bluuebunny/crossref_metadata_2025 huggingface dataset:
PB2003 ADDED RADIOTHERAPY IMPROVES PROGNOSIS IN HD PATIENTS TREATED WITH ABVD
Authors: Karanfilski O. , Amzai G. , Trpkovska Terzieva S. , Pavkovik M. , Sotirova T. , Genadieva Stavrik S. , Krstevska Balkanov S. , Cvetanoski M. , Ridova N. , Kocoski B. , Stojanovik A.
Published: June 2019

Background:

Results from many analyses and trials have shown that combined modality treatment contributes to better vital statistics for HD patients, compared to chemotherapy‐only treatment. In previous analyses, we have also argumented this point, validating it on our patient population. However, our previous analyses were performed mainly on HD patients initially treated with COPP‐like regimens.

Aims:

To analyze whether HD patients initially treated at our Clinic with the ABVD (and derived) regimen(s) still benefit from the addition of radiotherapy as a treatment component.

Methods:

Within the past two decades we used ABVD as initial treatment in a total of 272 HD patients. In more than 70% of these, chemotherapy only was the treatment mode administered. Almost 30% of these patients required addition of radiotherapy, as part of a recommended combined modality treatment option, or, in a minority of cases, as adjuvant treatment to sites of residual or bulky tumor mass.

Results:

ABVD as induction treatment achieves 5yOS in 91% of patients, and 10yOS for 85% of the patients. The survival curve maintains a plateau at 82.5% after the 150‐month mark. The 77 patients treated with the combined modality treatment/adjuvant chemotherapy maintain a 4% margin of superiority in the OS, across the first 10 years of follow‐up. Nevertheless, both survival curves almost merge after the 15th year, and maintain a continuous plateau thereafter. The benefit is more evident when PFS is analyzed. All clinical stages maintain a continuous difference between the plateaus of the curves, starting from the third year of follow‐up, varying from 2‐6% among different CS categories. Although a small category (8 patients), even the advanced stage patients treated with adjuvant radiotherapy benefit from this option, maintaining a 100% OS and PFS line. It should be clearly stated that in our analysis the differences do not reach a statistically significant level in terms of p‐values, probably due to the relatively small number of patients analyzed, the notable disproportion among the patients with completed vs. censored observations, as well as because of the numeric misbalance among the groups treated with the two treatment options.

Summary/Conclusion:

Having balanced all observations, we still recommend that radiotherapy is not omitted as a very beneficial mode of treatment across all stages of the disease (abiding firmly by the indications for evidence‐based utilization of this option), contributing to a (maybe) marginal, but still a continuous advantage in the vital statistics of HD patients. Not neglecting the everlasting concerns of the community with regard to the adverse late effects of radiotherapy, hopes should turn towards dose modifications and field adjustments, as well as technological improvements of radiotherapy, rather than abandoning this treatment modality.
PB2029 HEPATITIS B REACTIVATION DURING TREATMENT OF TYROSINE KINASE INHIBITORS—EXPERIENCE IN 175 ADULT PATIENTS WITH CHRONIC MYELOID LEUKEMIA
Authors: Wang Y.‐H. , Liang J.‐D. , Sheng W.‐H. , Tien F.‐M. , Chen C.‐Y. , Tang J.‐L. , Tien H.‐F.
Published: June 2019

Background:

The cause of hepatitis B virus (HBV) reactivation in patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs) is unclear.

Aims:

Taiwan has a high prevalence of HBV infection, and this study aimed to investigate the epidemiology of HBV reactivation in patients with CML treated with TKIs.

Methods:

We retrospectively reviewed 175 adult patients with CML who were treated using TKIs at National Taiwan University Hospital between January 2008 and July 2018. HBV infection status and reactivation were reviewed during follow‐up.

Results:

A total of 99 men and 76 women with a median age of 46 years (range: 18–97) were enrolled in this study. Twenty‐one (12%) of 175 patients were carrying HBV when they were diagnosed with CML. Eight HBV carriers were prophylactically treated using an antiviral agent, and the others were closely followed‐up. At a median follow‐up period of 41 months (range 1–129 months), 6 (28.6%) of the 21 HBV carriers had 7 episodes of HBV reactivation. Two (1.3%) of the 154 negative hepatitis B surface antigen (HBsAg) patients had reverse seroconversion and became positive HBsAg, and both patients had acute blastic transformation and allogeneic transplantation. A univariate analysis revealed positive HBsAg and negative anti‐Hepatitis B surface antibodies (anti‐HBs Ab) significantly correlated with HBV reactivation. In this retrospective cohort study, the incidence of HBV reactivation was 0.5 per 100 person‐years in patients with CML carrying HBV who had been treated with TKIs and 0.076 per 100 person‐years in all patients with CML treated with TKIs.

Summary/Conclusion:

HBV reactivation could develop in patients with CML treated with TKI, especially in those who are HBV carriers. The incidence is lower than it is in hematological patients with HBV carrier status who have been treated with chemotherapy, immunotherapy and stem cell transplantation. We suggest that all patients with CML with positive HBsAg undergo prophylaxis with an antiviral agent. The cause of HBV reactivation in patients with resolved HBV infection and no allogeneic transplantation is unclear, and although the risk is low, further investigation is required.

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PB2035 ISAVUCONAZOLE AS PROPHYLAXIS AGAINST INVASIVE FUNGAL INFECTIONS IN STEM CELL TRANSPLANT PATIENTS: A DESCRIPTIVE SINGLE CENTER EXPERIENCE.
Authors: Pinzon S.F. , Marta V.M. , Izquierdo I. , Aules A. , Salvador E. , Garcia Ortego A. , Diez R. , Delgado P.
Published: June 2019

Background:

Isavuconazole is a novel triazole antifungal approved for treating invasive aspergillosis and mucormycosis with predictable pharmacokinetics compared to its counterparts; the handling of interactions with other medications is easier, which is the most important advantage of this antifungal. The aim of our study is to describe the experience with this Triazole in prophylaxis in our hospital.

Aims:

The aim of this study its to describe our experiencie with Isovuconazole.

Methods:

A retrospective review from the patients undergoing allogenic stem cell transplantation who received Isavuconazole in prophylaxis was performed. We analyze the demographic data and the risk factors related to the host, disease, treatment and the transplant.

Results:

From a sample of 6 patients with a main age of 52 age years, equal sex ratio, five patients have an acute myeloid leukemia (ALM) and one patient a myelodysplastic syndrome (MDS), all the patients has at least one high risk factor for the development of invasive fungal infections (IFI), described in the table 1. All of them was taking corticosteroids due to chronic/acute GVHD and one patient because of an autoimmune disease.

All patients were treated with oral Isavuconazole at 200 mg per day at least 14 days for prophylaxis; the reasons to choose Isavuconazole were elevated liver transaminases in four cases and Posaconazole intolerance in two patients.

Serum detection of galactomannan was performed for all patients every week during antifungal therapy and all the results were negative.

Summary/Conclusion:

Although the efficacy and safety of Isavuconazole, there is no indication in the technical sheet for prophylaxis with this triazole. At this time, none of our patients developed an IFI or intolerance to treatment. There are few studies that evaluate prophylaxis, most related to the experience in solid organ transplantation, but it is not known what is happening in the real world of hematological diseases. In our experience seems to be a useful and safe drug, however, more studies are needed to verify this hypothesis.

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PB2036 EFFECTS OF DIFFERENT IRON FORMULATION SUPPORT ON SELECTION OF SOME PATHOGENS IN HUMAN GUT FLORA: MONOCENTRIC STUDY
Authors: Giordano G. , Lucchesi A. , magri M. , niro G. , gasperi M.
Published: June 2019

Background:

Food and micronutrients support modify the composition of our intestinal flora.

Aims:

Aim of this study is to see how different iron formulations used in human iron support are able to expand gut pathogen flora.

Methods:

36 female patients (6 per group) with sideropenic anemia due to hypermenorrhea received 60 mg/day of different iron formulations: sulphate, Sucrosomial®, heminic bisglycinated, bisglycinated chelated, micronized encapsulated.

Median age of patients was 30y (R20‐38). A stool culture test was performed in each patient at start of treatment and one month after. If at time 0 a culture was positive for a pathogen, patient was excluded from the study.

Cultural stool test were performed for E. coli enteropathogen, enterohemorragic, salmonella, shigella, clostridium, yersinia entherocolica.

Results:

Before treatment: 1 patient receiving iron sulphate had a yersinia positivity and 1 receiving heminic bisglycinated iron showed an E. coli.

After treatment: 2 patients receiving heminic bisglycynated iron showed positivity for E. coli enteropathogenic, 1 for shigella; 4 patients receiving iron sulphate showed positivity for E. coli enteropathogenic; 2 patients receiving micronized encapsulated iron and 2 with bisglycinated chelated iron showed positivity for E. coli enteropathogenic, 1 with Sucrosomial® iron showed positivity for yersinia enterocolica.

Summary/Conclusion:

Different type of iron supplements differently affect pathogen gut flora selection. Molecular complexes iron carriers probably influence differently pathogen selection. The most represented selected pathogen flora is E. coli entheropathogenic.
PB2040 EMERGENT INFECTIONS ASSOCIATED TO THE TREATMENT WITH NEW MOLECULES IN CHRONIC LYMPHOCYTIC LEUKEMIA ‐ SINGLE CENTER EXPERIENCE
Authors: Tomescu A.A. , Enache A. , Dragan R. , Vasilica M. , Coriu D. , Ursuleac I.
Published: June 2019

Background:

During the last years, the overall response to the treatment of patients with chronic lymphocytic leukemia (CLL) has improved due to the introduction in the therapeutical armentarium of the new molecules ‐ Bruton kinase (BTK) inhibitors (Ibrutinib) and Phosphoinositide 3‐kinases (PI3Ks) inhibitors ‐ Idelalisib. The main late adverse reaction of the treatment with these 2 products is immunosupression with high infectious risk, including viral reactivations and opportunistic de novo infections (bacterial, mycotic or viral).

Aims:

To find the risk factors associated to the risk of infections in CLL patients treated with new molecules

Methods:

A retrospective, clinico‐epidemiological study including 12 CLL patients diagnosed in our centre with various infections during therapy with Idelalisib or Ibrutinib.

Results:

12 CLL patients (6 men, 6 women) have been observed: 2 treated with Idelalisib 150 mg BID and 10 treated with Ibrutinib 420 mg QD; median age ‐ 56 years (35 – 75). There have been studied: the number of anterior therapeutic lines (2 – 5 patients, 3 – 5 patients, 4 – 2 patients), treatment‐free period before new molecules have been introduced (medium 15 months), therapy duration before the onset of the infection (19 months medium); additional risk factors ‐ previous hypogammaglobulinemia (observed in all the studied patients). We have identified viral reactivations (CMV, VZV, HSV), fungal (Aspergillus sp.) and bacterial (Klebsiella sp., E. coli, Corynebacterium bovis, MRSA) infections. The localizations were: cerebral (2 cases of aspergillosis and CMV), pulmonary (3 cases of aspergillosis), genito‐urinary (3 cases of multiresistent E. coli and HSV) and cutaneous (2 cases of HSV and MRSA). 5 deaths occurred due to uncontrolled disease and infection.

Summary/Conclusion:

Treatment with new molecules is associated with high infectious risk. We have identified multiple causes: advanced stage of disease, heavily treated patiens, hypogammaglobulinemia and comorbidities (diabetes). These patients should be closely monitored for infectious risk during treatment with new molecules.
PB2045 EFFICACY & SAFETY OF INTRAVENOUS FERRIC CARBOXYMALTOSE IN IRON DEFICIENCY ANEMIA: A PROSPECTIVE STUDY
Authors: Nath U.K. , Chetia R.
Published: June 2019

Background:

Iron deficiency anemia (IDA) is the most common nutritional anemia globally. Goal of iron replacement therapy are correction of anemia and repletion of body iron stores. Oral iron replacement is the preferred route in general. However, response to oral iron replacement therapy is often suboptimal due to poor compliance to treatment resulting from gastrointestinal intolerance and prolonged duration of oral iron therapy. Ferric carboxymaltose is a relatively recently approved parenteral iron formulation which can be administered in large doses of upto 1000 mg in a single infusion.

Aims:

The present study describes the efficacy & safety of intravenous ferric carboxymaltose for treatment of iron deficiency anemia in a tertiary institution in India.

Methods:

This non‐randomised prospective study included 77 patients of age ≥ 12 years with confirmed diagnosis of iron deficiency anemia between January 2018 & January 2019. Detailed history was taken & examination performed for signs & etiology of IDA. The cut‐off serum ferritin level for IDA diagnosis was < 15 ng/ml. Pregnant females and patients with concurrent vitamin B12 deficiency were excluded. All patients were treated with Injection Ferric Carboxymaltose (FCM) by I.V. infusion over 30 minutes in day care. Total dose of parenteral iron was calculated according to Ganzoni Formula: Total iron deficit (mg) = 2.4 x body weight (kg) x [target haemoglobin – actual haemoglobin (g/dl)] + 500 mg (depot iron). The maximum dose of FCM administered in a single infusion was 1000 mg. Patients with total iron dose > 1000 mg received two divided doses one week apart. Patients also received oral folic acid at 5 mg/day dose for at least 3 weeks. Appropriate workup for etiology of IDA was performed in all patients. Therapeutic response was assessed after 3 weeks of first FCM dose & was defined as hemoglobin increase of ≥ 2 g/dl from baseline.

Results:

The median age of patients was 33 years (range 16 ‐ 75 years) and majority (78%) were females. The median baseline hemoglobin was 5 g/dl (range 2.0 ‐ 8.6 g/dl). Therapeutic response was achieved in 100% patients. Mean increase in haemoglobin at 3 weeks was 4.2 g/dl (range 2.8 ‐ 5.5 g/dl). One patient had mild headache during FCM infusion. There was no infusion‐related toxicity or any other adverse event.

Summary/Conclusion:

In our study, intravenous ferric carboxymaltose was found to be highly effective & safe alternative to oral iron for treatment of iron deficiency anemia, with excellent patient compliance. It is ideally suited for patients who require rapid replenishment of iron stores.
PB2071 GENETIC VARIATIONS IN TUMOR NECROSIS FACTOR‐RELATED APOPTOSIS‐INDUCING LIGAND RECEPTOR‐1 (TRAIL‐R1) GENE AND THE SUSCEPTIBILITY TO B CELL NON‐HODGKIN LYMPHOMA IN EGYPT
Authors: Khorshied M. , Soliman N. , Bakr S. , Khorshid O.
Published: June 2019

Background:

Apoptosis is essential for normal tissue homeostasis, cellular differentiation and development. Inhibition or blockade of Tumor Necrosis Factor‐Related Apoptosis‐Inducing Ligand‐Receptor 1 (TRAIL‐R1) may alter its apoptotic function, and subsequently provide growth advantage to neoplastic cells. Genetic polymorphisms in TRAIL‐R1 gene were involved with susceptibility to many cancers, however dearth of reports about B‐non‐Hodgkin lymphomas (B‐NHLs) particularly from Arab African nations.

Aims:

To assess the possible association between TRAIL‐R1 ‐A1322G, ‐C626G and ‐A683 C and polymorphisms and B‐NHL risk among Egyptians.

Methods

Genotyping of TRAIL‐R1 ‐C626G, ‐A683 C and ‐A683 C was performed to 100 B‐NHL patients and 150 controls.

Results:

The frequency of polymorphic alleles of ‐A1322G and ‐C626G was higher in B‐NHL compared to controls with almost twofold increased risk of B‐NHL (OR = 2.04; 95%CI = 1.02‐4.07 and OR = 1.76; 95%CI = 1.01‐3.07 respectively), while there was no statistical difference in the distribution of ‐A683 C polymorphic allele (OR = 1; 95%CI = 0.5‐2). Combined genotypes analysis revealed that co‐existence of the three variants conferred fourfold increased risk (OR = 4.1; 95% CI = 1.01‐17.63), while co‐inheritance of ‐C626G and ‐A1322G, and co‐inheritance of ‐A683 C and ‐A1322G conferred fivefold and threefold increased the risk respectively.

Summary/Conclusion:

TRAIL‐R1–C626G and ‐A1322G polymorphisms could be considered as molecular risk factors for B‐NHL in Egyptian population. Furthermore, the growing interest in TRAIL‐based interventions has led to the development of recombinant human TRAIL (rhTRAIL) as a promising target therapy. Accordingly, screening for TRAIL‐R1 gene polymorphisms is mandatory for selecting patients who will gain benefit from this novel therapeutic modality
PB2093 CLINICAL, PARACLINICAL CHARACTERISTICS AND OUTCOME IN ALGERIAN MYELODYSPLASTIC SYNDROMES: A SINGLE CENTER EXPERIENCE
Authors: Talbi T. F. , abbadi M. R. , menouer S. , belakhel S. , djouadi K. , ardjoun F. Z.
Published: June 2019

Background:

Myelodysplastic syndromes refer to a heterogeneous group of clonal diseases affecting the hematopoietic stem cell resulting in qualitative and quantitative abnormalities of the three myeloid lineages. The overall incidence is 03‐05/105 hbts/year without ethnic difference; it increases with age (03‐15/105 hbts/year between 50‐70 years and 15‐50/105 hbts/year> 70 years).

Aims:

we analyzed the characteristics of our patients and we investigated the impact of prognostic factors and parculier comorbidities on their future

Methods

a single‐center descriptive retrospective study, including all MDS diagnosed in the hematology department of military hospital over a 21‐year period (1994‐2014) from patient records. The diagnosis is retained on blood and bone marrow cytology and Perls staining (the karyotype was carried out in a few cases) after exclusion of a vitamin deficiency (ferritin, folate, vitamin B12: dosage or therapeutic test), or associated pathology (thyroid, lever, inflammatory or haemolytic). We have classified our patients according to the WHO classification (2016).

Results:

n = 85 evaluable pts: the clinical, biological and cytological characteristics of patients are summarized in the following table I, the observed comorbidities: cardiovascular d (40%), diabetes (30%), and respiratory insufficiency (29%): more frequent (HR = 1.65, 95% CI = 0.65‐ 3, 66) in men/women and more severe (≥3 points: 12 patients): HR: 4.5: 95% CI: 1, 88‐5) P = 0.012. Patients 65 years and older have a high prevalence of comorbidities (vs young): HCT‐CI score: HR = 0, 19 (95% CI: 0, 023‐0, 89): p = 0.01, with a very negative impact on survival (p = 0.001).

Summary/Conclusion:

the presentation of MDS in our series is similar to that of national and international series with a particularly poor prognosis since this pathology preferentially affects the elderly, with in most cases associated defects making the management very difficult. Immunomodulatory agents could improve the evolution of these patients.

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PB2113 IMPACT OF CLONAL HETEROGENEITY IN COMPLEX KARYOTYPES OF MULTIPLE MYELOMA PATIENTS WITH FIRST LINE BORTEZOMIB‐BASED THERAPY: A SINGLE‐INSTITUTION EXPERIENCE IN BULGARIA
Authors: Angelova S. , Ignatova K. , Ganeva P. , Lozenov S. , Jagurinoski M. , Balatzenko G. , Spassov B.
Published: June 2019

Background:

Multiple myeloma (MM) is genetically heterogeneous with varied clinical outcomes, primarily due to the coexistence of diverse numerical and structural cytogenetic abnormalities (CA). The data about prognostic significance of clonal evolution and cumulative effect of multiple high‐risk (HR) CA in complex karyotypes (CK) of MM patience (pts) is controversially.

Aims:

1) to make cytogenetics profiling of CK in our MM pts with first line bortezomib‐based therapy (BBT); 2) to find relationship between clonal heterogeneity in CK and therapeutic response and OS of our MM pts.

Methods

We examined the cytogenetic features in 78 pts with newly diagnosed MM using conventional cytogenetics and molecular‐genetics (for t(4;14)/MMSET‐IgH) analysis for 5 years (2014‐2018) in SBALHZ–Sofia, Bulgaria. The followed CA were considered as clinically relevant: hyperdiploidy, hypodiploidy, gap 1q, ‐13/13q‐, ‐17/17p‐, t(4;14), t(11;14). OS was calculated using Kaplan‐Meier estimates.

Results:

The CK was occurred in about 38% (30/78) of our pts: in 77% (23/30) with hyperdiploidy and in 23% (7/30) without it. The features of clonal evolution (2 or more aberrant cell clones) were defined in 57% (17/30) CK and predominantly were connected with hyperdiploidy (15/17). The coexistence of 2 or more adverse prognostic CA was defined in 60% (18/30) CK. The proportion of pts with normal karyotype (NK) who achieved CR and VGPR was two and half times more than in pts with CK (16,7% vs 41,7%). The autologous stem cell transplantation (ASCT) was applied at 26,7% (8/30) pts with CK and 31% (15/48) pts with NK. We have not found a statistically significant difference in the OS of our pts with signs of clonal evolution or multiple HR CA in CK compared to other CK pts. Although the mean OS of pts with HR CA or clonal heterogeneity in CK without ASCT was lower than OS of CK pts treated with ASCT, the difference in OS wasn’t statistically significant (19.0 mths vs 25.2 mths, p = 0.419). Only groups that stratified according to Mayo Stratification of Myeloma (with HR CA, intermediate‐risk CA and standard‐risk CA) had a statistically significant OS difference (p < 0,006).

Summary/Conclusion:

We have not found cumulative adverse effect of multiple HR CA or signs of clonal evolution in CK on OS of our MM pts.
PB2114 NEUTROPHILIC LEUKEMOID REACTION ASSOCIATED WITH SMOLDERING MULTIPLE MYELOMA
Authors: Martínez‐Cordero H. , Valdes‐Cespedes J. , Enciso‐Olivera L. , Alfaro‐Acosta L. , Otero D. , Spirko P. , Patiño‐Escobar B.
Published: June 2019

Background:

Chronic neutrophilic leukemia is a rare chronic myeloproliferative neoplasm characterized by splenomegaly, sustained neutrophilia, elevated B12 levels, and negative BCR/ABL translocation. It can be confused with leukemoid reactions in the context of plasma cell neoplasms.

Aims:

To describe the clinical case of a female patient with neutrophilic leukemoid reaction in the context of latent IgA multiple myeloma treated at the National Cancer Institute of Colombia.

Methods

Clinical case report

Results:

We present a 67‐year‐old woman with a history of type 2 diabetes mellitus and rosacea with headache, epistaxis, fatigue, intermittent chest pain, hyperleukocytosis in the hemograma and qualitative negative PCR BCR ABL in peripheral blood. She received treatment with hydroxyurea since January 2016 extra institutionally. Upon admission to our institution a complete bone marrow study was requested confirming the BCR ABL negativity by cytogenetics and JAK2 V617F negative mutational state, however the myelogram showed infiltration by plasma cell disorder with dohle bodies and moderate megaloblastic changes in the myeloid and erythroid series. Bone marrow biopsy was hypercellular with 30% infiltration by abnormal plasma cells. The immunophenotype of the plasmacytic population in flow cytometry revealed a positive population for CD38/CD138/CD56/B2‐m and negative CD19/CD45 with lambda restriction. Protein electrophoresis showed a monoclonal peak in the beta region, immunofixation was positive for lambda IgA, high IgA levels with a value of 3874 mg/dL. No monoclonal component was detected in the urine, including immunofixation. The free light chains in serum showed a monoclonal lambda of 116.52 mg/L, Kappa 11.01 mg/L with a ratio of 10.5. No CRAB component was shown including PET CT without bone or extramedullary lesions. Despite treatment with hydroxyurea, hyperleukocytosis persisted with 47330 cels/ul with neutrophilia (44060/uL). Finally, smoldering IgA lambda high risk multiple myeloma diagnosis was made. She started treatment with lenalidomide and dexamethasone attaining partial response after two cycles and progresive resolution of leukemoid reaction.

Summary/Conclusion:

The neutrophilic leukemoid reaction or a similar clinical picture should alert to the existence of a plasma cell neoplasm. The associated morphological characteristics are usually the toxic granulations and Dohle bodies like in our patient. It is not clear if neutrophilia becomes a factor of poor prognosis in smoldering multiple myeloma, for this reason the risk should be stratified according to existing guidelines. There are still controversies about the need for treatment even in higk risk patients. The fact of being IgA, having a peak greater than 3 grams in SPEP, the ratio of light chains greater than 8 were the high‐risk characteristics seen in our patient that they defined in management.

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PB2115 NRF1‐DEPENDENT PATHWAY: SALVAGE PATHWAY AFTER THE PROTEASOME INHIBITION IN MULTIPLE MYELOMA AND MANTLE CELL LYMPHOMA?
Authors: Fassmannová D. , Sedlák F. , Šašková K. Grantz
Published: June 2019

Background:

Proteasome inhibitors (PI) are compounds with anti‐neoplastic effect in various hematological cancers. Bortezomib, the first FDA approved PI compound, represents the backbone therapy in case of multiple myeloma (in the first line therapy and in relapse) and has proven efficacy in mantle cell lymphoma. However, the resistance to proteasome inhibitor treatment often occurs and limits the possibility of subsequent therapy. The mechanism of resistance to PI is not fully understood. Usually, it is associated with high expression of proteasome subunits or, in some cases, could be caused by mutations in proteasome subunits that hinder the binding site of the inhibitor. One of the homeostasis pathways that regulates the synthesis of proteasome subunits is the nuclear factor erythroid‐derived 2 related factor 1 (Nrf1)‐dependent pathway. Nrf1 is a transcription factor responsible for the regulation of the genes involved in protecting cells from oxidative stress and regulating proteasomal activity. In normal conditions, it is embedded in the membrane of endoplasmatic reticulum, retrotranslocated by VCP/p97 complex to cytosol, deglycosylated and processed by proteasome. However, when proteasome is inhibited, Nrf1 is cleaved by DDI2 protease, becomes active and acts as a transcription factor in the nucleus where it upregulates the synthesis of the proteasome.

Aims:

Evaluation of the roles of individual factors of Nrf1‐dependent pathway under the PI treatment of hematologic neoplasias.

Methods

The cell lines with various sensitivity to PI generated from various hematologic neoplasias (mainly multiple myeloma, mantle cell lymphoma) were treated by several PIs and the levels and forms of the components in the Nrf1‐dependent pathway were measured.

Results:

The presence of the Nrf1‐dependent pathway components in hematologic neoplasia was confirmed. The PI treatment in the majority of cell lines led to the increase of the levels of the activated form of Nrf1 while the DDI2 levels did not significantly change.

Summary/Conclusion:

The activation of the Nrf1‐dependent pathway responsible for the proteasomal units expression after the PI treatment in hematologic neoplasia derived cells suggests that the inhibition of this pathway can improve the sensitivity to PI and might potentially open up new approaches to the PI refractory disease therapy.
PB2129 PRETREATMENT D‐DIMER LEVELS PROVIDE PROGNOSTIC INFORMATION IN PATIENTS WITH MULTIPLE MYELOMA
Authors: Peipei X.
Published: June 2019

Background:

High D‐dimer levels are associated with poor overall survival in patients with general cancer.

Aims:

This retrospective study aimed to investigate the prognostic value of D‐dimer levels in patients with multiple myeloma (MM).

Methods

A total of 214 patients newly diagnosed with MM were retrospectively enrolled. The correlation between pre‐treatment plasma D‐dimer levels and clinical factors was evaluated. The cut‐off value of D‐dimer for predicting survival was set as 0.8 μg/ml based on receiver operating curve analysis. Patients with a D‐dimer level ≥ 0.8 mg/ml had more adverse clinical features, including advanced R‐ISS stage, higher International Myeloma Working Group risk stratification, more abnormal chromosome, and increased serum creatinine level. The prognostic value of d‐dimer levels was explored.

Results:

Patients with a D‐dimer level ≥ 0.8 mg/ml showed poor overall survival (OS) and progression‐free survival (PFS). Multivariate analyses revealed that the D‐dimer levels were independent predictors of OS and PFS (hazard ratio = 10.15 and 0.27, 95% confidence interval = 4.86–21.19 and 0.18–0.42, P < 0.001 and P < 0.001).

Summary/Conclusion:

In conclusion, D‐dimer levels might be considered as a simple and effective prognostic marker in patients with MM.
PB2133 IMPACT OF THE PRE‐TRANSPLANT INDUCTION (PTI) DURATION ON THE SURVIVAL OF PATIENTS WITH MULTIPLE MYELOMA (MM)
Authors: Pereira S. , Sarmento L. M. , Fernandes M. Leal , Brito R. , Monteiro A. , Ferreira G. , Costa F. , de Sousa A. Botelho
Published: June 2019

Background:

The first‐line strategy consensually accepted as the most effective in MM is a triplet PTI followed by autologous hematopoietic progenitor transplantation (AHPT). The proportion of patients eligible for AHPT has been steadily increasing as its safety and efficacy are documented in older patients. In this context, the duration of PTI gains relevance in real life: the standard recommendation of 3‐4 cycles is defined based on the unproven statement that a longer PTI may have negative effects on patient outcome, a conviction recently denied by the evidence published by Chakraborty et. al. (2018). Additionally, the possibility of prolonging PTI, although potentially associated with undesirable toxicity, may be beneficial in improving response depth prior to AHPT and sustain the response until transplantation is possible according to the transplantation center schedule.

Aims:

Evaluate the impact of PTI duration on the 3 month (mo)‐CR rate post‐AHPT, on median progression‐free survival (mPFS) and overall survival (OS) in MM patients transplanted at our center over a 12‐year period.

Methods

Data from 273 MM patients consecutively transplanted after PTI between September 2005 and March 2018 was collected. 104 patients were excluded from the analysis: 75 due to > 12 mo interval from PTI beginning to AHTP, 10 due to > 1 PTI line prior to AHPT and 19 due to missing data.

Results:

We analyzed 169 patients, median age 61 (30‐73), comparing those treated with PTI up to 4c (n = 70) with those subjected to > 4c (n = 99). The proportion of patients with unfavorable ISS, high‐risk cytogenetics, or that received doublet PTI did not differ among the groups. With a median follow‐up of 40mo, the 3mo CR rate post‐AHPT was similar between the 2 groups (41 vs 51%, p = 0.2) as were the mPFS (37 vs 33mo, p = 0.3) and the 5y OS (68 vs 59%, p = 0.1). We also explored the influence of PTI duration in particular subpopulations: high‐risk cytogenetics; VGPR pre‐AHPT; or treated with doublet PTI (vs triplet). No significant differences were found, except for the mPFS in the subgroup treated with VCD (NA vs 27mo, p = 0.02).

Summary/Conclusion:

Our results suggest that a prolonged PTI beyond 4c does not improve post‐AHPT outcomes. These findings are similar to those of the Mayo Clinic study. Nevertheless, the conclusion we find most relevant is that a prolonged PTI, which may be required to deepen pre‐AHPT response or to sustain response up to transplantation, is not more deleterious in terms of PFS and OS.
PB2140 IMPACT OF EXTRAMEDULLARY DISEASE IN THE OUTCOMES OF MEXICAN PATIENTS WITH MULTIPLE MYELOMA
Authors: Vargas‐Serafin C. , Rangel‐Patino J. , Perez‐Samano D. , Acosta‐Medina A. , Ordonez‐Perez I. , Bourlon C.
Published: June 2019

Background:

Extramedullary myeloma (EMM) is the synchronous presence of clonal plasma cells (CPC) at bone marrow and distant sites. Its frequency is reported among 6‐20% of multiple myeloma (MM) patients and manifest as bone‐dependent plasmocitoma (BP) or tissue‐dependent plasmocitoma (TP). Previous reports state a more aggressive clinical course, whether at diagnosis or relapse. There is no data regarding the clinical course and prognosis in Mexican patients with EMM.

Aims:

To analyze and describe the impact of EMM on overall survival (OS) and progression free survival (PFS) of Mexican patients diagnosed and treated at monoclonal gammapathies clinic of our institution.

Methods

Retrospective analysis including >18 year‐old patients with MM diagnosis according to IMWG criteria. EMM was defined as presence of CPC corroborated by immunohistochemistry in BP or TP or demonstration of a synchronous tumor by imaging method and no accessible to biopsy.

Results:

A total of 199 patients were included. Sixty‐three patients had EMM (31.8%), 45 cases (71.4%) presented at diagnosis and 18 (28.6%) at progression. Forty‐eight cases (76.2%) were diagnosed by biopsy and 15 (23.8%) by imaging. Fifty‐four percent (n = 34) cases presented BP and 46% (n = 29) TP. Most frequently involved sites were abdomen (34.5%), thorax (27.6%) and lymph nodes (13.8%) in TP and spine (50%), chest wall (26.3%) and head/neck (13.2%) in BP. EMM was associated with lower comorbidity rate and higher renal failure. Population characteristics are shown in Table 1. Mean PFS and OS was 22.9 and 43.7 months, respectively. EMM at any time of disease resulted on lower PFS and OS (p = 0.03, p = 0.04), while TP showed lower OS (p < 0.01). A higher ECOG PS and lower deep response was associated with worse PFS (HR 1.05‐2.60 (p = 0.03) and HR 0.20‐0.38 (p < 0.01), respectively) while ISS and lower deep response resulted on worse OS (HR 1.0‐2.2 (p = 0.02) and HR 0.37‐0.73 (p < 0.01)) at multivariate regression.

Summary/Conclusion:

A higher EMM rate was found in the studied population. EMM was associated to higher renal failure and low incidence of comorbidities, as shorter PFS and OS, particularly in TP. Identification of this high risk myeloma population allows an attempt for more intensive treatment with intention to improve prognosis.

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PB2180 EXPERIENCE VRD‐PACE‐LIKE REGIMEN IN PATIENTS WITH PRIMARY REFRACTORY MYELOMA FOR PERIPHERAL STEM CELL MOBILIZATION
Authors: Nakastoev I. , Ryzhko V. , Novikova A. , Balzhanova Y. , Grachev A. , Abramova T. , Samtcova M. , Vasilchenkova P. , Danilina A. , Kanaeva M. , Gribanova E.
Published: June 2019

Background:

High‐dose chemotherapy followed by autologous stem‐cell transplant (ASCT) is the current treatment in patients with multiple myeloma (MM). To obtain the effect of ASCT it is necessary to achieve a response to induction therapy. Lenalidomide‐based regimens as the second‐line therapy failed peripheral blood mobilization of CD34+ cells and increase the risk of its inadequate collection. Thus, intensive chemotherapy regimens as VRD‐PACE and its modifications are used to enhance treatment response and effective mobilization.

Aims:

To estimate safety and efficacy of VRD‐PACE‐like regimens for peripheral stem cell mobilization.

Methods

A total of 7 patients with primary refractory multiple myeloma were enrolled in the study. All patients received VRD‐PACE‐like regimens in conventional doses followed by granulocyte colony‐stimulating factor (G‐CSF 10 μg/kg/day) started after reducing leukocytes count ≤ 1.0 × 109/L. As mobilizing regimen in 3 patients was administred VRD‐PACE, 3–RD‐PACE and 1–KRD‐PACE.

Results:

A total of 7 patients with primary refractory myeloma were enrolled in the study. The median age was 51 (range 40–56 years), of them 3 were men. These patients didn’t receive suboptimal response to bortezomib‐based regimens. Therefore, administration of second‐line therapy was required. Patients received in average 6 cycles of chemotherapy (6–10) and three lines of therapy. At initiation treatment with VRD‐PACE only 1 patient had very good partial response (VGPR), 3–partial response (PR), 3–disease progression. One patient with VGPR had adverse cytogenetic abnormalities and for this reason was treated with VRD‐PACE. All patients who received VRD‐PACE‐like regimens achieved decline of serum monoclonal protein, of them 2 obtained VGPR. Mobilization failure was in 2 patients due to inadequate collection of CD34+ cells. Before mobilization each of these patients received only 2 lenalidomide‐based cycles. Afterwards, high‐dose cyclophosphamide‐based mobilization was performed and sufficient amount of CD34+ cells was received. In the others 5 patients CD34+ cells were collected enough for tandem ASCT (6–12.4 × 106/kg). VRD‐PACE‐like regimens were not associated with severe complications. Only 1 patient was diagnosed with parietal thrombosis of the common femoral vein and 1 patient had Herpes labialis. One patient needed packed red cell and platelet transfusion.

Summary/Conclusion:

VRD‐PACE‐like regimens are an effective option for treatment of refractory/relapse MM. We concluded that VRD‐PACE‐like regimens are well‐tolerated and effective option for mobilization of CD34+ cells in patients with suboptimal treatment response or aggressive MM.

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PB2199 MESENCHYMAL STEM CELLS IN PH‐NEGATIVE MYELOPROLIFERATIVE NEOPLASMS: IDLE OBSERVERS OR PART OF THE DISEASE?
Authors: Santoro M. , Di Stefano A. B. , Di Piazza F. , Re J. Lo , Accurso V. , Mancuso S. , Russo A. , Cordova A. , Siragusa S.
Published: June 2019

Background:

Pathogenesis in Philadelphia‐negative Myeloproliferative Neoplasms (MPNs) is surely linked to genomic alterations in Hematopoietic Stem Cells (HSCs), most of all on genes which can carry mutations referred to as driver mutations: JAK2, CALR and MPL. Inflammation, neoangiogenesis and fibrosis are part of the clinical and biological picture of MPNs. Recent studies have hypotized a possible HSC‐independent, active role of the Mesenchymal Stem Cells (MSCs) in the pathogenesis of these diseases.

Aims:

Our aim is to characterize the molecular profile of bone marrow MSCs (BM‐MSCs) of patients with diagnosis of MPNs to explore their possible contribution in the pathogenesis of the disease. In particular, we focused on the study of specific miRNA and mRNA already known in literature to be involved in processes of inflammation, neoangiogenesis and fibrosis in MPNs.

Methods

Primary cultures of BM‐MSCs were obtained from bone marrow samples of patients with diagnosis of MPNs. Genic expression profile was evaluated with Real‐Time Polymerase Chain Reaction compared to mesenchymal human healthy cell line.

Results:

We found that some markers known to be involved in angiogenesis, as miR221, miR20a, HIF‐1a and VEGF, are upregulated in BM‐MSCs of MPNs patients. Regarding bone marrow fibrosis, expression analysis of THSB1, TGF‐beta mRNAs and miR21 in BM‐MSCs highlighted sensible upregulation in all samples, strongly suggesting a possible role of the MSCs in the mediation or induction of the fibrosis process in the bone marrow, in these diseases.

Summary/Conclusion:

Our data suggest a possible role of the BM‐MSCs in fibrosis and neoangiogenesis in MPNs. In subgroup analysis, no significant differences were found between specific diseases (polychythemia vera, essential thrombocytemia, myelfibrosis and MPN‐unclassifiable). Being driver mutations not enough to explain different clinical and histological presentations, it maybe that the study of the pathological MSCs will help comprehend the complex machine of pathogenesis in MPNs and possibly find new targets to develop drugs that may change the natural history of these diseases.
PB2200 PREVALENCE OF JAK2V617F, CALR AND MPL MUTATIONS IN PATIENTS OF MYELOPROLIFERATIVE NEOPLASMS AND SPLANCHNIC VEIN THROMBOSIS IN INDIA
Authors: J.  , Arya V. , Gupta N. , Arora A. , Sharma A. , Kotwal J.
Published: June 2019

Background:

Recurrent somatic mutations in the JAK2, MPL, and CALR genes have been described in patients diagnosed with Philadelphia‐negative Myeloproliferative neoplasms (MPNs), including Polycythemia vera (PV), Essential thrombocythemia (ET) and Primary myelofibrosis (PMF). MPN is also the most common etiology in splanchnic vein thrombosis (SVT). MPNs account for approximately 40% of Budd Chiari syndrome (BCS) and 31% of portal vein thrombosis (PVT).

The present study was aimed at studying the prevalence of JAK‐2V617F, MPLW515L/K and CALR exon 9 mutations in BCR‐ABL1 negative myeloproliferative neoplasms (MPNs) and splanchnic vein thrombosis (SVT) patients. There is paucity of such data in the Indian patients.

Aims:

The study had two aims:

Identification of incidence of JAK2V617F, CALR exon 9 mutations and MPLW515L/K mutations in BCR‐ABL1 negative MPNs in India

Identification of incidence of JAK2V617F, CALR exon 9 mutations and MPLW515L/K mutations in Indian patients of SVT

Methods

A total number of 60 patients of SVT and 59 MPN patients (10 PV, 19 ET, and 30 PMF) were included in the study. The mutation analysis for JAK2V617F, CALR exon 9 and MPLW515L/K mutations were performed using the Allele specific oligonucleotide‐polymerase chain reaction (ASO‐PCR) was used to detect JAK‐2, CALR and MPL mutations.

Results:

Among 59 patients of MPNs and 60 SVT; JAK‐2 mutation was found in 61.0% (36/59) and 23.3% (14/60) respectively. On sub‐classification, JAK‐2 mutation was detected in 80.0% (8/10) of PV; 42.1% (8/19) of ET and 66.7% (20/30) of PMF patients.

All the patients of MPNs and SVT were subjected to CALR mutation analysis. The overall rate of CALR mutations in PMF and ET was 10% (3/30) and 21.0% (4/19) respectively. Limiting the analysis to JAK2V617F negative patients of PMF and ET, it was seen that 30% (3/10) PMF and ∼36.36% (4/11) ET cases were CALR mutated. Of these 7 CALR mutations; L367fs∗46 (type‐1) and K385fs∗47 (type‐2) mutations were found in 5 and 2 patients respectively. MPL mutation was identified in 5.26% (1/19) ET cases. Triple negative ET and PMF were ∼31.5% (∼6/19) and ∼23.3% (7/30) respectively. None of the SVT patients were observed to be CALR mutated and none showed the MPLW515L/K mutations.

Summary/Conclusion:

Indian patients exhibit a lower incidence of CALR mutations in Primary myelofibrosis than that seen in the western literature. However, the incidence of CALR mutations is the same as that reported earlier in Indian patients of Essential thrombocythemia. Triple negative cases constitute 31.5% of all cases of Essential thrombocythemia and 23.3% of Primary myelofibrosis Indian patients show a Testing for CALR mutations and MPLW515L/K mutations in splanchnic vein thrombosis is not justified.
PB2207 EARLY SPLEEN RESPONSE IS A GOOD PROGNOSTIC FACTOR OF RUXOLINIB OUTCOME IN PATIENTS WITH MYELOFIBROSIS
Authors: Lomaia E. , Siordiya N. , Dimov G. , Senderova O. , Mihalev M. , Furtovskaya A. , Ochirova O. , Li O. , Trizna K. , Otmorskaya A. , Sokurova E. , Khazieva A. , Zaritskey A.
Published: June 2019

Background:

Ruxolitinib(RUXO) improves long‐term prognosis in patients(pts) with primary or post‐polycythemia/post‐thrombocythemia myelofibrosis(MF). The most patients experience spleen response. Meanwhile there are a few data how the speed of spleen response in MF affects RUXO treatment outcome.

Aims:

Evaluate prognostic significance of early spleen response on results of RUXO treatment in patients with MF and assess the factors associated with spleen response.

Methods:

In the multicenter real world ptactice study 42 patients (male 18, 43%) with MF and spleen data available at least at 3 months were included. Median age at the time of RUXO initiation was 55(25‐75)yrs. Median time from MF diagnosis to RUXO was 52(2‐346)mos. Median time on RUXO was 29 (4‐81)mos. Spleen response(SR) was assessed by palpation. Median spleen length before RUXO was 19(5‐33 cm) with massive spleen >10 cm in the most pts ‐ 36(86%). Constitutional symptoms had 40(95%) of pts. DIPSS score was low, inter‐1 or inter‐2/high in 1(3%), 23(59%) and 15(38%) of 39 evaluable pts.

Results:

Spleen length reduction at 3mos was: <25% in 13(31%)(Group 1), 25‐<50% in 14(33%) (Group 2) and ≥50% in 15(36%)(Group 3) pts. At 6 mos 3/12(25%) and 3/14(21%) evaluable pts from Gr1 and Gr2 improved their SR. Some more pts from these groups experienced spleen reduction later, but mainly in case of RUXO dose elevation. SR, assessed according to IWG‐MRT criteria, was 13/42(31%) and 17/41(41,5%) in evaluable pts at 3mos and 6 mos, respectively. In all groups a few pts lost their SR. RUXO was stopped in 11(26%) pts, mainly due to disease progression or/and death. Depth of sSR significantly correlated with overall survival. All pts of Gr3 remained alive, whereas 7/29(24%) pts dead in Gr2 and Gr3 overall(p = 0,021). Less pts in Gr3 had huge spleen(>20 cm), blasts 1% or more, low hemoglobin and were treated with low RUXO dose. There were equal symptoms burden in in different groups (Table 1).

Summary/Conclusion:

The majority of pts respond to RUXO. Depth of SR at 3 mos significantly influenced RUXO long term outcome – all pts with >50% of spleen reduction at 3 mos are alive. It seems that pts with higher dose of RUXO, no periferal blasts, less spleen size and higher hemoglobin level are more responded to RUXO. Larger cohort of pts is needed to confirm statistical significance of this data.

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PB2215 HOW TO PREDICT RESPONSE TO RUXOLITINIB IN PATIENTS WITH MYELOFIBROSIS
Authors: Montero M.I. , Reinoso M. , Pérez‐Ortega L. , Márquez F.J. , Rodríguez‐Arbolí E. , Rodríguez N. , Falantes J.F. , Espigado I. , Pérez‐Simón J.A.
Published: June 2019

Background:

Myelofibrosis (MF) is a classical myeloproliferative neoplasm characterized both in its primary and secondary form by splenomegaly, constitutional and disease‐related symptoms as well as by cytopenias. Aberrant constitutive activation of the JAK‐STAT pathway is core to its pathogenesis and the inhibitors of this pathway such as ruxolitinib, approved for MF treatment seven years ago, have been proven effective in a majority of patients.

Aims:

To describe ruxolitinib response and median survival in a group of patients diagnosed with MF in a single center and correlate it with the molecular profile, hematimetric data and previous myeloproliferative neoplasm (polycythemia vera (PV) or essential thrombocytosis (ET)).

Methods:

Of a total of one‐hundred twenty four patients diagnosed with MF in our center, thirty eight patients were treated with ruxolitinib between April 2012 and September 2018. Diagnosis of myelofibrosis was made based on bone marrow examination and according to the updated WHO criteria. Molecular study was carried out in peripheral blood for the mutation JAK2V617F as well as allele‐specific PCR for mutations type 1 and type 2 of exon 9 of calreticulin (CALR) gene, and exon 10 of myeloproliferative leukemia virus (MPL) gene. The prognostic risk stratification was carried out according to the International Prognostic Index (IPSS). All patients treated with ruxolitinib belonged to the intermediate group‐2 or were classified as high risk. Statistical analyses were performed in SPSS 15.0.

Results:

Average age of the group was 63 years (range 36‐88). 58% were males and 42% female. Average leukocyte, haemoglobin and platelet counts at diagnosis were 9,8x10e9/l (1.9‐62), 10.3 g/dl (6‐15.7) and 236x10e9/L (52‐789), respectively. 47% of patients had a previous diagnosis of another MPN (50% PV and 50% ET). JAK2V617F mutation was present in 70.3%, and CARL and MPL mutation in 12.5% and 2.6%, respectively. All patients responded to ruxolitinib although 39% finally lost this response, with a 13% evolution to acute leukemia, 40% of this group being subjected to allogeneic SCT. Currently, 73% of patients are alive. Six‐year overall survival of patients with JAK2V617F mutation was 80% compared to 60% of those with wild‐type mutational status, statistical significance not being reached. Patients with previous MPN also had greater six‐year overall survival (70%) than those with idiopathic MF (56%).

Summary/Conclusion:

Patients with MF with JAK2V617F mutation and previous MPN present a greater duration of response to ruxolitinib than others, probably due to greater inhibition of the preponderant pathogenetic mechanism and the more effective action of the drug on a more differentiated progenitor than in idiopathic MF, although broader studies are required to confirm these results.