bluuebunny/crossref_metadata_2025 huggingface dataset:
The Separate Diagnosis of Hodgkin Lymphoma (HL) and Non-Hodgkin Lymphoma (NHL) In a Single Patient May Not Signify a Common Clonal Origin
Authors: Ganzel Chezi , Pogrebijsky Galina , Krichevsky Svetlana , Neuman Tzahi , Ben-Yehuda Dina
Published: October 2019

Abstract 4824

Background:

HL and NHL have traditionally been considered as two distinct entities. However, there have been reported rare cases of patients that over time develop both diseases. It is an unresolved issue whether the origin of the two diseases is from the same clone. The literature is replete with anecdotal reports but it has never been prospectively or retrospectively evaluated in consecutive patients from a large series. In this study we attempted to retrospectively investigate this phenomenon by reviewing the clinical and molecular aspects of a group of patients who developed both lymphomas. Although not absolutely definitive, a differing gene rearrangement (GR) pattern is currently thought to be highly suggestive of a different clonal origin.

Methods:

Study patients were all patients treated at the Hadassah University Medical Center, Jerusalem, Israel, who developed both kinds of lymphoma throughout their lives and were treated for at least one of the lymphomas during the period 1989–2010. The clinical and pathologic records of these patients were reviewed.

Archival, formalin fixed, paraffin embedded tissue samples from all the patients that had available samples from both diseases were obtained. The rearranged immunoglobulin heavy-chain variable region genes from both diagnoses were amplified by polymerase chain reaction (PCR) and were compared to each other.

Results:

There were 26 patients who presented with two diagnoses. Twelve had HL as the primary disorder and the majority of these (75%) presented with aggressive lymphoma as the second lymphoma. The mean survival from the second lymphoma was 4.06 years. Five patients are still alive. In contrast, in the 11 patients where NHL was the primary disorder, this was usually (82%) of low grade histology. The mean survival in this case was 2.16 years. Four patients are still alive. Three patients were diagnosed concurrently with both diseases.

For 11 patients there were available diagnostic samples for molecular analyses from both diagnoses of HL and NHL. In 6 of these 11 patients gene rearrangement studies were informative providing data for both diagnoses. The same GR was not found in any of the 6 patients.

DLBCL=Diffuse Large B Cell Lymphoma, CLL/SLL=Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, marginal=marginal zone lymphoma, low grade=low grade B cell lymphoma unspecified

Although the numbers are small, these data suggest that it is likely that in the case of two different lymphoproliferative disorders they are of separate clonal origin.

Conclusions:

The development of HL and NHL at different time points should be assumed to be a different biologic disease, until proven otherwise.

Disclosures:

No relevant conflicts of interest to declare.
STIM1 Deficiency Results In Impaired Platelet Procoagulant Activity and Protection From Arterial Thrombosis
Authors: Ahmad Firdos , Stefanini Lucia , Ouellette Timothy Daniel , Greene Teshell K , Feske Stefan , Bergmeier Wolfgang
Published: October 2019

Abstract 485

Platelet activation is a central event in thrombosis and hemostasis. We recently demonstrated that most aspects of platelet activation depend on synergistic signaling by two signaling modules: 1) Ca2+/CalDAG-GEFI/Rap1 and 2) PKC/P2Y12/Rap1. The intracellular Ca2+ concentration of platelets is regulated by Ca2+ release from the endoplasmic reticulum (ER) and store-operated calcium entry (SOCE) through the plasma membrane. Stromal interaction molecule 1 (STIM1) was recently identified as the ER Ca2+ sensor that couples Ca2+ store release to SOCE. In this study, we compared the activation response of platelets lacking STIM1−/− or CalDAG-GEFI−/−, both in vitro and in vivo. To specifically investigate Ca2+-dependent platelet activation, some of the experiments were performed in the presence of inhibitors to P2Y12. The murine Stim1 gene was deleted in the megakaryocyte/platelet lineage by breeding Stim flox/flox mice with PF4-Cre mice (STIM1fl/fl). STIM1fl/fl platelets showed markedly reduced SOCE in response to agonist stimulation. aIIbβ3 activation in STIM1fl/fl platelets was significantly reduced in the presence but not in the absence of the P2Y12 inhibitor, 2-MesAMP. In contrast, aIIbb3 activation was completely inhibited in 2-MesAMP-treated CalDAG-GEFI−/− platelets. Deficiency in STIM1, and to a lesser extent in CalDAG-GEFI, reduced phosphatidyl serine (PS) exposure in platelets stimulated under static conditions. PS exposure was completely abolished in both STIM1fl/fl and CalDAG-GEFI−/− platelets stimulated in the presence of 2-MesAMP. To test the ability of platelets to form thrombi under conditions of arterial shear stress, we performed flow chamber experiments with anticoagulated blood perfused over a collagen surface. Thrombus formation was abolished in CalDAG-GEFI−/− blood and WT blood treated with 2-MesAMP. In contrast, STIM1fl/fl platelets were indistinguishable from WT platelets in their ability to form thrombi. STIM1fl/fl platelets, however, were impaired in their ability to express PS when adhering to collagen under flow. Consistently, when subjected to a laser injury thrombosis model, STIM1fl/fl mice showed delayed and reduced fibrin generation, resulting in the formation of unstable thrombi. In conclusion, our studies indicate a critical role of STIM1 in SOCE and platelet procoagulant activity, but not in CalDAG-GEFI mediated activation of aIIbb3 integrin.

Disclosures:

No relevant conflicts of interest to declare.
A New Pathogenomic Mechanism In FPD/AML by a Constitutional T(16;21) Involving 16p13 ATF7IP2 and 21q22 RUNX1 Loci
Authors: Buijs Arjan , van der Crabben Saskia , van der Zwaag Bert , van Binsbergen Ellen , Poot Martin , de Weerdt Okke , van Gijn Marielle , Nieuwenhuis H. Karel
Published: October 2019

Abstract 4851

Familial platelet disorder with propensity to myeloid malignancy (FPD/AML) is an autosomal dominant disorder characterized by platelet abnormalities and a predisposition to acute myeloid leukemia (AML). FPD/AML is caused by inherited mutations in 21q22 RUNX1. Recent publications by us and others reported on RUNX1 copy number changes as a pathogenomic mechanism next to point mutations in diagnosing FPD/AML. Given the clinical heterogeneity of FPD/AML, the syndrome could be overlooked, and has resulted in the past in stem cell transplantation (SCT) of patients from affected siblings before detection of the inherited RUNX1 mutation.

Here we report on the identification of two novel missense mutations (G143R and Q235X), and a constitutional RUNX1 gene rearrangement as a result of a t(16;21)(p13;q22) as a novel pathogenomic mechanism in FPD/AML. The 16p13 breakpoint was confined to the ATF7IP2 (MCAF1) locus, a transcription factor associated with Sp1, which is involved in myeloid differentiation, and in proliferation in human cancer by epigenetic transcriptional control of Sp1-dependent maintenance of telomerase activity. This is the first report on genomic involvement of the ATF7IP2 locus in cancer. We will discuss ongoing studies to molecularly identify the breakpoints.

Our data indicate that in diagnosing FPD/AML FISH has to be performed for structural abnormalities along with sequencing and copy number analysis of RUNX1. Furthermore, this is the first report on a constitutional chromosome translocation with an oncogene rearrangement as a pathogenomic mechanism in a hematological malignancy.

Disclosures:

No relevant conflicts of interest to declare.
Some Leukemia Cells Are Dependent on Glutamine as Energy Source
Authors: Miwa Hiroshi , Shikami Masato , Imai Norikazu , Suganuma Kazuto , Goto Mineaki , Mizuno Shohei , Takahashi Miyuki , Nitta Masakazu
Published: October 2019

Abstract 4861

In cancer cells, glucose uptake is elevated and glycolysis persists even under aerobic conditions (Warburg effect). Glutamine metabolism is another target for alteration in cancer development. Glutaminolysis (catabolism of glutamine to generate ATP) is known to increase in tumors. We examined the dependency of the leukemia cells (Kasumi-1, THP-1, HL-60 and NB4) on glucose or glutamine by measuring the growth (MTS count) in glucose- or glutamine-deprived condition. Glucose withdrawal greatly suppressed the growth of all 4 cell lines. However, glutamine withdrawal showed different growth suppressive effects among the cell lines (Kasumi-1: 55% of control, THP-1: 60%, HL-60: 39%, NB4: 70%). HL-60 was most sensitive to glutamine deprivation. The growth suppression of HL-60 due to glutamine withdrawal was partially rescued by oxaloacetate (OAA), a TCA cycle metabolite, while the growth of other cell lines was not rescued by OAA. In the course of glutamine catabolism, ammonia is liberated. Although basal level of the ammonia concentration was not so different among each cell line, glycolysis inhibitor (2-deoxyglucose) treatment enhanced the ammonia generation in HL-60 (Kasumi-1: 2.8% increased, THP-1: 1.7%, HL-60: 6.1%, NB4: 2.8%). Glutaminase, an enzyme converting glutamine to glutamate, is most abundantly expressed in HL-60 in western blot analysis. In addition, HL-60 was most sensitive to the treatment with aminooxyacetate, an inhibitor of glutamate-dependent transaminases that convert glutamate into a-ketoglutarate in the glutaminolytic pathway (Kasumi-1: 86% of control, THP-1: 97%, HL-60: 79%, NB4: 83%). Taken together, HL-60 was considered as glutamine dependent cell line. Therapies targeting glutamine metabolism, such as glutamine depletion or use of inhibitor of glutaminolytic pathway, might be effective against some leukemia.

Disclosures:

No relevant conflicts of interest to declare.
Acute Tumor Lysis Syndrome. Modulation of Cyclooxygenase-2, Alpha V Beta Integrin and Microsomal Prostaglandin E Synthase-1 In Human Immunodeficiency Virus-1 (HIV-1) Squamous Cell Carcinoma (SCC) of the Penis with Selenomethionine/Nsaids
Authors: McPherson Eugene
Published: October 2019

Abstract 4880

Invasive squamous cell carcinoma of the penis overexpress Cyclooxygenase-2 (cox-2), Microsomal Prostaglandin E Synthase-1 and Alpha V Beta Integrins. Trace minerals selenium (selenomethionine) is deficient in many neoplasia conditions especially SCC of the penis in HIV-1 patients. Selenium, an essential trace element, has been shown to inhibit tumorigenesis. Hence, selenium and arachidonic acid metabolism may be linked to SCC. Penile cancer (SCC histology) displays elevated COX-2 and PGE2 can be regulated by selenium supplementation.

We present a 47 We present a 47 yo male with HIV-1, CD4-133/cumm, VL of 95,000 copies/ml with T4 advanced stage SCC of the penis post XRT, surgical skin graft with extensive lymphedema, pain and KPS score of 40–50%. CT scan of Abdomen/Pelvis was c/w extensive disease of his right inguinal region, bladder compressed and displaced into left pelvis and tissue massof the right and left groin with ill defined nodular densities within RLL and left hepatic lobe. Bone marrow was hypocellular, M:E ratio of 8:1 with foamy macrophages. When treated for selenium deficient level and pain with selenomethionine and COX-2 inhibitor, acute tumor lysis syndrome developed with hyperkalemia, hyperuricemia and hypocalcemia defervesing with aggressive therapy with hydration, alkalinization and allopurinol.

Conclusion:

Overexpression of COX-2, mPEGS-1, alpha V beta integrin leads to phenotypic changes in epithelial cells that could enhance tumorigenesis. Selenium supplementation and COX-2 inhibition may help regulate COX-2 alternating cellular adhesion and promote apoptosis in SCC of the penis and upon treatment of these HIV-1 patients, with heavy tumor burden, tumor lysis syndrome along with disease Invasive squamous cell carcinoma of the penis overexpress Cyclooxygenase-2 (cox-2), Microsomal Prostaglandin E Synthase-1 and Alpha V Beta Integrins. Trace minerals selenium (selenomethionine) is deficient in many neoplasia conditions and PGE2 can be regulated by selenium supplementation. especially SCC of the penis in HIV-1 patients. Selenium, an essential trace element, has been shown to inhibit tumorigenesis. Hence, selenium and arachidonic acid metabolism may be linked to SCC. Penile cancer (SCC histology) displays elevated COX-2.

Disclosures:

No relevant conflicts of interest to declare.
Does Upfront Therapy with Fludarabine Increase the Risk of Histological Transformation In Patients with Follicular Lymphoma?
Authors: Yaqub Sobia , Gress Todd W. , Ballester Oscar
Published: October 2019

Abstract 4885

Introduction:

Fludarabine has been reported to increase the incidence of relapse and histological transformation in chronic lymphocytic leukemia (Thornton PD, Leukemia research, 2005) and Waldenstrom macroglobulinemia (Leleu X, J Clincal Oncology, 2009). The purpose of our study was to investigate the role of Fludarabine and the risk of transformation and relapse in follicular lymphoma (FL).

Patients and Methods:

This is a retrospective single institution study. We included 50 patients consecutively diagnosed with FL Grade I and II based on WHO classification of lymphoid malignancies. Grade III patients were excluded from the study. Median follow up is 2.86 years. Patients were grouped according to the initial therapy chosen by their treating physicians: Group 1(n=14) included patients on observation and radiation therapy, Group 2 (n=6) included patients on Fludarabine based regimens, Group 3(n=13) included CVP-R and other rituximab regimens and Group 4(n=17) included R-CHOP. Data collected included time to the onset of biopsy proven transformation, time to relapse, mortality and overall survival. Level of significance was set at <0.05.

Results:

Median age of the patients was 56.5 and it was not significantly different for the various groups. High risk FLIPI score was seen in 66% of patients treated with Fludarabine regimens as compared to 61% of R-CHOP treated patients. Overall, relapse occurred in 38% patients and transformation occurred in 16% patients during the follow up period. Fludarabine treated patients had the highest relapse rate: 50% (p=0.03). R-CHOP group has lowest relapse rate: 11%. Transformation rate was highest in the Fludarabine group: 33%, as compared to 13% to 17% in other groups (p=0.10). Mortality rate was 7% in group 1, 16% in group 2, 23% for group 3 and 5% in group 4 (p=0.44). Time to relapse/progression in group 1 was 2.9 years; in group 2 was 2.1 years; in group 3 was 2.7 years and in group 4 was 5.8 years.

Conclusions:

In our study, Fludarabine treated patients appear to be at higher risk for relapse and transformation compared to patients treated with R-CHOP. The differences can not be explained on the basis of known prognostic factors such as age or FLIPI score. The retrospective nature of the study and the small numbers of patients preclude more definitive conclusions. Further research is needed with large number of patients.

Disclosures:

No relevant conflicts of interest to declare.
Treatment of Sezary Syndrome with Combined Therapy
Authors: Corinaldesi Giorgio
Published: October 2019

Abstract 4928

The Sezary syndrome (SS) is an erythrodermic cutaneous T-cell lymphoma with a leukemic component and lymphadenopathy, characterized by atypical T-lymphocytes, and a CD4 + T-helper/memory; these cells may express the markers CD45RO, and CD25 with frequent loss of the CD26, CD7, CD2, CD3, and with cerebriform nuclei.

The strategies for patients with SS in early stage, when the disease is limited to the skin, includes topical therapies with corticosteroids (clobetasol), carmustine, retinoids (bexarotene, tazarotene) and phototherapy with PUVA (psoralen and ultraviolet light), in the refractory or relapsed patients polychemotherapies (CMED/AB, Pegylated liposomal doxorubicin, gemcitabine) may reduce tumor burden, as well as the symptoms, and most interestingly, it may delay tumor progression and preserve significantly the quality of life; the most typical approach might be constituted by a high dose of chemotherapy followed by allogenic bone marrow transplantation.

We have studied 2 patients with advanced stage IIB. One of them was a 52-year old patient (T3, NP0, M0, B0), and the other one was a 62-year old patient (T3, NP1, M0, B1); both of them were treated with the following drug-combination: bexarotene 150 mg os daily, and vorinostat 400 mg os once daily, and localized treatment with clobetasol. This scheme had a significantly high clinical response and little side effects (fatigue, lethargy, thrombocytopenia, headache), and the patients remained in remission the first for 4 years DFS and the latter for 3 years DFS; both of them were initially treated with PUVA, MTX 50 mg, and INF-alfa 3 MU per day.

Disclosures:

No relevant conflicts of interest to declare.
Clinical Safety of Long-Term Intravenous Itraconazole for the Treatment of Invasive Fungal Infection In Severely Ill Patients with Hematological Malignancies
Authors: Xie Yaping , Qian Shenxian , Gao Daquan , Huang Xilian , Shi Pengfei , Chen Kuang , Tan Junfeng , Liu Lirong
Published: October 2019

Abstract 4943

The clinical safety of intravenous itraconazole use exceeding 14 days is unknown. However, many cases need further treatment, but the absorption of itraconazole oral in severely ill patients is variable and unpredictable. Gastric acidity and food influence the absorption of oral formulation. The intravenous formulation, on the other hand, achieves adequate blood levels more rapidly and its bioavailability is predictable and invariable compared to the oral formulation. We performed this study to investigate the clinical safety of long-term intravenous itraconazole for the treatment of invasive fungal infection (IFI) in severely ill patients with hematological malignancies. 20 patients (median age, 70 years; range, 38–82 years) with hematological malignancies who had met the IFI inclusion criteria were enrolled. All the infection sites were the lung. These patients were given intravenous itraconazole for 14 days. There were significant effective but the lesions were not fully absorbed and no severe adverse events were found. So the long-term intravenous itraconazole therapy was enabled. Clinical efficacy and adverse events were recorded. Itraconazole 200 mg via intravenous infusion (administered over 1 hour) twice a day for 4 doses followed by 200 mg once a day until the lesions was fully absorbed. The treatment median time was 27(18-58) days. During this period, closely monitor changes in vital signs, chest CT, liver enzymes, renal function, electrocardiogram and electrolytes were assessed. We found that the patients achieved composite endpoints including survival, defervescence and undetectable lesions, except one patient died of primary disease - acute myeloid leukemia. Treatment-related adverse events were found in 7 patients (35%) during the study and none of them were severe adverse events. Such as hypokalemia (10.0%), gastrointestinal disorders (10.0%), elevation of liver enzymes (10.0%) and pleural effusion (5.0%). All the adverse events occurred during the first two weeks of the treatment and no significant exacerbation in the following days.

In conclusion, long-term intravenous itraconazole therapy was effective for IFI and the drug-related adverse events have been shown to be generally predictable and manageable.

Disclosures:

No relevant conflicts of interest to declare.
Concomitant Usage of Rasburicase and Allopurinol May Augment Toxic Epidermal Necrolysis Syndrome TEN
Authors: Jajeh Ahmad
Published: October 2019

Abstract 4949

Rasburicase is used succesfully in conjunction with Allopurinol in the tratment and prevention of tumor lysis syndrrome. Rasburicase is a recombinant form of urate oxidase, which is an enzyme present in primates but not humans and convert uric acid to allantoin, which is five to ten time soluble than uric acid. This abstract represent our experience in four males patients, mean age is thirty five years, two with Acute Lymphoblastic Leukemia ALL and two patients with Burkitt's Lymphoma. Three patients has successful outcome in the treatment with Rasburicase followed by allopurinol. Only one patient with Burkitt's Lymphoma arising from congenital combined immunodeficiency syndrome who developed fatal Toxic Epidermal Necrolysis syndrome TEN. TEN is a relatively rare incidence and can be deadly. The mechanism of action is different for both drugs. In this patient Rasburicase was used initially with excellent reduction of uric acid levels, then patient was put latter on allopurinol. The TEN syndrome appeared after three days of initiating the drug and progressed rapidly. High dose Methotrexate and sever neutropenia may contributed to the fast progression and not respoding to steriods after allopurinol was stopped. Since this patient has combined humoral and cellular immunodeficiency with no recent administartion of immunoglobulins therapy, it is difficult to explain the allopurinol reaction based on any type of immune response, particulary type IV hypersensitivity reaction.

In conclusion: This particular case may draw the light on Rasburicase possible role in contribution or augumentation of TEN syndrome induced by allopurinol.

Disclosures:

No relevant conflicts of interest to declare.
A 2-Year Single Center Experience of Decitabine Treatment for the Patients with MDS and CMML
Authors: Yi Jun Ho , Jung Chul Won , Kim Dong Hwan (Dennis) , Kim Kihyun , Jang Jun Ho
Published: October 2019

Abstract 4952

Purpose:

Decitabine is effective to MDS and CMML patients. However few long term follow up data has been reported. We report a 2 year, single-institutional data of decitabine treatment in patients with MDS and CMML.

Patients and Methods: Patients were treated with decitabine 20 mg/m2 by IV infusion daily for 5 consecutive days every 4 weeks. Bone marrow examination was performed every 2 cycles. The response was evaluated according to IWG 2006 criteria.

Results: Fifty-four patients were evaluated. The median age was 63.5 years (range, 23–80) and the median cycle was four. (range 2–15). Among 54 patients, 13 were complete responses(CR), 1 partial response, 10 marrow CRs(mCR), 6 hematologic improvements, respectively. The overall response rate was 44.3% and overall improvement rate was 55.6% which included six patients with hematologic improvement. Among responders, 28 (93.4%) patients showed response at least in two cycles. Out of 18 patients with intermediate or poor cytogenetic abnormalities, only one patient had demonstrated cytogenetic CR. Out of total 326 cycles, 24 events of febrile neutropenia, nine events of bacterial pneumonia, eight events of fungal pneumonia, four events of bleeding and two events of hepatic dysfunction were occurred, and most complications were medically manageable. 10 out of 13 CR patients were maintained CR with decitabine treatment. The median overall survival duration was 20.2 months (95% CI 14.6 – 25.8). Stopping decitabine treatment had led to leukemic progression within 3 to 5 months in four patients who had achieved mCR and three patients who had achieved CR.

Conclusion: Five day scheduled decitabine treatment demonstrated rapid and durable response in patients with MDS. However, even after achieving clinical response, keeping decitabine treatment seems to be necessary to prevent leukemic progression. Further study for role of maintenance therapy is needed.

Disclosures:

No relevant conflicts of interest to declare.
Expression of CD123 and CD114 on the Bone Marrow Cells of Patients with Myelodysplastic Syndromes
Authors: Shao Zonghong , Yue Lanzhu , Fu Rong , Wang Huaquan , Li Lijuan , Hu Haoran , Fu Lin
Published: October 2019

Abstract 4966

Background

Recent studies have shown that interleukin-3 receptor α(CD123) is highly expressed on leukemia stem cells of patients with acute myeloid leukemia, and is correlated with tumor load and poor prognosis. The expression of CD123 may also be high in patients with myelodysplastic syndromes (MDS). In this study, the expression of CD123 as well as granulocyte colony stimulating factor (G-CSF) receptor (CD114) on the bone marrow cells of patients with MDS was investigated in order to explore the molecular marker of the malignant clone of MDS.

Methods

Forty-two patients with MDS, who were diagnosed in the hematological department of General Hospital of Tianjin Medical University from 2008 to 2009, and twelve normal controls were enrolled in this study. FACS was used to measure the expression of CD123 on CD34+CD38- cells and CD114 on CD34+ cells of the bone marrow of these patients and controls and the clinical significance was analyzed. The expression of CD114 on CD123+CD34+CD38- cells was further measured to explore the molecular marker of the malignant clone in MDS.

Results

The ratio of CD34+CD38-/CD34+ in the bone marrow cells of MDS patients was [(14.03±5.27)%], significantly higher than that of normal controls [(7.70±4.36)%] (P<0.01); The ratio of CD123+CD34+CD38-/CD34+CD38- in the bone marrow cells of MDS patients[(48.39±28.15)%]was significantly higher than that of normal controls [(8.75±11.71)%] (P<0.01), and was significantly positively correlated with the proportion of bone marrow blasts(r=0.457, P<0.05). The ratio of CD114+CD34+/CD34+ in the bone marrow cells of MDS patients [(33.05±21.71)%] was lower than that of normal controls [(38.99±19.07)%], but with no significance(P>0.05). The expression of CD114 on CD123+CD34+CD38-cells [(34.82±29.58)%] was significantly lower than that on CD123-CD34+CD38-cells [(53.48±27.41)%] of MDS patients (P<0.05).

Conclusions

MDS patients displayed higher proportion of CD34+CD38-/CD34+ than normal controls. CD123 was highly expressed in the bone marrow of patients with MDS, significantly correlated with the proportion of bone marrow blasts, thus might be the marker of MDS malignant clone. CD123+CD34+CD38-cells exhibited lower expression of G-CSF receptors, which might partly explain why MDS clone responsed worse to G-CSF in vitro and in vivo.

Disclosures:

No relevant conflicts of interest to declare.
Activated Protein C Resistance (APC-R) Analyzed as a Continuous Variable Is Significantly Decreased In Patients with Multiple Myeloma (MM) Compared to Normal Individuals
Authors: Berno Tamara , Boucher Kenneth , Zhan Fenghuang , Fink Louis M. , Tricot Guido J. , Mughal Benjamin , Zangari Maurizio
Published: October 2019

Abstract 4988

Background:

Increased risk of venous thromboembolism (VTE) has been described in multiple myeloma (MM) patients, particularly when exposed to immunomodulatory drugs. Epidemiological studies have showed that monoclonal gammopathy of undetermined significance (MGUS) patients also have an increased risk of VTE compared with normal subjects. Acquired activated protein C resistance (APC-R) is an independent risk factor for VTE in hematologic malignancies.

Methods:

We reviewed the records of patients with MM and MGUS for APC resistance by PREFAKIT APC-R test. We excluded from the analysis patients with a documented Factor V Leiden mutation. The PREFAKIT APC-R is a plasma-based functional clotting assay based on the ratio of patient clotting time with and without APC which is standardized and reported as normalized ratio (normalized to results obtained on pooled normal plasma which is performed on each run).

Results:

APC-R results from 33 MGUS and 75 MM patients were compared with 39 normal subjects. The median APC-R for MM, MGUS and normal subjects were 1, 1.05 and 1.1 respectively. MM patients compared to normal subjects, had significantly lower APC-R (P = 0.0016). No significant difference was observed between MGUS and normal subjects (P= 0.11) (Figure 1). Baseline characteristics from the three groups were similar in terms of age, sex, and performance status.

Conclusion:

APC-R measured as continuous variable shows a statistically significant decrement in patients with paraproteinemias compared to normal subject and correlates to the underline hypercoagulability observed in patients with MGUS and MM.

Disclosures:

No relevant conflicts of interest to declare.
Direct Myeloma Cell Invasion as One of the Major Causes of Renal Impairment In Myeloma A Pathological Analysis of Renal Findings In 41 Autopsied Cases
Authors: Tagashira Amane , Takano Junichiro , Hagiwara Shotaro , Mochizuki Makoto , Endo Hisako , Hirai Risen , Tanimura Akira , Takeshita Masataka , Murakami Hirokazu , Miwa Akiyoshi
Published: October 2019

Abstract 5001

Background:

Renal insufficiency is one of the main complications in myeloma patients. Various causes were reported to be responsible for renal damage. Through analysis of an autopsied cases we would show the diversity of the renal diseases in myeloma.

Methods:

We studied 41 autopsied myeloma cases from 1979 to 2008 at the National Center for Global Health and Medicine. The kidneys were evaluated by light microscopy using hematoxilin-eosin-stained sections, as well as Congo-red stain when amyloidosis was suspected.

Results:

There were 21 men and 20 women. Mean age at autopsy was 64.5 years old. The most common lesion was cast nephropathy (41.5%). The giant cell invasion was found in 35.3% of patients with cast nephropathy. Plasma cell tumor involvement was detected in 29.3% of all 41 autopsied cases. Fourteen per cent of cases had both cast nephropathy and plasma cell tumor involvement. In 75.6% of the patients, arteriosclerosis was found. In addition, 32% of the patients had the glomerular sclerosis which involved more than 20% of the glomerulus. Other findings include acute tubular necrosis (31.7%), AL-amyloidosis (19.5%), renal calcification (17.1%), bacterial and fungal infection (7.7%), micro thrombo-embolism (7.7%), mesangial proliferation (4.9%). At least one of above findings were detected in all cases and combined findings were detected in 65.9% cases.

Conclusion:

We evaluated the renal manifestations in 41 autopsied cases in detail. In all cases, at least one pathological finding was detected. Cast nephropathy was the most common renal manifestation. However, direct myeloma cell invasion was found in 29.3% and combined pathologic findings were common.

Disclosures:

No relevant conflicts of interest to declare.
Evaluation of Serum Free Light Chains In Chinese Multiple Myeloma Patients
Authors: Fu Chengcheng , Qu Shiqiang , Depei Wu
Published: October 2019

Abstract 5011

Purpose:

Serum Free-Light Chain (sFLC) Assay is a sensitive tool recently used for diagnosis and response assessment of plasma cell disorders, especially in light chain multiple myeloma, nonsecretory multiple myeloma and primary amyloidosis. According to assemble analysis of multiple large-scale clinical research results, guideline of sFLC analysis was introduced by IMWG in 2008. But sFLC assay has not been routinely used in China and the clinical significance of the item has been explored in this study.

Patients and Methods:

Serum specimens from 36 cases of MM patients identified by IFE were analyzed. The median age was 56.2(36-74). 24(66.7%) patients were male. The M protein type was IgG in 50%, IgA in 22%, IgD in 3%, light chain in 25%. According to D-S staging, 11% pts was inIIA, 58% in IIIA, 31% in IIIB. 8% patients was in±of ISS staging, 17% inII and 75% in III. Normal range for FLC measurements is as follows: κ3.3–13.1 mg/L, λ5.7–26.3 mg/L, and κ/λ ratio of 0.26–1.65.

Results:

Abnormal rFLCs were detected 100% in 14 newly-diagnosed patients. 86% patients had measurable disease. In κ-MM patients, levels of sFLC-κ were (553.1±471) mg/L; sFLC-λ were (14.2±4) mg/L; the median of rFLC was 32.62. In λ-MM patients, levels of sFLC-κ were (5.3±2.67) mg/L; sFLC-λ were (2503±1043) mg/L; the median of rFLC was 0.002.

22 MM patients were detected during the follow up after treatment. Abnormal clonal rFLC could be found 100% in 3 PD patients, 66.7% in 12 PR/SD patients and 0 in 7 ≥VGPR patients. There was no statistical significance between sFLC and sTLC (p≥0.05). The value of iFLC in ≥VGPR group was statistical different from other response assessment groups (p<0.05). In 24 patients with measurable disease (9 with κ-MM,15 with λ-MM), an elevated level of iFLC was associated with increased myeloma cells in bone marrow and β2-microglobulin, but not with ALB, LDH.

Conclusions:

sFLC assay is a highly sensitive diagnostic and response monitoring tool for multiple myeloma. An elevated level of iFLC was associated with increased myeloma cells in bone marrow and β2-microglobulin, but not with ALB, LDH in measurable disease. More patients and longer follow-up are needed to further evaluate the diagnostic and prognostic significance of this judgment parameter.

Disclosures:

No relevant conflicts of interest to declare.
PTH- PTHR1 Axis Control on Anti-Myeloma Effect of Proteasome Inhibitors
Authors: Zangari Maurizio , Xiao Fang , Yang Ye , Xu Hongwei , Tricot Guido J. , Zhan Fenghuang
Published: October 2019

Abstract 5017

Multiple myeloma (MM) is a plasma cell malignancy with high osteolytic capacity and impaired bone formation. Our recent studies have demonstrated that PTH serum increases are associated with Bortezomib responses in multiple myeloma patients, indicating a possible role of PTH in anti myeloma effect of Bortezomib. We first tested the 5TGM1 cell line for sensitivity to bortezomib, PTH, and [TYR34]bPTH-(7-34) bovine (a specific PTHR1 inhibitor) in various combinations. In an in vitro study, 5TGM1 cells were sensitive to cytotoxicity of bortezomib and PTH in a dose dependent fashion. TYR compound was found to have no effect as single agent on 5TGM1 cell survival, but was able to partially block the inhibitory effect of bortezomib on cell growth (Figure 1). In an in vivo study using the 5TGM1 C 57BL/KaLwRijmice, we tested PTH-PTHR1 axis on bortezomib anti-myeloma activity. As shown in Figure 1, mice survival was positively affected by bortezomib administration (P = 0.04), and the combination of PTH + bortezomib showed a trend to further improve survival (P = 0.09). Interestingly, the concomitant use of [TYR] compound with bortezomib completely abrogated the efficacy of the proteasome inhibitor on survival. Tumor burden assessed by M-protein levels decreased consistently in mice treated with bortezomib alone, PTH alone, or a combination of PTH + bortezomib compared with the control group treated with PBS (P = 0.003, P = 0.05, P = 0.01 respectively). Importantly the tumor burden in the mice treated with bortezomib was significantly lower than in mice treated with bortezomib plus the PTH inhibitor (TYR), again indicating that the PTHR inhibitor abrogates the effect of Bortezomib on tumor growth. Similar results were obtained using the same systems for other commercially available proteasome inhibitors. Thus, we conclude that the PTH- PTHR1 pathway appears essential for proteasome inhibition activity in myeloma. Our observations may lead to novel treatment approaches in myeloma.

Disclosures:

No relevant conflicts of interest to declare.
A New Induction Combination Therapy (ThalDoDex) for Multiple Myeloma. Preliminary Results of a Phase II Study
Authors: Sammassimo Simona , Agazzi Alberto , Bassi Simona , Calabrese Liliana , Bertazzoni Paola , Vanazzi Anna , Gardellini Angelo , Gigli Federica , Andreola Giovanna , Martinelli Giovanni
Published: October 2019

Abstract 5030

Treatment for multiple myeloma is dramatically changed over the past 5 years. Thalidomide containing regimen is now widely accepted as standard treatment for multiple myeloma in first line. The mechanism of action and the toxicity profile of Thalidomide, make this drug suitable for combination with chemotherapeutic agents.

We report clinical results in terms of efficacy and safety of an antracycline containing regimen [liposomal doxorubicin (Myocet), Dexamethasone and Thalidomide (ThalDoDex)] In multiple myeloma before autologous transplantation.

From June 2007 to June 2010, ThalDoDex was delivered to 28 previously untreated multiple myeloma patients. Median age was 59 years (range 42–71); 5 patients were staged IIA and 21 patients staged IIIA and 2 IIIB; 15, 8 and 5 patients were ISS I, II, III respectively. Fifteen patients presented IgG monoclonal immunoglobuline, 6 IgA, 5 patients light chains myeloma, 1 patient plasma cell leukaemia and one other secretory multiple myeloma. Treatment schedule was as follows: Thalidomide 100 mg/day for 14 days then 200mg/day until the end of induction; Dexamethasone 40 mg days 1à4; Liposomal Antracycline (MYOCET) 50 mg/sqm day 1 for 4 cycles at 4 weekly intervals. LMWH 100UI/kg/day was added to all patients for DTV prophylaxis. All patients were considered for a peripheral blood stem cell transplantation program according to age and clinical outcome.

Twenty-five patients are evaluable for response. Fifteen patients (60%) achieved a CR (1 pt) or a nCR (5 pts), or a VGPR (9 pts) with an overall response rate of 80% (CR, nCR, VGPR, PR).

Six patients developed transient febrile neutropenia which solved with antibiotics. During neutropenia two patients developed pneumonia treated with appropriate antimicrobial therapy. No major haematological toxicity was observed. No neurological toxicity or thrombotic event was reported.

Our experience suggests that ThalDoDex is effective and safe as induction phase in newly diagnosed multiple myeloma patients. The clinical results are similar to those reported with other Thalidomide containing regimens. Liposomal doxorubicin in combination with Thalidomide and steroid may induce an important rate of CR and nCR as requested for the best clinical result of subsequent autologous transplant procedure. Our combination regimen avoiding alkylating agents and proteosome inhibitors may deserve the use at eventually subsequent relapse.

Disclosures:

No relevant conflicts of interest to declare.
Acute Myeloid Leukemia Cells Fuse with Vascular Endothelium
Authors: Masri Azzah Al , Goldman Devorah C , Asbaghi Steven A. , Clark Hilary A. , Leon Ronald P. , Liu Qiuying , Hickey Raymond D. , Grompe Markus , Kurre Peter , Fleming William H
Published: October 2019

Abstract 504

The hematopoietic niche supports both normal and malignant hematopoiesis. We have evaluated the functional interactions between leukemic cells and the endothelial cell component of the hematopoietic niche. Highly enriched populations of circulating human acute myeloid leukemia (AML) cells were obtained by therapeutic leukapheresis. These primary AML cells rapidly homed to and associated with pre-existing vascular tubes in vitro. Co-culture of human lung microvascular endothelial cells (HLMVEC) with AML cells both inhibited AML apoptosis by ∼50% (p <0.005) and significantly increased AML cell number (p<0.01), indicating an important supportive effect of the endothelium on AML growth. A direct pro-angiogenic effect of the AML cells was revealed by the induction of vascular tube formation by HLMVECs in co-culture. Screening of known angiogenic factors showed an induction of GCSF expression and an increase in IL-6 levels in AML and HLMVEC co-cultures. Together, these findings indicate a mutually supportive, functional interaction between AML cells and endothelium in vitro. To evaluate the interactions of AML and vascular endothelium in vivo, primary human AML cells were transplanted into NOD/SCID IL2Rγ null mice. In highly engrafted mice (>50% human AML cells in the bone marrow) we observed leukemic infiltration into the perivascular region of both large and small vessels of the mouse liver, and AML cells were frequently integrated into the vascular endothelium. Confocal microscopy surprisingly revealed the co-expression of human CD45 and the mouse endothelial cell marker CD31. To evaluate these apparently fused leukemia/endothelial cells further, single cell suspensions from the livers of mice engrafted with AML cells were FACS sorted based on the co-expression of human CD33 and mouse CD31. Multiplex PCR analysis of single hCD33+/mCD31+ cells verified the presence of both mouse genes (fah and tspy or D2Mit206) and human genes (flt3 and tty-15). The presence of the patient specific, leukemia-associated Flt3-ITD mutation confirmed that fusion occurs between malignant cells and vascular endothelium. AML and endothelial cell fusion was also confirmed by interphase fluorescent in situ hybridization (FISH) with species specific centromeric probes. In conclusion, the results from this study indicate that the functionally important cross-talk between normal hematopoietic stem/progenitor cells and vascular endothelium extends to malignant hematopoiesis. The fusion of primary AML cells with normal endothelial cells raises the possibility that vascular endothelium may serve as a reservoir for occult leukemia.

Disclosures:

No relevant conflicts of interest to declare.
Small Compound 6-O-Angeloylplenolin Induces Mitotic Arrest and Exhibits Therapeutic Potential In Multiple Myeloma
Authors: Liu Ying , Chen Xiaoqin , Cheng Yongxian , Zhou Guangbiao
Published: October 2019

Abstract 5043

Multiple myeloma (MM), the second most frequent hematological malignancy that remains incurable, is a disease of cell cycle dysregulation and loss of apoptotic control. Here we report that 6-O-angeloylplenolin (6-OAP), a sesquiterpene lactone extracted from Centipeda minima L. (Compositae), suppresses the proliferation of drug-sensitive and drug-resistant cell lines and primary CD138+ MM cells, but does not affect normal peripheral blood mononuclear cells. 6-OAP caused mitotic arrest, accompanied by upregulation of cyclin B1 and downregulation of phospharylated Cdc2, indicating activation of cyclin B1/Cdc2 complex which is critical to the control of G2-M transition. We show that 6-OAP activates spindle assembly checkpoint, enhances Mad2/Cdc20 binding activity, leading to inhibition of ubiquitiniation and subsequent proteasomal degradation of cyclin B1. 6-OAP potentiates cytotoxicity of dexamethasone, doxorubicin and bortezomib, and overcomes the protective effects of interleukin-6 and insulin-like growth factor-2 on MM cells. Moreover, 6-OAP inhibits tumor growth but does not affect animal body weight in an in vivo xenograft model for human MM. Taken together, these results indicate that 6-OAP is a new cell cycle inhibitor which shows therapeutic potential for treating MM.

Disclosures:

No relevant conflicts of interest to declare.
Hereditary Haemorrhagic Telangiectasia Spectrum of ALK1/ENG Mutation
Authors: Corinaldesi Giorgio
Published: October 2019

Abstract 5066

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease characterized by two common criteria: angiodysplastic mucocutaneous telangiectasies, and epistaxis; hematemesis, melena, hemoptysis, stroke and visceral artero-venous malformation (AVMv) have also been associated with a significant risk of morbidity and mortality; HHT is divided into two forms: HHT-1 which is caused by a mutation in ENG (endoglin) gene mapping on chromosome 9q33–34, and HHT-2 which is caused by a mutation in ALK1 (activin receptor-like kinase 1) gene mapping on the pericentromeric region of chromosome 12q12–13.

Endoglin is an homodimeric disulphide-linked integral membrane glycoprotein (CD105) expressed on endothelial cells of all vessels; it binds TGF-beta 1 and 3, and it is very important to mediate vascular remodelling, the increase of blood flow, cellular migration and adhesion, extracellular matrix synthesis, through the modulation on endothelial cells, smooth muscle cells, fibroblasts and pericytes.

ALK1 increases in response to vessel wall stress or injury, and has a specific role in the differentiation of new vessels.

The majority of mutations in both genes are null, nonsense or splite-site and are non coding; the spectrum of mutations that have been reported of the two genes are short insertions, deletions, or missense and are present with a high level of consanguinity; homozygous patients with these mutations have severe haemorrhages.

We have identified on chromosome 12 a large deletion in exon 7, (8.4 kbp long fragment) of ALK1 encoding for the extracellular ligand-bindig domain involved in the TGF-beta/kinase activity signalling pathway, and in exon 8 (6.4 kbp long fragment) of ALK1 encoding serine-threonine kinase activity. The latter was a 28-year-old woman showing skin telangiectasies, recurrent and significant nosebleeds; the typical puntiform telangiectasies were evident since the age of 16, she also demonstrated with gastrointestinal endoscopy numerous gastric telangiectasies; abdominal and thoracic CT were performed and pulmonary involvement was present with a single artero-venous malformation and minimal respiratory symptoms (dyspnea, cyanosis); on the other hand, MRN did not revealed any cerebrovascular damage.

Mutations that disrupt ALK1 affect endothelial cells development and the process of angiogenesis; they are associated with mild clinical manifestation, and it has been observed that pulmonary arteriovenous malformations occur less frequently.

Disclosures:

No relevant conflicts of interest to declare.
Evaluation of the Mantle Cell Lymphoma International Prognostic Index (MIPI) as An Indicator of Overall Survival, Progression Free Survival, Survival From Relapse
Authors: Shah Bijal D. , Cultrera Jennifer L. , Sokol Lubomir , Chervenick Paul A. , Bello Celeste M. , Sagatys Elizabeth M. , Moscinski Lynn C. , Zhang Ling , Tao Jianguo , Sotomayor Eduardo M.
Published: October 2019

Abstract 5082

Background:

Prognosis for survival in mantle cell lymphoma (MCL) has recently been characterized using the MIPI algorithm. Using a retrospectively generated dataset of 150 patients with MCL seen at the H Lee Moffitt Cancer Center we sought to validate this approach in a more heterogeneous population.

Methods:

Patients were identified by physician survey, and through the use of our pathology and Total Cancer Care databases. Retrospective analysis was conducted with approval of our Institutional Review Board. In total 150 patients with MCL were identified, among whom MIPI data was available for 85 patients with a median followup of 36.8 months. Survival (expressed in months) was verified using our institutional records and the Social Security Death Index. Exploratory analysis of progression (n=79) and survival from the time of relapse (n=43) as stratified by MIPI were also conducted among evaluable patients. Data were compared using Kaplan-Meier survival analyses.

Results:

Median age was 65y (range 31–87), 73% male, 3% ECOG >1, 88% stage III/IV disease, 36% with extranodal involvement, and 38% with splenomegaly. Evaluation of the entire cohort shows median OS 57 (95% CI: 48, 70.9), median PFS 21.8 (95% CI: 14.2, 25.6), and median survival after relapse 27.6 (95% CI 25.4, 30.8). No benefit in OS was observed among patients receiving Cytarabine (HR 1.04, p=0.91) and/or Rituximab (HR 1.31, p=0.61) with initial chemotherapy. Relationship between PFS and survival after relapse demonstrated rho=0.51 (p<.0001).

Among 85 evaluable patients 36% had elevated LDH, while 36% were MIPI-Low, 38% MIPI-Int, and 28% MIPI-High. Stratification by MIPI shows median OS of 30.4 (12.4, 42) for MIPI-High, 64.8 (53,-) for MIPI-Int, and has not been reached by MIPI-Low, with little separation between MIPI-Low and MIPI-Int groups before 60 months. PFS was 6.3 (3.7,15) for MIPI-High, 25.6 (16.5,31) for MIPI Int, and 26.5 (14,40.3) for MIPI-Low, with little separation between MIPI-Low and MIPI-Int groups before 30 months. Survival after relapse was 12.4 (9.1,25.4) for MIPI-High, 34.2 (27.6,-) for MIPI-Int, and was not reached for MIPI-Low, again with little separation between MIPI-Low and MIPI-Int groups before 30 months.

Conclusions:

In our experience, the MIPI remains an effective tool for stratification of OS in MCL, however, extended followup is needed to realize such differences among those with MIPI-Low and MIPI-Int disease. The MIPI was similarly effective in predicting a poor PFS and survival from relapse among those with high risk disease, though was of less utility among MIPI-Low and MIPI-Int patients.

Disclosures:

No relevant conflicts of interest to declare.