bluuebunny/crossref_metadata_2025 huggingface dataset:
Rituximab and High-Dose Dexamethasone (R-dex) Is Effective In The Treatment Of Relapsed/Refractory Chronic Lymphocytic Leukemia
Authors: Simkovic Martin , Belada David , Motyckova Monika , Smolej Lukas , Zak Pavel
Published: October 2019

Introduction

High-dose methylprednisolone (HDMP) in combination with rituximab is active in the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) but serious infections are frequent. Recently published data suggest that high-dose dexamethasone might be equally effective to HDMP despite lower cumulative dose.

Aims

To assess efficacy and safety of high-dose dexamethasone combined with rituximab (R-dex) in relapsed/refractory CLL.

Patients and Methods

A total of 60 pts (pts) with relapsed/refractory CLL treated at a single tertiary center between September 2008 and October 2012 were included in this retrospective analysis. Basic characteristics are summarized in Table 1. The schedule of R-dex consisted of rituximab 500 mg/m2 i.v. day 1 (375 mg/m2 in cycle 1) and dexamethasone 40 mg orally on days 1-4 and 10-13. Treatment was repeated every 3 weeks for a maximum of 8 cycles. All pts received antimicrobial prophylaxis with sulfamethoxazole/trimethoprim and aciclovir.

Results

Median number of administered R-dex cycles was 6 (range, 1-8). The overall response (ORR)/complete remissions (CR) were achieved in 75/3%. At the median follow-up of 9 months, median progression-free survival was 8 months and median overall survival 24 months. Significant predictors of short PFS in univariate analysis were bulky lymphadenopathy (p=0.023) and refractoriness to fludarabine (p=0.02). Interestingly, activity of R-dex in bulky fludarabine-refractory CLL was similar to ofatumumab (ORR 62 %, median PFS, 4 months, median OS, 12 months) (Wierda et al., 2010). R-dex was successfully used as a debulking regimen before allogeneic stem cell transplantation in 8 patients. Serious (CTCAE grade III/IV) infections occurred in 29% of patients; 19% pts developed steroid diabetes requiring temporary short-acting insulin.

Conclusions

Our data show that R-Dex is an active and feasible treatment for patients with relapsed/refractory CLL; however, major infections remain relatively frequent despite combined antimicrobial prophylaxis. In addition, durable responses are infrequent. Therefore, further optimization of this therapeutic approach is warranted. Updated results will be presented.

Disclosures:

No relevant conflicts of interest to declare.
TIM-3, a Leukemia Stem Cell Marker, Plays a Role In Leukemic Transformation Through Autocrine Stimulatory Signaling By Its Ligand, Galectin-9
Authors: Kikushige Yoshikane , Yuda Junichiro , Shima Takahiro , Miyamoto Toshihiro , Akashi Koichi
Published: October 2019

Acute myeloid leukemia (AML) originates from self-renewing leukemic stem cells (LSCs), an ultimate therapeutic target for AML. We have reported that the T-cell immunoglobulin mucin-3 (TIM-3) is expressed on LSCs in most types of AML but not on normal hematopoietic stem cells (HSCs) (Kikushige et al, Cell Stem Cell, 2010). We extended the analysis of TIM-3 expression into various types of human hematological malignancies, and found that human TIM-3 is expressed in the vast majority of CD34+CD38- LSCs of human myeloid malignancies including chronic myeloid leukemia, chronic myelomonocytic leukemia and myelodysplastic syndromes (MDS). Although CD34+CD38- normal bone marrow stem cells do not express TIM-3, TIM-3 is expressed in the CD34+CD38- population in MDS, and is further up-regulated with progression into leukemia. The average percentages of TIM-3+ cells in the CD34+CD38- population was 7.8% in RCMD (n=10), 19.2% in RAEB-1 (n=10), 84.0% in RAEB-2 (n=10) and 92.2% in overt AML (n=10). The close association of TIM-3 expression with transformation into AML led us to hypothesize that TIM-3 itself has a function in AML stem cell development. TIM-3 is a type 1 cell-surface glycoprotein and has a structure that includes an N-terminal immunoglobulin variable domain followed by a mucin domain, a transmembrane domain and a cytoplasmic tail. Tyrosine residues are clustered in the cytoplasmic tail, suggesting that TIM-3 can induce signal transduction in TIM-3+ AML cells. To understand the function of TIM-3, we investigated the interaction between TIM-3 and its ligand galectin-9 in AML LSCs. We found that AML patients showed significantly higher serum galectin-9 concentration than healthy individuals (healthy controls: 18.3+4.3 pg/ml, AML patients: 139.1+33.4 pg/ml, P<0.05). Unexpectedly, we found that leukemic cells expressed a high level of galectin-9 protein, as compared to other hematopoietic cells including T cells, B cells and monocytes. Using KASUMI-3 (TIM-3+ AML cell line) and primary AML samples, we confirmed that AML cells could secrete galectin-9 after TLR stimulation in vitro. Furthermore, microarray analysis demonstrated that TIM-3 stimulation by the physiological concentration of galectin-9 induced significant gene expression changes toward pro-survival axis including up-regulation of MCL-1, the important survival factor for HSCs and LSCs. These results collectively suggest that AML cells can produce and secrete galectin-9, and galectin-9 can bind and stimulate TIM-3-expressing AML cells including LSCs in an autocrine manner to support their survival or leukemia progression.

Disclosures:

Miyamoto: Kyushu University Hospital: Employment.
Stem Cell and T-Cell Gene Therapy Using SIN-Lentiviral Vector In Type 3 Familial Hemophagocytic Lymphohistiocytosis
Authors: Rivière Julie , Soheili Tayebeh , Verhoeyen Els , Galy Anne , de Saint Basile Geneviève , Fischer Alain , Andre-Schmutz Isabelle , Cavazzana Marina
Published: October 2019

Familial hemophagocytic lymphohistiocytosis (FHL) is the genetic form of hemophagocytic lymphohistiocytosis with an autosomal recessive form of inheritance and early onset. FHL is characterized by prolonged fever, hepatosplenomegaly and pancytopenia. Type 3 of FHL (FHL3) which accounts for 30-35 % of all FHL patients, results from mutations in UNC13D gene encoding Munc13-4 protein. Munc13-4 controls fusion of lytic granules with the plasma membrane in cytotoxic lymphocytes and its defect leads to impaired cytotoxic activity in T and NK lymphocytes. The only curative method for FHL3 is allogenic hematopoietic stem cell (HSC) transplantation. For those patients without compatible bone marrow donor, gene therapy could represent a therapeutic option.

Our study is based on a comparative analysis to investigate the efficacy and safety of stem cell and T-cell gene therapy for FHL3. To this end we have generated SIN-lentiviral constructs expressing Munc13-4 and used them to produce either VSVG or T-cell specific pseudotyped lentiviral vectors. We also could obtain functionally mature T-cells in vitro, derived from umbilical cord blood HSCs which respond to TCR stimulation and show cytotoxic effect. Using these approaches, first we demonstrated that our SIN-lentiviral constructs are able to transduce efficiently human T-cells and HSCs. We used then these vectors to complement the FHL3 patient’s cells. Transduction of FHL3 CD8 effector cells restored their cytotoxic function that was comparable to that of control cells. In addition we noted that the overexpression of Munc 13-4 in normal human HSCs didn’t alter in vitro differentiation of these cells towards T-cells. The effect of this overexpression on B-cells and myeloid differentiation is currently under investigation.

These preliminary results will be followed by ex vivo gene transfer experiments in Munc13-4 deficient “Jinx” mice to further investigate the functional restoration as well as toxic effects. This strategy, if approved, could offer a safe therapeutic method not only for FHL3 patients but also for other genetic or acquired dysfunctions of T-lymphocytes.

Disclosures:

No relevant conflicts of interest to declare.
Preclinical Development Of a Nanomedicne Approach For Multiple Myeloma Targeting The Myc Oncoprotein
Authors: Soodgupta Deepti , Pan Dipanjan , Hu Grace , Senpan Angana , Yang Xiaoxia , Weilbaecher Katherine N , Prochownik Edward V. , Lanza Gregory M , Tomasson Michael H
Published: October 2019

Purpose

This study investigated alpha 4 beta 1/ Very Late Antigen-4 (α4β1/ VLA-4)-integrin targeted nanotherapy approach to deliver a new lipase-labile prodrug.

Experimental Design

A phospholipid-based MYC-MAX inhibitor prodrug (MI1-PD) was synthesized, and its inherent anti-proliferate potency was compared to the lipid-free compound (MI1) using mouse multiple myeloma (MM) cell line (5TGM1). VLA-4-targeted perfluorocarbon (PFC) nanoparticles binding to 5TGM1 cells was measured and compared to biomarker expression assessed with flow cytometry using antibodies. The efficacy of MI1-PD incorporated into non-targeted and VLA-4-targeted PFC NP exposed to 5TGM1 cells was assessed with MTT assays, Annexin V and cell cycle analysis.

Results

MI1-PD was more potent by several orders of magnitude than its free drug counterpart in culture. Targeted NP binding correlated well with biomarker expression assessment by flow cytometry in 5TGM1 cells. Non-targeted NPs had no appreciable binding to 5TGM1 cells. High anti-MM potency of MI1-PD was noted in VLA-4-targeted NPs compared to the non-targeted NPs demonstrating that the efficacy was dependent on expression of the targeted biomarker to afford particle-to-cell drug delivery.

Conclusions

These results suggest the feasibility of an improved integrin VLA-4- targeted nanotherapy approach to deliver a lipase- labile prodrug construct, MI1-PD.

Disclosures:

No relevant conflicts of interest to declare.
Tmem14c Plays An Essential Role In Mitochondrial Heme Metabolism
Authors: Paw Barry H. , Yien Yvette Y. , Robledo Raymond F , Schultz Iman J. , Takahashi-Makise Naoko , Philllips John , Miyata Non , Gwynn Babette , Dailey Tamara A. , Pierce Eric , Hildick-Smith Gordon J. , Cooney Jeffrey D. , Chen Wen , Shah Dhvanit I. , Hattangadi Shilpa M , Kingsley Paul D , Palis James , Cantor Alan B. , Koehler Carla M. , Lodish Harvey F. , Kaplan Jerry , Dailey Harry A. , McVey Ward Diane , Peters Luanne L.
Published: October 2019

Red cells synthesize large amounts of heme during terminal differentiation. Central to this process is the transport and trafficking of heme synthesis intermediates within the cell. Despite the importance of transport during heme synthesis, the molecules involved in this process are largely unknown. In a screen for genes that are upregulated during erythroid terminal differentiation, we identified Tmem14c, a predicted multi-pass transmembrane protein as an essential component of the porphyrin metabolism pathway.

Here, we report that Tmem14c facilitates the synthesis of mitochondrial protoporphyrin IX from coproporphyrinogen III and is thus required for heme synthesis. Tmem14c is a mitochondrial inner-membrane protein enriched in vertebrate hematopoietic tissues and is required for terminal erythropoiesis. Tmem14c gene-trap mouse embryos are severely anemic and mostly die by E13.5 (Fig. A). Fetal liver erythroid cells derived from gene-trap embryos experience maturation arrest. shRNA silencing of Tmem14c in Friend murine erythroleukemia (MEL) cells results in a significant decrease in de-novo heme synthesis. The biochemical defect is due to a decrease in mitochondrial protoporphyrin IX synthesis, while cytoplasmic porphyrin levels remain normal (Fig. B). The heme synthesis defect in Tmem14c-silenced MEL cells is complemented with a protoporphyrin IX analog. These data show the role of Tmem14c in regulating the terminal steps in mitochondrial porphyrin trafficking.

Our findings collectively demonstrate that Tmem14c is required for the transport of mitochondrial porphyrins in developing erythroid cells. Due to its inner-mitochondrial localization and its relative proximity to heme synthetic enzymes coproporphyrinogen oxidase and protoporphyrinogen oxidase (Rhee et al., 2013 Science), Tmem14c can function as a molecular adaptor that facilitates the interaction of proteins involved in porphyrin transport, or as a protoporphyrinogen IX transporter (Fig. C). The identification of Tmem14c as an essential regulator of porphyrin transport and heme synthesis provides a novel genetic tool for exploring erythropoiesis and disorders of heme synthesis such as porphyria and anemia.

Disclosures:

No relevant conflicts of interest to declare.
Whole Body PET-CT In Management Of Lymphoblastic Lymphomas In Adults: Does It Have a Prognostic Impact?
Authors: Sengar Manju , Jain Hasmukh , Menon Hari , Epari Sridhar , Agrawal Archi , Rangarajan Venkatesh , Shet Tanuja , Gujral Sumeet , Laskar Siddhartha
Published: October 2019

Introduction

The two relevant questions that emerge and remains unanswered in the management of adult lymphoblastic lymphomas (LBL) are- how to select patients for mediastinal radiation and whom to subject for autologous transplant. Mediastinal radiation or intensification of therapy may reduce the mediastinal recurrence- a common site for relapse. It is also understood that not all patients with residual mediastinal mass relapse. The inability of computed tomography to differentiate between necrotic and viable disease in a residual mediastinal mass post induction therapy led us to explore PET-CT as modality to differentiate the same. In a retrospective analysis we evaluated the role of post-induction chemotherapy PET-CT in predicting the risk of relapse or progression in adult LBL patients.

Methods

In a single centre retrospective analysis we included newly diagnosed LBL patients (>15 years) who were treated with ALL- like therapy between January 2010 and February 2013. All patients who underwent PET-CT after induction chemotherapy were analysed. SUVmax was used to assess the response. Details of demographic variables, diagnosis, subtype, baseline LDH, bone marrow involvement, cerebrospinal fluid analysis, chemotherapy, radiotherapy, responses, relapse/progression, death and its cause and last follow up date were taken from electronic medical records.

Results

Twenty-two patients (17 males and 5 females) with median age 24.5 years (range, 16-44 years) were analysed. All patients had T- LBL. Thirteen patients (13/22) had stage IV disease (Ann Arbor stage) and all had bulky mediastinal mass at diagnosis. None of the patient had CSF or bone marrow involvement. Raised LDH and low albumin were present in 80% and 60% of patients respectively. Median WBC was 10,200/cumm (range, 4400-15300/cumm). All but 4 patients received BFM-90 ALL protocol based therapy. After induction 19 patients achieved complete remission on PET-CT. Patients who had residual mediastinal masses on PET-CT relapsed during later phase of therapy (all within 6 months) in mediastinum and died subsequently. Mediastinal radiation was given to one of these patients but it did not prevent a subsequent relapse. One patient who achieved complete response had bone marrow relapse after 16 months of therapy. Three patients had treatment related death (sepsis). At median follow up of 14 months 1-year overall survival was 69% and progression free survival was 78%.

Conclusion

Post induction therapy PET-CT seems to have prognostic role and may predict relapse for patients with residual disease activity. Such patients should be considered for treatment intensification. However, the role and timing of mediastinal radiation in such patients remains investigational.

Disclosures:

No relevant conflicts of interest to declare.
Absence Of BRAF and KRAS Hotspot Mutations In Primary Mediastinal and Other Diffuse Large B-Cell Lymphoma
Authors: Nagel Philipp D , Feld Fenja M , Weissinger Stephanie E , Stenzinger Albrecht , Moeller Peter , Lennerz Jochen K
Published: October 2019

Recently whole-exome-sequencing has identified oncogenic BRAF and KRAS mutations as likely drivers in diffuse-large B-cell lymphoma (DLBCL). It is currently unclear whether primary mediastinal B-cell lymphoma (PMBL), a clinicopathologically distinct variant of diffuse-large B-cell lymphoma, harbors such mutations. Here, we screened 100 samples (84 primary tumors and 16 cell lines), composed of 52 PMBL and 48 DLBCL samples for BRAF (V600/601) and KRAS (G12-K16) hotspot mutations using a sensitive pyrosequencing approach. All 100 samples were BRAF and KRAS wild-type. When combining our results with those reported in the literature (Table 1), the overall mutation frequency in DLBCL for BRAF is ∼2.4% (n=13/541) and for KRAS is ∼1.6% (n=7/445). We demonstrate the absence of BRAF and KRAS hotspot mutations in PMBL. The overall prevalence of KRAS and BRAF mutations argues against hotspot genotyping as part of the diagnostic workup in PMBL/DLBCL.Table 1Summary of DLBCL genotyping resultsBRAFKRASMut./tested%Mut./tested%Lohr et al., 20112/554,12/554,1Pasqualucci et al., 20110/4800/480COSMIC*11/3383.25/2422,0Subtotal13/4413.07/3452.0Nagel et al., (here)0/10000/1000Summary13/5412,47/4451,6%*At time of review, COSMIC did not include the results from Lohr et al. and Pasqualucci et al.

Disclosures:

No relevant conflicts of interest to declare.
Role Of Aggressive Chemotherapeutic Regimens In Double Hit Lymphoma- Can Alternate Aggressive Induction Regimens Overcome The Poor Prognosis Of Diffuse Large B Cell Lymphoma?
Authors: Tsai Judy , Greer John P , Morgan David S. , Li Shaoying , Reddy Nishitha M.
Published: October 2019

Background

Double-hit (DH) diffuse large B cell lymphomas (DLBCL), characterized by concurrent translocations involving MYC and BCL2, or BCL6, portend to have an aggressive clinical course. Recent studies have highlighted the fact that DH lymphomas are resistant to standard R-CHOP or experience a short disease free interval. There is however limited data evaluating patient outcomes with alternative therapy that include aggressive regimens often used to treat high grade lymphoma.

Methods

Five hundred sixty patients (pts) diagnosed with DLBCL at a single institution between January 2004 and December 2012 were included in our analysis after obtaining IRB approval. Descriptive statistics, Wilcoxon signed rank sum test and Kaplan-Meier analysis were performed using SPSS.19 software.

Results

Of the 560 pts, 34 were confirmed as DH based on FISH analysis. The median age at diagnosis was 63 yrs (range 36-87). Twenty pts (59%) were male. Thirty-one pts (91%) were Caucasian. Fourteen pts (53%) had an Eastern Cooperative Oncology Group performance status of 2-3. Thirty pts (89%) had advanced stage disease (stages III and IV). Thirteen pts (38%) had bone marrow involvement, and twenty-six pts (76%) had more than one extranodal site. The majority of pts (70%) had high intermediate or high risk based on the International Prognostic Index (IPI). Of the 34 pts, 15 (46%) received R-CHOP, 6 (18%) received R-Hyper CVAD/Ara-C/MTX, 8 (24%) received DA-R-EPOCH and 2 (6%) received other aggressive forms of chemotherapy. Two pts died before any therapy was initiated. Ten pts (29%) received central nervous system prophylaxis. Five pts (15%) underwent stem cell transplant, 2 of which in CR1. Twenty-eight pts (82%) were alive at the time of analysis. At a median follow up of one year, the median overall survival (OS) of all pts was 12.2 months. The median OS was 16.8 months for pts who received R-CHOP and 12.2 months for pts receiving other aggressive chemotherapy (P=0.07) (figure 1). The progression free survival for pts who received R-CHOP was 32.6 months as compared with 7.6 months in pts treated with R-hyper CVAD/Ara-C/MTX or DA-R-EPOCH. This was not statistically significant (P=0.44) (figure 2). In addition, there was no significant difference in disease free interval between the two groups of patients.

Conclusion

Our data suggests that prognosis of patients with DH-DLBCL remains poor independently of the chemotherapy administered, whether conventional R-CHOP or more aggressive regimens such as R-HyperCVAD or DA-R-EPOCH. Durable long term remission with R-CHOP is still possible in a minority of patients. There is a need to modify and incorporate novel agents in the initial treatment strategy for DH-DLBCL.

Disclosures:

No relevant conflicts of interest to declare.
The Spectrum Of Pathological Findings Of Kidney Injury In The Cases Of Multiple Myeloma: A Clinico-Pathological Study Of 93 Consecutive Autopsy Cases
Authors: Mine Sohtaro , Hagiwara Shotaro , Hirai Risen , Tanimura Akira , Nakamura Miki , Takeshita Masataka , Miwa Akiyoshi , Igari Toru
Published: October 2019

Background

Kidney injury and/or renal failure are common complication in multiple myeloma. Well known mechanism is deposition of free immunoglobulin light chains in renal tubules leading to cast nephropathy and renal failure. In addition, not only cast nephropathy, but also invasion of myeloma cells is frequently found in autopsied cases of multiple myeloma.

Recent development of treatment improved the remission rate and survival of multiple myeloma. Few data exist about pathological findings of kidney injury and it is not well known about kidney findings in autopsy cases at era of novel agent. We investigated the pathological findings and the factors associated with kidney injury in the consecutively autopsy cases.

Methods

We reviewed the autopsy reports and medical records of 93 consecutively autopsied multiple myeloma cases between 1979 and 2012 at the National Medical Center for Global Health and Medicine in Tokyo, Japan. Patient profile, the clinical records including treatment and the duration of illness, the type of monoclonal gammopathy, clinical stage and history of treatment were studied. Durie & Salmon's criteria was used for diagnosis and staging. The pathological findings like cast nephropathy, invasion of myeloma cell at kidney and the other findings of whole samples were studied gross and microscopically. Immunohistochemistry and Congo-red stain were performed.

The pathological findings and the factors were statistically analyzed using Student's t-test and the chi-square test.

Results

In 93 autopsy cases, 58% was male. Mean age and the duration of illness were 64.3(38-85) years old and 41 months (24.4-37.5). Thirteen patients and 14 were treated with SCT and hemodialysis (Table. 1). Cast nephropathy and direct invasion about kidney were observed in 51.2% and 29.3%, respectively. Other frequent finding associated with myeloma was renal amyloidosis (29%). Frequent non-specific findings were arteriosclerosis (76 %), glomerulosclerosis (61%). Combination of findings were found in 66% cases (Fig.1).

The tumor volume in bone marrow (percentage of myeloma cells in cellular component) had correlation to incidence of direct invasion (Pearson's correlation factor is 0.55, p<0.005).

Conclusion

Autopsy findings of the kidney are various, complicated pathological findings of two or more was not uncommon. Frequency of cast nephropathy was high, but the direct invasion of the tumor cells was observed in about one-third of the cases. Correlation was observed between the kidney and invasive tumor burden in the bone marrow. Therefore, in the advanced stage myeloma, when tumor cell occupy more than about 60% of the bone marrow should be considered renal failure mechanism by myeloma cell infiltration.

Disclosures:

No relevant conflicts of interest to declare.
Observations On Eosinophil Ifiltrates in The Bone Marrow Of Patients With Multiple Myeloma. Clinicopathological Correlates
Authors: Brito-Babapulle Finella MC , Cranfield Tanya , Corser Robert B , Dignum Helen , James Christopher , Ganczakowski Mary
Published: October 2019

Mouse eosinophils have been shown in 2011 to be required for the maintenance of long lasting plasma cells in the bone marrow and in maintaining the bone marrow plasma cell microenvironment. Human eosinophils have been shown by Wong et al to support multiple myeloma cell proliferation via a mechanism independent of IL6.

We looked at bone marrow biopsies taken from patients who had a paraprotein and in whom a diagnosis of multiple myeloma was suspected. These samples were taken solely for the purposes of diagnosisng multiple myeloma and were retrospectively reviewed from the point of view of degree of eosinophil infiltration and its correlation with tumour load, bone lytic lesions, plasma cell morphology, whether blastic, crystalline inclusions, Mott cells, flame cells and or lymphoplasmacytoid. There were no cases of IGD or E myeloma or osteosclerotic myeloma.Nonsecretory myeloma and cases of light chain myeloma with or without amyloid were included in the series. Biopsies were not performed from osteolytic lesion unless biopsy was necessary to make a diagnosis of myeloma. Myeloma was diagnosed when plasma cell infiltrate was greater than 10% on bone marrow aspirate with a paraprotein and or lytic lesions. Eosinophil infiltration did not correlate with any of the tumour clinicopathological markers but showed an inverse correlation with degree of plasmacytosis. Eosinophils were hardly ever found in marrow aspirates that had over 70% plasma cells. They were usually found in trephine sections of bone marrow in areas where there was Grade I/II fibrosis and were often found in close proximity to focal areas of plasma cell infiltration. Whether eosinophils play a role in preventing or maintaining malignant plasma cell recurrence is currently being studied.

Disclosures:

No relevant conflicts of interest to declare.
Conservative Management Vs. Allogeneic Hematopoietic Cell Transplantation For Polycythemia Vera: A Systematic Review and Decision-Analysis
Authors: Lacevic Jasmin , Reljic Tea , El Jurdi Najla , Kharfan-Dabaja Mohamed A , Nishihori Taiga , Komrokji Rami S. , Kumar Ambuj , Djulbegovic Benjamin
Published: October 2019

Background

Conservative treatment which typically includes phlebotomy or hydroxyurea or other cytoreductive therapy (plus aspirin) (ConsRxAsa) is effective treatment with acceptable complications for management of polycythemia Vera (PV) but is not considered curative [thus resulting in a shorter life expectancy (LE) in comparison to LE in the general population]. On the other hand, an allogeneic hematopoietic cell transplantation (allo-HCT) from a HLA compatible donor is considered a curative treatment option, but is potentially associated with high-risk of life-threatening complications. We sought to answer the question of which of these two treatment options results in better survival.

Methods

Because there are no direct randomized controlled trials (RCT) addressing the question if ConsRxAsa is superior to allo-HCT, we resorted to a decision-analysis to answer this question. We constructed a Markov model to represent and analyze the decision of ConsRxAsa vs. Allo-HCT.  The results of the model were expressed in terms of life expectancy (LE) and survival probabilities. We performed a systematic review (and when possible a meta-analysis) to inform parameters in the model. ConsRxAsa arm was modeled by simulating the natural history of PV. For Allo-HCT arm, we adopted our previously published model (Biol Blood Marrow Transplant 2009;15:1415-21) but modified it to evaluate the effect of both conventional and reduced-intensity allo-HCT performed in chronic phase of PV.

Results

We identified 165 relevant articles of which only 7 described testing various treatments for PV in RCTs. However, most data used to populate the decision model came from one RCT and one cohort study. Using base case of age of 45 years, we estimated a probability of survival at 10 and 20 years of 86% and 67% for ConsRxAsa versus 55% and 32% for allo-HCT (Fig).  This translates into an average LE of 17.1 years for ConsRxAsa vs. 11.6 years for allo-HCT, respectively. Sensitivity analysis according to age, early transplant-related mortality, risk of bleeding or thrombosis did not affect the results. Adopting median age of 65 years and comparing reduced-intensity allo-HCT vs. ConsRxAsa, we found that the average LE was 8.6 years for allo-HCT vs. 12.5 in the conservative treatment arm. Again, conservative treatment remained superior under a wide range of assumptions.

Conclusions

integration of current best existing evidence into the decision model shows that conservative management of PV appears to provide a better survival compared to offering  an allo-HCT in chronic phase of P. Vera.

Disclosures:

No relevant conflicts of interest to declare.
Low Expression Of Abelson Interactor-1 Is Linked With Systemic Persistence and Acquired Drug Resistance In Bcr-Abl-Induced Leukemias
Authors: Dubielecka Patrycja Marta
Published: October 2019

The basis for persistence of leukemic stem cells in the bone marrow microenvironment (BMME) remains poorly understood. We present evidence that signaling crosstalk between α4 integrin and Abelson interactor-1 (Abi1) is involved in acquisition of an anchorage-dependent phenotype and drug resistance in Bcr-Abl positive leukemia cells. Comparison of Abi1 (ABI1) and α4 integrin (ITGA4) gene expression in relapsing Bcr-Abl positive CD34+ progenitor cells demonstrated a reduction in Abi1 and an increase in α4 integrin mRNA in the absence of Bcr-Abl mutations. This inverse correlation between Abi1 and α4 integrin expression, as well as linkage to elevated phospho-Akt and phospho-Erk signaling, was confirmed in imatinib mesylate (IM) resistant leukemic cells. These results indicate that the α4-Abi1 signaling pathway may mediate acquisition of the drug resistant phenotype of leukemic cells.

Disclosures:

No relevant conflicts of interest to declare.
Severe Adverse Skin Reaction Used For Sclerodermatous Chronic Graft Versus Host Disease Of The Skin
Authors: Hamm Caroline , Kanjeekal Sindu M. , Shum David , Elfiki Tarek , Mathews John
Published: October 2019

Treatment of sclerodermatous chronic graft versus host disease remains a daunting challenge. Supportive care measures remain the primary mode of therapy with little evidence of treatments that reverse the process. Photopheresis has been used with varying success in this disorder. Recently, case reports and case series have reported on the successful use of imatinib in this disorder(1, 2) Drug intolerance was reported in four of the patients treated.

We report a case of a 40 year old man with extensive scelerodermatous chronic graft versus host disease (GVHD) of the skin ( Skin : score of 3 using the NIH Criteria).

Four years earlier, he underwent a matched unrelated stem cell transplant for chronic myelogenous leukemia. His transplant course was complicated with TTP associated with all standard immune suppressive agents (cyclosporine, tacrolimus, sirolimus). This gentleman developed progressive sclerodermatous skin GVHD. Photopheresis was carried out for two years with stabilization, but no improvement in his symptoms. Imatinib was started due to persistent symptoms (joint restriction Score of 2 in NIH criteria, > 50% of skin involvement, joint Ð score of 3 NIH). 3

Imatinib was started for progressive symptoms and within five days, he was hospitalized with a generalized erythroderma with associated skin sloughing. The Imatinib was stopped and he received high dose steroids with slow improvement of his symptoms. Skin biopsy at that time revealed subcorneal pustular dermatosis; there was no herpes viral effects and special stains were negative for bacterial or fungal organisms. There was a diffuse infiltration of neutrophils. Histological differential diagnosis included pustular psoariasis and Sneedon-Wilkinson syndrome. In view of the history, the concluding diagnosis was exanthematous pustulosis secondary to imatinib.

We recommend that close attention be paid to patients with chronic GVHD treated with imatinib and early intervention with stopping the Imatinib. Steroid worked in this case and should be considered.Blood 2009 Mar. Magro et alArch Dermatol 2008 Sept; 144(9): 1106-9

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. Diagnosis and Staging Working Group Repor Alexandra H. Filipovich,1 Daniel Weisdorf,2 Steven Pavletic, et al Biology of Blood and Marrow Transplantation 11:945-955 (2005).

Disclosures:

No relevant conflicts of interest to declare.
CMV Reactivation Is Associated With a Lower Incidence Of Relapse After Allo-SCT For ALL
Authors: Tian Hong , Xu Yang , Yang Zhen , Chen Guanghua , Qiao Man , Liu Huiwen , Depei Wu
Published: October 2019

Background

CMV reactivation is an important cause of morbidity and mortality of allogeneic stem cell transplantation (allo-SCT). Recent studies demonstrated reduction of relapse risk after early replicative CMV infection in acute myelocytic leukemia (AML) and chronic myeloid leukemia (CML) patients. Here, we studied the relationship between CMV reactivation and leukemic relapse in acute lymphoblastic leukemia (ALL) patients.

Patients and Methods

115 patients (median age, 28 years; range, 14-56) with de novo ALL underwent allo-SCT from HLA-matched sibling (n=59) donors or unrelated (n=56) donors. CMV pp65 antigenemia was used for monitoring posttransplant CMV reactivation.

Results

CMV reactivation before day 100 was observed in 47 patients (40.9%) (median day, 44 days, range, 10-100 days). The follow-up time varied from 10 to 90 months (median, 43 months), the estimated overall survival at 5 years was 52% in patients without opposed to 68% in patients with early pp65-antigenemia (P =.035). The 5-year disease free survival (DFS) was 39% vs 47% (P =.018). CMV pp65 antigenemia was associated with a decreased risk of relapse by day 100 among patients with ALL (HR 0.41, 95%CI 0.2-0.9) by multivariate analysis. Furthermore, CMV reactivation was associated with increased non-relapse mortality (HR 1.15, 95% CI 0.3-3.6).

Conclusion

Early replicative CMV infection is an independent and substantial factor associated with decreased leukemic relapse risk in ALL transplant recipients.

Disclosures:

No relevant conflicts of interest to declare.
Low Dose Thymoglobulin Results In Improved Outcomes After Allogeneic Unrelated Hematopoietic Stem Cell Transplantation (HCT) For Patients With Acute Myeloid Leukemia/ Myelodysplastic Syndrome Conditioned With Intravenous Busulfan and Fludarabine
Authors: Khaled Yasser , Smith Megan , Smith Tori , Balls Jason , Matar Abraham , Lamontagne Deborah , Ambinder Roy M. , Zakari Ahmed , Solh Melhem M.
Published: October 2019

Low Dose Thymoglobulin Result in Improved Outcomes after Allogeneic Unrelated Hematopoietic Stem Cell Transplantation (HCT) for Patients with Acute Myeloid Leukemia/ Myelodysplastic Syndrome Conditioned with Intravenous Busulfan and Fludarabine.

Intravenous Busulfan/Fludarabine (Bu/Flu) based conditioning regimens have resulted in lower treatment related mortality (TRM) after allogeneic HCT in both reduced and full intensity dosing in AML/MDS. The addition of thymoglobulin to such regimens to minimize the risk of graft versus host disease after unrelated donor (MUD) HCT has been linked to the increased concerns of relapse risk.

Method

In order to study the impact of addition of low dose thymoglobulin to Bu/Flu regimens in MUD recipients, the medical records of 38 consecutive AML/MDS patients who underwent MUD HCT with BU/Flu and low dose thymoglobulin were retrospectively reviewed. All the patients received single daily dose of iv Bu 3.2 mg/kg for 2 days (RIC, Bu2-Flu) or 4 days (FIC, Bu4-Flu) based on age,  older or younger than 65 respectively. Fludarabine was given as a single daily dose of 40 mg/Kg for 4 days. Graft versus host disease prophylaxis was Tacrolimus/Methotrexate in FIC recipients and Tacrolimus/Mycophenolate in RIC recipients. Additionally, all the patients received thymoglobulin 1.5 mg/Kg on day -3, -2 and -1. All patients received peripheral stem cells except one patient with mismatch MD who received bone marrow product.

Results

Patient Characteristics are shown in Table 1. All the patient engrafted except one who received marrow product.  All the patients but 3 (8%) achieved 90% or more donor chimerism by day 100. With Mean follow up of 500 days (range, 100-1242) the overall survival (OS) was 77% ± 7 (CI 63-91%) at 1 year and 67% ± 9 (CI 49-85%) at 2 years. Similarly, disease free survival was 66% ±8 (CI 50-82%) at 1 and 2 years. Cumulative incidence of acute GVHD grade II-IV was 55% with grade III-IV 12%. Cumulative incidence of chronic GVHD at 1 year was 43% with extensive chronic GVHD in 17%. The regimen was associated with low treatment related mortality (TRM) with cumulative incidence of only 5% at one year, CI 14-21%. The cumulative incidence of relapse at one year was 29%, CI 17-49%. On univariate analysis only high risk CIBMTR status was predictive of poor OS (p=0.05).

Conclusion

The addition of low dose thymoglobulin to RIC and FIC regimens with iv Busulfan/Fludarabine prior to MUD HCT results in low TRM and improved OS for patients with AML/MDS. Relapse rate does not seem to be increased in this cohort by the addition of low dose thymoglobulin in comparison to historical control.

Disclosures:

No relevant conflicts of interest to declare.
The Role Of Vitamin D In Pediatric Hematopoietic Stem Cell Transplantation
Authors: Hansson Magnus EA , Norlin Anna-Carin , Omazic Brigitta , Wikström Ann-Charlotte , Winiarski Jacek , Remberger Mats , Sundin Mikael
Published: October 2019

Gathering evidence suggest that sufficient vitamin D levels are beneficial for patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Vitamin D deficiency seems common in the pediatric population, especially in children undergoing treatment for hematologic malignancies. In the present study we followed 123 pediatric patients for up to eight years post-HSCT with the main objective to evaluate the clinical importance of vitamin D status in children following HSCT.

The patients underwent HSCT at our center mostly due to hematologic malignancies, but patients with non-malignant conditions and primary immunodeficiency disorders were also included. Procedures and conditioning regimens followed international guidelines. Data on each patient were obtained from medical records and included basic parameters, transplant characteristics, outcome parameters, data on vitamin D and immunoglobulin substitution and data on nutritional support.

Patients were divided into two cohorts based on calcidiol (25-OH-vitamin D) level pre-SCT; low level (<50 nM) and sufficient level (≥ 50 nM). The distribution of ethnic origin differed between the groups and patients with insufficient levels were older. No differences in other characteristics were seen between the groups.

Acute GvHD (aGvHD) occurred in almost every other patient with higher frequency in the sufficient level group (47 vs. 29 %). Chronic GvHD (cGvHD) occurred in 17 % of patients with higher frequency of moderate to severe cGvHD in the low level group. Neutrophil granulocyte numbers rose faster during the first 3 months in the sufficient group whereas no such difference was observed during the later follow-up. The number of infections did not significantly differ between the groups. Overall survival in patients with malignant diseases was significantly better in the sufficient level group (87 % vs. 50 %). Graft rejection did not occur in patients with sufficient levels of vitamin D. Relapse was more common among patients in the low level group.

We conclude that vitamin D seems to have a role in the outcome for children undergoing HSCT as hypovitaminosis D was associated with increased risk of death, relapse and cGvHD. At the same time effects on immune reconstitution and risk of infections were not obvious and aGvHD occurred more frequently among patients with sufficient vitamin D levels at baseline. It might be postulated that vitamin D has both inhibiting and stimulatory effects on the immune system. This study is an important step towards understanding the role of micronutrients such as vitamin D in pediatric HSCT.

Disclosures:

No relevant conflicts of interest to declare.
Serum Levels Of Vitamin D In Patients Undergoing Hematopoietic Stem Cell Transplantation
Authors: Pereira Andrea Z , Silva Juliana Bernardo , MF Pivocari Silvia , Tanaka Marcia , Lucio Fabiana , N Barrere Ana Paula , Castro Claudio Galvão , Feitosa Ribeiro Andreza Alice , Hamerschlak Nelson
Published: October 2019

Introduction

There are few studies on the behavior of vitamin D in patients undergoing Hematopoietic Stem Cell Transplantation (HSCT), although vitamin D serum levels are associated with use of corticosteroids and immunosuppressive drugs. In some studies, vitamin D deficiency in patients after HSCT is associated with reduced bone density, increased of parathyroid hormone and GVHD.

Objectives

To study vitamin D deficiency in patients undergoing to HSCT.

Methods

51 patients who underwent HSCT at Albert Einstein Hospital, São Paulo, Brazil, were studied (28 male, 23 female) with a mean age of 50 ± 16 years, in the period from 2012 to 2013.

Results

54 % had serum levels of vitamin D ≤ 50 nmol/l. And, 12% had serum levels of vitamin D ≤ 25 nmol/l. A multivariate analysis showed that more age and higher Body Mass Index (BMI) were significantly associated to lower serum levels of vitamin D. A negative correlation was found between BMI and serum level of vitamin D (rp=0,37).

Conclusion

The use of corticosteroids, immunosuppressive drugs and less lack of sun exposure during the HSCT and during the first year post-HSCT are associated with a greater tendency to deficiency of vitamin D. This deficiency can cause muscle and bone diseases, which can be prevented with diagnosis and early treatment. The deficiency of vitamin D should be carefully investigated in the elderly and obese patients.

Disclosures:

No relevant conflicts of interest to declare.
Impact Of ABO Incompatibility On Overall Survival After Unrelated Cord Blood Transplantation a Single Institute Experience In China
Authors: Zimin Sun , Mengmeng Ji , Wen Yao , Changcheng Zheng , Juan Tong , Huilan Liu , Liangquan Geng , Tang Baolin , Xiaoyu Zhu , Kaidi Song , Ding Kaiyang
Published: October 2019

Umbilical cord blood transplantation (UCBT) has now become a more common treatment for patients with hematologic malignancies who lack matched related or unrelated donors. However, few reports have addressed the impact of ABO incompatibility on the clinical outcomes, such as engraftment, transfusion requirements and survival after UCBT. Therefore, we retrospectively analyzed the impact of ABO mismatching on the clinical outcomes of 121 patients, including 51 ABO-identical, 23 minor, 39 major, and 8 bidirectional ABO-incompatible recipients after UCBT. With a median follow-up of 11 months (range, 5-151 months), the disease-free survival (DFS) rates among the ABO-identical, minor, major, and bidirectional ABO-incompatible groups were 71.7%, 60.0%, 37.1%, and 71.4%, respectively (P=0.014), whereas the OS did not differ significantly among the four groups (76.1%, 65.0%, 48.6%, and 71.4%, respectively; P=0.078). The DFS (68.2%, 42.9%; P=0.009) and OS estimates (72.7%, 52.4%; P=0.031) of the ABO identical/minor incompatible group also differed significantly from the ABO major/bidirectional incompatible group. These results were confirmed in the multivariate analysis. No signiﬁcant differences in the engraftment times, transfusion requirements, graft-versus-host disease (GVHD), relapse, and non-relapse mortality (NRM) were noted among the groups. Severe immune hemolysis or pure red cell aplasia did not occur among these patients. These results indicate that ABO incompatibility somewhat affects the DFS and OS in UCBT, but further studies are still required.

Disclosures:

No relevant conflicts of interest to declare.
Martial Arts Intervention Decreases Pain Scores In Children With Malignancy
Authors: Cohen Cindy , McCrae Jocelyn , O'Malley Barbara , Goldberg Elimelech , Bluth Martin H
Published: October 2019

Background

Martial arts intervention in disease has been mostly limited to inflammatory, musculoskeletal or motor diseases (rheumatoid / osteoarthritis, fibromyalgia, Parkinson’s disease) where a mechanical intervention effects positive change. However, the application and benefit to malignancy is not well described.

Methods

Ninety four children with childhood malignancies enrolled in a martial arts program which encompassed both “soft” (meditation, chi gung) and “hard” (karate) martial arts platforms over the course of 12 months. Pain scores were recorded pre and post intervention. Data are reported as percent change from baseline pre intervention values compared with post using Wilcoxen Signed Ranks test comparing pain score means for all cases; with significance p< 0.05)

Results

The majority of participants were African American (>95%) with a M:F ratio of 3:1. Further, most participant scored improvement in pain after 1-3 encounters. Pain scores prior to intervention were recorded on a scale of 0-10. Patients who partook in the martial arts program demonstrated a reduction in pain scores of 14-30.2% (p<0.05) based on mean comparisons as a group or when corrected for number of visits. Differences in pain scores trended as more pronounced in older vs. younger children, but were not significant (p>0.05). Differences in gender were not significant (p>0.05).

Conclusion

Martial arts can provide a useful modality to decrease pain in childhood cancer. This can improve patient compliance with respect to medical and surgical management thus reducing disease morbidity and healthcare costs.

Disclosures:

No relevant conflicts of interest to declare.
Vitamin B12 Deficiency In Patients With Normal Blood Count
Authors: Al-Momen Abdul Kareem M , AL-Aqeel Abdullah A. , Student Medical , Aseeri Mohammed A. , Student Medical , Al-Fawaz Khaled A. , Student Medical , Al-Molhem Abdulaziz , Student Medical , Hasanato Rana M
Published: October 2019

Background

Vitamin B12 (Cobalamine) is essential for protein synthesis, cell proliferation and optimal systemic function, particularly for nervous system and blood. Moderate vitamin B12 deficiency is common even with normal hematological parameters. Diagnosis and treatment are delayed because of non-specific symptoms, normal blood count and lack of awareness.

Objectives

To find out the prevalence of hidden vitamin B12 deficiency in patients with normal blood count.

Materials and Methods

We reviewed the results of vitamin B12 tests which were ordered for patients at King Khalid University Hospital, King Saud University between 1st of January- 30thof December 2012. Those with low vitamin B12 and normal blood count were contacted and interviewed and were asked for consent to participate in this retrospective study and to answer detailed medical history questions on dietary habits, medical illnesses, gastro-intestinal surgical procedures, and long term medications.

Results

 Out of 3045 patients, there were 415 (155 males and 260 females, aged  36 +/- 18 years) with normal blood count, but low vitamin B12 level, which was between 40-140 pmol/l ( normal 145-637). 350 patients agreed (81 males and 170 females), but complete information was obtained only from 251 patients (71.71%). Symptoms included fatigue, tingling and numbness, impaired short-term memory, insomnia and impaired concentration. Identified causes of Vitamin B12 deficiency were as follows: 65 patients (26%) had partial gastrectomy, 12 (5%) had resection of the terminal ileum, 16 (6%) had gastric atrophy, 18 (7%) had celiac disease, 36 (14%) were vegetarians, 49 (20%) were diabetic on metformin, 47 (19%) were on proton pump inhibitors, and in 8 (3%) the cause could not be identified.

Conclusion

Vitamin B12 deficiency is common   even in patients with normal hematological values. There is a need for continuous  awareness program for physicians, dietitians, and general population to identify risk factors, and to implement guidelines for prevention, early detection and treatment of hidden Vitamin B12 deficiency.

Disclosures:

No relevant conflicts of interest to declare.