III-IV) selected from November 2006 to April 2009. Eighty-six patients underwent fascial replacement surgery with ProliftTM System with a dual transobturator access in the anterior district and a transperineal posterior access with a synthetic polypropylene type I mesh (Group A). Seventy-two patients who underwent pelvic organ prolapse surgery with Avaulta/Avaulta PlusTM System with a dual transobturator access in the anterior district and a dual transperineal posterior access with a biosynthetic polypropylene type I mesh coated with a film of hydrophilic porcine collagen were placed in Group B. There were no intra and postoperative complications. Results of mean 20.8 month follow-up showed an effective anatomical cure rate of 89.5% in group A and 86.1% in group B and a low percentage of erosive complications, 8.1% and 5.6% respectively. Validated questionnaires for prolapse, the UDI 6 s.f., the IIQ7 s.f. and the PISQ-12 all showed a statistically significant improvement of quality of life in patients undergoing the two procedures (Wilcoxon test: P<0.001).

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Metabolic Tumor Volume for Early Response Assessment in Early-Stage Unfavorable Hodgkin Lymphoma Treated with Nivolumab in the GHSG Nivahl Phase II Trial

Blood ◽

10.1182/blood-2019-123641 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4020-4020

Author(s):

Conrad-Amadeus Voltin ◽

Jasmin Mettler ◽

Horst Mueller ◽

Michael Fuchs ◽

Christian Baues ◽

...

Keyword(s):

Survival Data ◽

Research Funding ◽

Early Stage ◽

Response Assessment ◽

Early Response ◽

Percentage Change ◽

Response To Treatment ◽

Deauville Score ◽

Group A ◽

Group B

Background: Metabolic tumor volume (MTV) measured by FDG-PET/CT is becoming established as an independent risk factor for treatment failure in Hodgkin lymphoma (HL). Moreover, response to treatment with novel agents including checkpoint inhibitors may be better reflected by a decrease in MTV than by currently used response criteria. Our aim was to evaluate the early response to first-line HL treatment with the PD-1 inhibitor nivolumab using MTV. Methods: The analysis set included 59 patients with newly diagnosed, early-stage unfavorable HL treated within the prospective, multicenter, open label, randomized, phase II NIVAHL trial of the German Hodgkin Study Group (GHSG). Patients in NIVAHL were randomized to receive either four double cycles of nivolumab, doxorubicin, vinblastine, and dacarbazine (4x Nivo-AVD, group A, n=31) or a sequential therapy starting with 4x nivolumab monotherapy followed by 2xNivo-AVD and 2x AVD (group B, n=28). Early response to treatment was assessed at a 1st interim restaging after either 2x Nivo-AVD or 4x nivolumab. All NIVAHL patients who underwent PET at both initial staging and early response assessment, with images available to the central review panel for quantitative analysis before April 30th 2019, were included. MTV was calculated using a fixed SUV threshold of 4 for both staging and restaging. Results: Patient characteristics of the MTV analysis subset presented here did not differ in any relevant way from the overall NIVAHL trial population. Median age of the 59 patients was 27 years (range 18-57) with a female predominance (61%). All patients presented with stage II disease (IIB 27%) and ≥3 involved areas was the most common risk factor (75%) followed by elevated erythrocyte sedimentation rate (51%), extranodal disease (17%) and large mediastinal mass (14%). Mean MTV at initial staging was 124 ml (range 4 - 578 ml) and 177 ml (11 - 581 ml) in groups A and B, respectively. In both groups a marked decrease in MTV was observed at the 1st interim restaging (Figure 1): After 2x Nivo-AVD all patients in group A showed a reduction of MTV >80% (mean percentage change in MTV -99.8%). In group B a reduction of MTV >80% was observed in 26/28 patients (93%), while in 2/28 patients an increase <10% was observed (mean percentage change in MTV -91%; Figure 1). The mean residual MTV at interim restaging after 2x Nivo-AVD was 0.4 ml (range 0 - 8) in group A and 11 ml after 4x nivolumab in group B (range 0 - 176). The reduction of MTV was observed irrespective of initial MTV with a similar mean percentage change in patients above and below the median MTV in both groups. When applying the Deauville score, however, the number of patients presenting with a Deauville score ≥4 was higher in the group with an initial MTV above the median MTV than in the group where initial MTV lay below the median value. Using the Lugano criteria and a Deauville score of 4 or higher as cut-off for PET-positivity, early interim complete remission was observed in 81% of patients after 2xNivo-AVD, as compared to 51% after 4x nivolumab monotherapy. Further analyses regarding MTV and response at the 2nd and end-of-treatment restaging as well as survival data are not yet available due to limited follow-up. These data will be available at the time of presentation and shown at the meeting. Conclusions: Marked reductions of MTV demonstrate an excellent early efficacy for both 2x Nivo-AVD and 4x nivolumab as 1st-line therapy for early-stage unfavorable HL. The unexpectedly and previously unreported high MTV reduction with nivolumab monotherapy indicates a relevant potential of anti-PD1 mono- or debulking-therapy in the 1st-line treatment of early-stage unfavorable HL. Early interim response assessment based on MTV may help to identify HL patients treated with anti-PD1 antibodies in whom a significant reduction or even omission of chemotherapy could be considered. MTV appears to have the potential to accurately measure response to immune checkpoint inhibition. However, correlation of early MTV reduction with response at the end of treatment or with survival data is pending. Disclosures Borchmann: Novartis: Honoraria, Research Funding. Bröckelmann:Bristol-Myers Squibb: Honoraria, Other: Travel Support, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel Support, Research Funding; MSD Sharpe & Dohme: Research Funding.

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A Randomized Clinical Trial Comparing Cytokine Administration Sites for Mobilization of Peripheral Hematopoietic Progenitor Cells for Patients with Hematological Malignancies Undergoing Autologous Stem Cell Transplantation.

Blood ◽

10.1182/blood.v114.22.4230.4230 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4230-4230

Author(s):

Heather Renfroe ◽

Edmund K. Waller ◽

Mike Arnold ◽

Louette Vaughn ◽

R. Donald Harvey ◽

...

Keyword(s):

Stem Cell ◽

Injection Site ◽

Research Funding ◽

Randomized Study ◽

Peripheral Blood Stem Cells ◽

Cd34 Cells ◽

Blood Stem Cells ◽

Group A ◽

Cell Mobilization ◽

Group B

Abstract Abstract 4230 Background The optimal injection site for cytokine administration when used to mobilize peripheral blood stem cells for collection is unclear. There are known differences in the pharmacokinetics of subcutaneously injected drugs based upon site adiposity. We hypothesized that injection in lower adipose-tissue-containing sites in the extremities would result in a reduced reservoir effect leading to lower exposures of granulocyte colony stimulating factor (G-CSF) and therefore reduced stem cell collection following cytokine mobilization. Methods We completed a prospective single institution IRB-approved randomized study to determine the efficiency and tolerability of different injection sites among patients with multiple myeloma or lymphoma undergoing stem cell mobilization and apheresis. The primary end-points were the total number of CD34+ cells collected and the number of days of apheresis required to collect target numbers (5 × 10E6 CD34+ cells/kg for patients with lymphoma; 10 × 10E6 CD34+ cells/kg for patients with myeloma). Forty patients were randomized to receive cytokine injections in their abdomen (group A) or extremities (group B). Randomization was stratified based upon diagnosis (myeloma; N=29 vs. lymphoma; N=11), age (≤50; N=13 vs. >50; N=27), and mobilization strategy (cytokines alone; N=27 vs. chemomobilization; N=13). Both group A and B were balanced with respect to the stratification criteria. Filgrastim was planned at a dose of 10 ug/kg/day for patients undergoing chemomobilization or 15 ug/kg/day for patients undergoing cytokine-only mobilization. Actual mean cytokine doses were 11.78 ug/kg/day using chemomobilization and 12.96 ug/kg/day using cytokines alone due to rounding to nearest vial size. Patients recorded the injection site for G-CSF and symptoms daily. Results Of those enrolled, 90% were evaluable with 18 patients in each group. Four were deemed non-evaluable due to failure to proceed to the planned mobilization procedure (1 in group A and 2 in group B) or lack of consistent injection site (1 patient). In addition, one patient in group B received a non-protocol specified injection of plerixafor due to poor mobilization and collected a total of 13.62 × 10E6 CD34+ cells/kg in 2 days of apheresis. Among the 36 evaluable subjects, 1 subject in each group failed collection with a total of < 2.0 × 10E6 CD34+ cells/kg collected. Mean BMI at the time of mobilization was not different between groups A and B (27.25 ± 4.7 versus 29.39 ± 5.7, respectively; p=NS). Mean numbers of CD34+ cells (±SD) collected were not different between groups A and B (9.15 ± 4.7 versus 9.85 ± 5 × 106/kg, respectively; p=NS). The mode and median duration of apheresis was 2 days for both groups. Subjects from both groups reported similar toxicities of pain and discomfort at the injection site. Conclusions Based upon the analysis, G-CSF administration site (extremities versus abdomen), does not affect the number of CD34+ cells collected by apheresis or the duration of apheresis needed to reach the target cell dose. Disclosures: Lonial: Celgene: Consultancy; Millennium: Consultancy, Research Funding; BMS: Consultancy; Novartis: Consultancy; Gloucester: Research Funding.

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Results of Salvage Autologous Stem Cell Transplantation (ASCT) for Relapsed Multiple Myeloma (MM) in the Era of Novel Agents: Outcome of Patients (Pts) Receiving Prior Bortezomib (BTZ)-Based Therapy

Blood ◽

10.1182/blood.v128.22.5821.5821 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5821-5821 ◽

Cited By ~ 2

Author(s):

Sara Farshchi Zarabi ◽

Esther Masih-Khan ◽

Christine Chen ◽

Vishal Kukreti ◽

Anca Prica ◽

...

Keyword(s):

Maintenance Therapy ◽

Induction Therapy ◽

Research Funding ◽

Chemotherapeutic Agents ◽

Novel Agents ◽

Remission Induction ◽

Group A ◽

Group B ◽

Relapsed Disease ◽

The Impact

Abstract Background: A second (salvage) ASCT has frequently been offered to MM patients with relapsed disease who experience benefit from the first procedure. We have previously reported that pts undergoing a salvage ASCT in the era of VAD or thalidomide (thal) have a median progression-free survival (PFS) of 19 months (mos). The best results were observed in pts who experienced ≥ 2 year benefit after their first ASCT (Jimenez-Zepeda VH et al. Biol Blood Marrow Transplant 2012; 18: 773-9). However, the utility of this approach after the introduction of novel chemotherapeutic agents--such as bortezomib (BTZ)--remains unclear. Initially, provincial funding for BTZ in Ontario was provided only for relapsed disease. However, in 2007, the combination of either BTZ + dexamethasone (BTZ-dex) or cyclophosphamide, BTZ + dex (CyBorD) was adopted as the standard induction regimen for newly diagnosed pts before ASCT performed as part of first-line therapy. We now examine the results of salvage ASCT in our centre after the availability of BTZ. Methods: We used the Princess Margaret Myeloma Database to identify and characterize patients with relapsed MM who had received a bortezomib (BTZ)-based regimen for remission induction prior to their first ASCT or for re-induction before salvage ASCT. A retrospective chart review was performed to investigate the PFS and overall survival (OS) outcomes of these pts. Results: Between 01/2005 and 07/2015, 64 pts with MM who had previously received BTZ-based therapies underwent salvage ASCT for relapsed disease at our centre (Table 1). Median age was 56.9 yrs (range 37-67.3); 37 (58%) were male. ISS stage was 1 in 32 (50%), 2 in 16 (25%), 3 in 14 (22%) and NA in 2 (3%). The median interval between first and salvage ASCT for all pts was 48.6 mos (range 26.9-130.3), reflecting our policy of preferentially offering salvage ASCT to pts with at least a 2-yr benefit from the first transplant; the median time between re- induction therapy and salvage ASCT was 6.3 mos (range 0.3-95.9). Group A pts (n=27) had received BTZ-based therapy before their first ASCT; 48% of these also received BTZ-based regimens again prior to salvage ASCT. Pts in Group B (n=37) received BTZ-based regimens before the salvage transplant only, while induction therapy before the first ASCT consisted of VAD (21), dex alone (8), thal + dex or other regimens (5). Twenty-two (34%) of the pts received maintenance therapy between the first and salvage ASCT (most often thal-based), while 35 (55%) of the pts received maintenance therapy following salvage ASCT (most frequently lenalidomide [len]-based). The survival outcomes are summarized in Table 2. Median duration of follow-up (F/U) following salvage ASCT was 19.1 mos (range 0.8-96.4). One patient (1.6%) died several days following salvage ASCT. No other transplant-related mortality occurred. The median PFS following salvage ASCT was 19.1 mos (range 0.8- 87.5) with a median OS of 26.5 mos (range 0.8-101.9) in all pts. The median PFS after salvage ASCT was 15.8 mos for Group A and 25.2 mos for Group B pts. Conclusions: Even in the era of novel agents, salvage ASCT may provide PFS benefit to pts with relapsed MM who were previously treated with a BTZ-based regimen. However, the details of the optimal approach in this setting are not certain, including the impact of maintenance therapy given after the first and/or salvage ASCT. We are performing additional analyses of this population to try to identify factors associated with the best outcomes. Disclosures Kukreti: Celgene: Honoraria; Lundbeck: Honoraria; Amgen: Honoraria. Prica:Janssen: Honoraria. Tiedemann:Novartis: Honoraria; Celgene: Honoraria; Takeda Oncology: Honoraria; BMS Canada: Honoraria; Amgen: Honoraria; Janssen: Honoraria. Trudel:Celgene: Honoraria; Novartis: Honoraria; Glaxo Smith Kline: Honoraria, Research Funding; Oncoethix: Research Funding. Reece:Merck: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding.

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A concise infertility work-up results in fewer pregnancies

Human Reproduction Open ◽

10.1093/hropen/hoab033 ◽

2021 ◽

Vol 2021 (4) ◽

Cited By ~ 1

Author(s):

J A M Hamilton ◽

J W van der Steeg ◽

C J C M Hamilton ◽

J P de Bruin

Keyword(s):

Success Rate ◽

Pregnancy Rate ◽

Semen Analysis ◽

Prognostic Score ◽

Ongoing Pregnancy ◽

Ongoing Pregnancy Rate ◽

Group A ◽

Group B ◽

Work Up

Abstract STUDY QUESTION Is pregnancy success rate after a concise infertility work-up the same as pregnancy success rate after the traditional extensive infertility work-up? SUMMARY ANSWER The ongoing pregnancy rate within a follow-up of 1 year after a concise infertility work-up is significantly lower than the pregnancy success rate after the traditional and extensive infertility work-up. WHAT IS KNOWN ALREADY Based on cost-effectiveness studies, which have mainly focused on diagnosis, infertility work-up has become less comprehensive. Many centres have even adopted a one-stop approach to their infertility work-up. STUDY DESIGN, SIZE, DURATION We performed a historically controlled cohort study. In 2012 and 2013 all new infertile couples (n = 795) underwent an extensive infertility work-up (group A). In 2014 and 2015, all new infertile couples (n = 752) underwent a concise infertility work-up (group B). The follow-up period was 1 year for both groups. Complete follow-up was available for 99.0% of couples in group A and 97.5% in group B. PARTICIPANTS/MATERIALS, SETTING, METHODS The extensive infertility work-up consisted of history taking, a gynaecological ultrasound scan, semen analysis, ultrasonographic cycle monitoring, a timed postcoital test, a timed progesterone and chlamydia antibody titre. A hysterosalpingography (HSG) was advised routinely. The concise infertility work-up was mainly based on history taking, a gynaecological ultrasound scan and semen analysis. A HSG was only performed if tubal pathology was suspected or before the start of IUI. Laparoscopy and hormonal tests were only performed if indicated. Couples were treated according to the diagnosis with either expectant management (if the Hunault prognostic score was >30%), ovulation induction (in case of ovulation disorders), IUI in natural cycles (in case of cervical factor), IUI in stimulated cycles (if the Hunault prognostic score was <30%) or IVF/ICSI (in case of tubal factor, advanced female age, severe male factor and if other treatments remained unsuccessful). The primary outcomes were time to pregnancy and the ongoing pregnancy rates in both groups. The secondary outcomes were the number of investigations, the distribution of diagnoses made, the first treatment (started) after infertility work-up and the mode of conception. MAIN RESULTS AND THE ROLE OF CHANCE The descriptive data, such as age, duration of infertility, type of infertility and lifestyle habits, in both groups were comparable. In group A, more than twice the number of infertility investigations were performed, compared to group B. An HSG was made less frequently in group B (33% versus 42%) and at a later stage. A Kaplan–Meier curve shows a shorter time to pregnancy in group A. Also, a significantly higher overall ongoing pregnancy rate within a follow-up of 1 year was found in group A (58.7% versus 46.8%, respectively, P < 0.001). In group A, more couples conceived during the infertility work-up (14.7% versus 6.5%, respectively, P < 0.05). The diagnosis cervical infertility could only be made in group A (9.3%). The diagnosis unexplained infertility differed between groups, at 23.5% in group A and 32.2% in group B (P < 0.001). LIMITATIONS, REASONS FOR CAUTION This was a historically controlled cohort study; introduction of bias cannot be ruled out. The follow-up rate was similar in the two groups and therefore could not explain the differences in pregnancy rate. WIDER IMPLICATIONS OF THE FINDINGS Re-introduction of an extensive infertility work-up should be considered as it may lead to higher ongoing pregnancy rates within a year. The therapeutic effects of HSG and timing of intercourse may improve the fertility chance. This finding should be verified in a randomized controlled trial. STUDY FUNDING/COMPETING INTEREST(S) No funding was obtained for this study. No conflicts of interest were declared. TRIAL REGISTRATION NUMBER N/A.

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Phenotypes of JAK2-Mutated Polycythemia Vera and Essential Thrombocythemia with and without Thromboembolic Events: Results of the Hinc-207 (OSHO #91) Study

Blood ◽

10.1182/blood-2020-139366 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 13-13

Author(s):

Tony Hennersdorf ◽

Nadja Jaekel ◽

Susann Schulze ◽

Dietrich Kaempfe ◽

Claudia Spohn ◽

...

Keyword(s):

Risk Factors ◽

Polycythemia Vera ◽

Essential Thrombocythemia ◽

Research Funding ◽

Thrombotic Event ◽

Patient Questionnaire ◽

Allele Burden ◽

History Of ◽

Group A ◽

Group B

Thrombosis is the major cause of morbidity and mortality in polycythemia vera (PV) and essential thrombocythemia (ET). Age ≥60 years (y) and/or history of thrombosis labels patients (pts) as high-risk for thrombosis. Yet, thrombosis frequently occurs prior to the diagnosis of PV/ET. In a multicenter study of the East German Study Group (HINC-207; OSHO #091), the interaction between age and time occurrence of the first thrombosis as risk factors for thrombosis after diagnosis was studied. Methods After IRB approvals, JAK2 mutated adults with PV or ET were prospectively enrolled in 9 centers and centrally stratified in a one to two ratio (group A: pts with a history of thrombosis; group B: pts without thrombosis) with a pre-planned minimum of 60:120 pts. Based on a longitudinal and cross-sectional design, clinical and laboratory data at diagnosis, last follow-up, and thrombosis (for group A) were collected. Thrombosis prior to diagnosis was labeled as A1 and thrombosis after diagnosis as A2. Thrombosis risk factors were grouped into age-, previous thrombosis-, thrombosis prior to PV/ET-, cardiovascular (CV)-, thrombophilia-, and disease- (JAK2 allele burden, Hct, and WBC) related. Additionally, therapies [aspirin (ASS), anticoagulation, phlebotomy, and cytoreduction] and data from a study-own patient questionnaire were included. All pts signed informed consent. The primary endpoint was the phenotypic diversity in JAK2-mutated ET and PV pts with or without thrombosis. Results From April to Dec, 2019, 246 pts were recruited. Data on 237 pts (median age 62y; 59% females, 58% PV) are available. At diagnosis, pts in group A (n=71, median age 59.5y) tended to be younger than those in group B (n=166, median age 63y) (p=0.07). Yet, 70.4% thrombotic events (venous: median age 46.5y; arterial: median age 57y) occurred in A1 and correlated with younger age (p=0.03). Only 3 pts developed a second event after diagnosis. These were counted in A2 (n=24, median age at thrombosis: 61y). Overall, thrombosis occurred either prior to or within the first 3y after diagnosis in 63/71 (89%) pts. Age>60y could not be identified as a risk factor for thrombosis or type of thrombosis at any time point. The 5 y probability of no thrombotic event after diagnosis in pts >60y was 90.4% vs. 89.2% for pts <60y (p=0.8) and that of a thrombotic event >3y after diagnosis in pts >60y was 3.7% vs. 4.9% for pts <60y (p=0.7). Similarly, A1 did not correlate with A2 (p=0.3). With 1691 patient-years for the entire cohort, the incidence of thrombosis after PV/ET diagnosis was 0.7 for arterial and 0.6 for venous events per 100 patient-years. Smoking was more prevalent in pts >60y (p=0.003) and was not associated with thrombosis. Irrespective of age, hypertension (65%, p=0.03), hyperlipidemia (19%, p=0.008), and diabetes (16.4%, p=0.05) were frequent and correlated with A2 while atrial fibrillation (p=0.03) and inherited thrombophilia risk factors (p<0.00) with A1. JAK2 allele burden (median 19%) and Hct >45% (median 45%) at diagnosis correlated strongly with age >60y (p=0.005) but not with A, A1, or A2, although Hct >45% at diagnosis correlated with A2 in PV (p=0.001). Surprisingly, a Hct >45% at thrombosis was more frequently present in A1 (55%) vs A2 (30%) (p<0.00). Median WBC at diagnosis was higher in B compared to A (p=0.004), strongly associated with age >60y (p<0.00) but not with A2. WBC >15% at thrombosis did not correlate with A. Age rather than thrombosis was the trigger for cytoreduction [82% hydroxyurea (HU) in B pts >60y vs 53% in A pts <60y] (p<0.00). In PV, ASS did not correlate with thrombosis (25% of pts in B did not receive ASS). Cytoreduction, interval between diagnosis and cytoreduction, nor the duration of exposure correlated with thrombosis. Conclusions: The majority of thrombotic events occurred prior to or within the first 3 years after the diagnosis of JAK2 mutated PV/ET and were associated with CV-risk factors rather than older age. Phenotypic features such as Hct >45%, high WBC, and JAK2 allele burden were associated with age >60y and less with thrombosis. Their value as surrogate markers for therapeutic interventions to reduce thrombosis needs to be critically evaluated in larger series. Whether adequate PV/ET- or CV-risk- treatments account for the low rate of CV events after diagnosis (despite a higher incidence of CV-risk factors) compared to the general population could not be answered due to study design and needs to be addressed prospectively. Disclosures Al-Ali: Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

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Integration of Deep Multi-Omics Profiling Veals New Insights into the Biology of Poor-Risk Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2020-141345 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 39-40

Author(s):

Ana Rio-Machin ◽

Pedro Casado-Izquierdo ◽

Juho Miettinen ◽

Findlay Bewicke-Copley ◽

Naeem Khan ◽

...

Keyword(s):

Research Funding ◽

Drug Sensitivity ◽

Germ Line ◽

Late Phase ◽

Rna Seq ◽

Poor Risk ◽

Group A ◽

Group B ◽

Acute Myeloid

Background: The poor-risk cytogenetic subgroup of acute myeloid leukaemia (AML) includes various chromosomal aberrations and represents a heterogeneous population of patients with a dismal 10-year overall survival. While the success of genetic landscaping studies is encouraging, it is debatable whether genomics, or indeed any single-omics platform alone, is sufficient to capture the biology of a disease that continues to evade our existing treatments so effectively. Instead, we need to develop a much better understanding of the complexity of this subgroup of AMLs: the relationship and interdependencies across biochemical pathways, how these may differ between patients and their impact on the leukemia and normal stem cell compartments. To launch this process, we have completed a multi-omics profiling programme to shed new light on the genetic and biochemical features of poor-risk AML (https://poor-risk-aml.bham.ac.uk/). Aims: Application of multi-omics and integrative approaches to decipher the complexities of cytogenetically poor-risk AML Methods: Sample inclusion criteria were based on cytogenetics and availability of sufficient diagnostic bone marrow or peripheral blood material for analysis. The 50 primary AMLs included 17 cases with complex karyotype, 13 -7/del(7), 11 KMT2A rearrangements (with the exception of t(9;11)), 4 t(6;9), 3 -5/de(5), 1 del(17) and 1 inv(3). Profiles consisted of a combination of genomics (whole genome sequencing (WGS, 60X for tumour and 30X for germ-line controls), targeted sequencing of 54 myeloid loci, and total RNA-seq (100 million reads per bulk sample), mass spectrometry proteomics and phosphoproteomics (with >6,000 proteins and > 25,000 phosphorylation sites detected and quantified), mass cytometry (CyTOF, 39 markers), drug screening (ranging from 200-500 approved or investigational compounds) and the selective generation of patient-derived xenograft (PDX) models. Results: Near complete datasets have been compiled on all 50 primary AMLs, with the exception of WGS analysis where profiling was restricted to cases where corresponding germline DNA was available. Integration of WGS and RNA-seq data identified 122 genes having notable allele-specific expression (ASE) in ≥ 5 samples supported by ≥ 3 SNPs and these included the transcription factor GATA2 and the DNA topoisomerase TOP1MT. Use of RNA fusion capture tools resolved novel inter- and intra- chromosomal gene rearrangements that were confirmed by WGS. The four t(6;9)(p23;q34)/DEK-NUP214 cases, with a mean age of diagnosis of 43.5 years and all harboring FLT3-ITD mutations, arose from the most immature hematopoietic compartment (CD34+CD117+ enrichment) and demonstrated a unique transcriptomic signature, which included upregulation of FOXO3 and GRP56. Collectively, t(6;9) primary samples also showed a selective drug sensitivity to XPO1 (selinexor and eltanexor) and JAK inhibitors (ruxolitinib, tofacitinib and momelotinib) compared to other cytogenetic risk groups. On the other hand, a comparison of in vitro drug sensitivity data with genomic data of our entire cohort of patients demonstrated that TP53 wt AMLs (n=37) were more sensitive to all four MDM2 inhibitors (AMG-232, idasanutlin, SAR405838 and NVP-CGM097) compared to TP53 mutated cases (n=13). Comparisons of transcriptomics with the in vitro sensitivity to drugs included in early/late phase AML clinical trials, identified signatures of response associated with MDM2 and Aurora B kinase (AZD1152-HQPA) inhibitors. Phosphoproteomics analysis and machine learning modeling separated KMT2A rearranged leukemias into 2 discrete groups (group A: MLLT4, MLLT10 and TET1; group B with MLLT6, ELL and SEP9 fusion partners). Functionally, group A presented with elevated HOXA10 protein expression and enhanced in vitro response to genotoxic drugs and cell cycle inhibitors when compared to group B leukemia. Conclusions: Our study demonstrates the feasibility of simultaneously generating omics data from several different platforms and highlights that a combination of genetic and proteomic profiles may help to inform the choice of therapies based on the underlying biology of a patient's AML. Disclosures Wennerberg: Novartis: Research Funding; Pfizer: Honoraria. Heckman:Celgene: Research Funding; Novartis: Research Funding; Oncopeptides: Research Funding; Orion Pharma: Research Funding; Innovative Mediicines Initiative project Harmony: Research Funding.

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Lenalidomide and Low Dose Dexamethasone in Previously Treated Multiple Myeloma Patients with Impaired Renal Function: Efficacy Analysis of PrE1003, a Precog Study

Blood ◽

10.1182/blood.v128.22.5712.5712 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5712-5712

Author(s):

Joseph Mikhael ◽

Judi Manola ◽

Sagar Lonial ◽

Brendan M Weiss ◽

Kurt Oettel ◽

...

Keyword(s):

Multiple Myeloma ◽

Renal Function ◽

Renal Insufficiency ◽

Research Funding ◽

Impaired Renal Function ◽

Response Rate ◽

Phase 2 ◽

25Mg Daily ◽

Group A ◽

Group B

Abstract Introduction: Lenalidomide (Len) and dexamethasone (dex) has proven to be a highly effective treatment for multiple myeloma (MM) and serves as the basis of other combinations in relapsed disease. However, nearly 1/3 of myeloma patients have renal insufficiency, and the optimal use of Len in this population is not well known. We undertook this study in 3 cohorts of pts: Group A had creatinine clearance (CrCl) of 30-60 ml/min, Group B with CrCl < 30 ml/min, and Group C, with CrCl < 30 ml/min and requiring dialysis. The Phase I component of the trial has been previously reported (ASCO 2014) demonstrating that full dose Len (25mg daily 21/28 days) can be given to all patients despite renal insufficiency, even when on dialysis. We now present data on response to treatment. Methods: In the Phase 2 component accrual was slow and the trial was terminated. However, prior to termination a modified exploratory analysis plan was established, including all 34 patients treated at the recommended phase 2 dose. This plan would declare the treatment worthy of further study if 18 or more of the 34 patients responded to treatment. This design had 84% power to distinguish a response rate of 60% from a null rate of 40%, using a 1-sided test with 10% type I error. Results: The Phase 2 efficacy cohort accrued 34 patients, consisting of 20 patients from Group A, 9 patients from Group B, and 5 patients from Group C. Response of PR or greater was seen in 17 patients, resulting in a 50% overall response rate (CI 37-63%). Treatment was well tolerated with expected adverse events; the most common adverse events were anemia, diarrhea, and fatigue. Eleven episodes of Grade 3 and one Grade 4 pneumonia were reported for 10 patients across all cohorts and dose levels; 3 were considered possibly related to treatment. Seventeen patients have remained on treatment for more than 12 cycles. In the exploratory analyses, median PFS was 7.5 months (95% CI, 3.6 - 19.7 months) and median OS was 19.7 months (95% CI, 10.4 - 42.5 months). Conclusions: Len Dex can be safely administered to patients with impaired renal function at full dose of 25mg daily 21/28 days, and is associated with a 50% response rate. Further investigation into other combinations with Len Dex in patients with renal impairment should be considered. Table Table. Disclosures Mikhael: Onyx: Research Funding; Sanofi: Research Funding; Abbvie: Research Funding; Celgene: Research Funding. Lonial:Merck: Consultancy; Novartis: Consultancy; Onyx: Consultancy; BMS: Consultancy; Onyx: Consultancy; Celgene: Consultancy; BMS: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Janssen: Consultancy. Weiss:Novartis: Consultancy.

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1166. Reverse Syphilis Screening and Adherence to The Congenital Syphilis Guidelines: Institutional Experience

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.1359 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S674-S675

Author(s):

Brandon Chatani ◽

Aida Chaparro ◽

Patricia Alvarez ◽

Kristopher Arheart ◽

Ivan Gonzalez ◽

...

Keyword(s):

Laboratory Tests ◽

Congenital Syphilis ◽

American Academy Of Pediatrics ◽

Institutional Experience ◽

Group A ◽

Syphilis Screening ◽

Maternal Syphilis ◽

Group B ◽

Work Up ◽

Positive Results

Abstract Background This study is analysis the consequences of the reverse syphilis screening on the management of newborns exposed to maternal syphilis, and pediatric physicians’ adherence to the existing guidelines. Methods We conducted a 5-year retrospective review of the maternal population and their newborns diagnosed with syphilis. Women with positive results (TT+/NTT+) and discordant (TT+/NTT-/TT+) and their newborns were included in the analysis. Results Per American Academy of Pediatrics (AAP), the 202 newborns were divided in two groups: proved or highly probable and possible congenital syphilis (Group A, n=102) and less likely and unlikely congenital syphilis (Group B, n=100). Except for the RPR, none of the other laboratory tests showed higher odds for predicting congenital syphilis. The RPR titers above 1:16 were only identified among newborns belonging to the Group A (5%); 32 patients (31%) in the Group A and 19 (9%) in the Group B had an RPR titer equal to or below 1:8. An RPR titer equal to or above 1:4 was almost three times more likely to be identified in patients from Group A (OR 2.91; CI 1.51- 5.59, p< 0.05). The newborns with non-reactive RPRs represented 64% of the patients in the Group A and 47% of them were born to mother with non-reactive RPR also (mothers with discordant results). Among the Group B, 82% of the neonates had a non-reactive RPR and 54% were delivered to mother with non-reactive RPRs. Babies in Group B had additional work-up performed 69% (n=37) of the time; 15% of these babies were treated with intramuscular penicillin which does not follow established AAP guidelines. Statistical analysis of the laboratory tests used for the congenital syphilis work-up Result table comparing the two groups of newborns Conclusion The reverse syphilis screening and non-adherence to the guidelines led to additional screening to half of the newborns in both groups. This study highlights the need for a comprehensive maternal history at the time of delivery that is effectively communicated between the providers. This might lead to greater congruence with the established AAP guidelines. Disclosures All Authors: No reported disclosures

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Clinical implication of right-sided augmentation pressure in patients with pulmonary hypertension

Pulmonary Circulation ◽

10.1177/2045894019833352 ◽

2019 ◽

Vol 9 (1) ◽

pp. 204589401983335

Author(s):

Dae-Won Sohn ◽

Jun-Bean Park ◽

Seung-Pyo Lee ◽

Hyung-Kwan Kim ◽

Yong-Jin Kim

Keyword(s):

Pulmonary Hypertension ◽

Prognostic Value ◽

Systolic Pressure ◽

Left Ventricular ◽

Pressure Waveform ◽

Female Ratio ◽

Augmentation Pressure ◽

Group A ◽

Group B ◽

Work Up

Similar to left ventricular and aortic pressure waveforms, augmentation pressure (AugPr) in the right ventricular (RV) pressure waveform is also frequent in patients with pulmonary hypertension (PH). This study sought to evaluate whether the degree of AugPr in RV pressure waveform has prognostic value. Forty-one patients (13 men; mean age = 50.7 ± 16.1 years) with group 1 PH (mean pulmonary artery pressure [mPAP] ≥ 25 mmHg) who underwent cardiac catheterization as part of their work-up were retrospectively enrolled. Patients were divided into three groups. Group A: AugPr/RV systolic pressure < 25%; group B: AugPr/RV systolic pressure ≥ 25%; and group C: no discernible AugPr but showing peaked RV pressure waveform. Ten patients were included in group A (male-to-female ratio 3:7; mean age = 45.9 ± 12.1 years), 12 in group B (4:8, 53.8 ± 14.6 years), and 19 in group C (6:13, 51.8 ± 18.7 years). No differences in mPAP were seen between the three groups. Pulse pressure was significantly higher in group C compared to group A. Eight patients died during the mean follow-up period of 35.9 ± 30.7 months; the incidence of death was significantly higher in group C than in the other groups (one patient in group A and seven patients in group C). AugPr in RV pressure waveform has prognostic value in patients with PH. Therefore, additional attention should be given to the RV pressure waveform in patients with PH undergoing invasive pressure measurements as a part of their work-up.

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