bluuebunny/crossref_metadata_2025_split huggingface dataset:
Defibrotide Low-Dose Continuous Infusion After Allogeneic Stem Cell Transplantation as Prophylaxis for Veno-Occlusive Disease of the Liver.
Authors: Bonini Alessandro , Imovilli Annalisa , Ghirarduzzi Angelo , Silingardi Mauro , Pilia Annalisa , Gugliotta Luigi , Merli Francesco 
Published: October 2019

Abstract
Abstract 3483
Defibrotide (DF) has been shown to be effective in the treatment and prophylaxis of the veno-occlusive disease (VOD) of the liver, a relatively common complication after allogeneic stem cell transplant (SCT). We report our experience in 46 consecutive adult patients (pts). The pts (mean age 41 yrs, range 16–66) were affected by leukemia (22), lymphoma (15), multiple myeloma (4), myelodisplasia (2), solid tumor (2), Fanconi anemia (1). Risk factors for VOD were: resistant disease 9, previous transplant 8, B virus hepatitis 6, liver metastases 1, lymphoma of the liver 1, increased transaminases before conditioning 7. All were transplanted from their HLA-identical siblings; the conditioning regimen was reduced in 17, while it was conventional in 29. All the pts received a combination of drugs as conditioning regimen, 23 of them received Busulfan and 8 of them oral Busulfan. 15 received bone marrow and 31 peripheral blood as source of stem cells. None was T-cell depleted; the GVHD prophylaxis regimen was: CsA alone or combined with MTX 45, FK506+MTX 1. For VOD prophylaxis no heparin was administered, while DF was given at the dose of 10 mg/Kg in continuous iv infusion starting on day +1 until day +21 after the SCT. DF was very well tolerated and no hemorrhagic complications were seen. Blood coagulation significant alterations were: prolonged PT (4/46), prolonged aPTT (3/46), elevated fibrinogen (24/46), (never over 800 mg/dl), low level (less than 50%) of ATIII and/or protein C and or protein S (2/46). By using the VOD Baltimore criteria, only 1 case of VOD was observed on day +29 in a patient who died at day +36 with VOD, aspergillosis and CMV pneumonia. The bilirubin was more than 2 times the normal value in 26/46; US-scan of the liver and Doppler, performed in 16 pts with a possible sign of VOD, was positive only in the patient who died for VOD. We documented 32 infectious complications (16 FUO, 9 gram positive bacteremias, 3 pneumonia and 4 invasive aspergillosis). We documented acute GVHD in 14 pts (12 grade I-II and 2 grade III). Five pts died between +36 and +100 but none for VOD (3 for progression of their disease and 2 for aspergillosis). Our laboratory data demonstrated modest alterations of the coagulative parameters, low consumption of coagulative factors and reduced fibrinolysis. Since in this at risk transplanted population only 1 VOD has been observed, DF low-dose continuous infusion, without heparin, seems able to play a relevant role in the VOD prophylaxis. On considering the favourable results by us and others, the absence of toxicity and the low cost of the drug, we intend to continue this experience with DF as VOD prophylaxis, even if we foretell a large randomized study to find better indications.

Disclosures:
No relevant conflicts of interest to declare.
Reduced-Dosage of Three Drugs Combination of Cyclophosphamide, Bortezomib and Dexamethasone (reduced-CyBorD) Retains High Response Rate with Less Toxicities in Elderly Patients with Multiple Myeloma
Authors: Yagi Hideo , Fujiwara Ryosuke , Sano Keigo , Mariko Fujita , Iizuka Takashi , Yamazaki Keiko , Hanamoto Hitoshi , Tubaki Kazuo 
Published: October 2019

Abstract
Abstract 1865

Background:
The three drugs combination of cyclophosphamide, bortezomib and dexamethasone (CyBorD) has been proven to be a powerful regimen for the treatment of the patients with multiple myeloma (MM). However, twice-weekly schedule of bortezomib and high dose dexamethasone has been shown to cause significant toxicities, including severe peripheral neuropathy (PN). Recently, once-weekly bortezomib induction therapy with CyBorD (modified-CyBorD) has shown less toxicity with high response rate equal to original regimen (Reeder, CB et al. Leukemia 2009). However, more than half of the patients developed bortezomib induced PN (BiPN) in modified-CyBorD. Thus it was still concerned adverse event for the transplant ineligible patients, especially frail elderly patients because it often caused interruption or withdrawal of the treatments, resulting in fewer efficacies. Under these circumstances, we introduced the reduced-dosage of CyBorD regimen (reduced-CyBorD) in the transplant ineligible patients with multiple myeloma for continuation of the treatment.

Methods:
The protocol consisted of bortezomib given intravenously at a dose of 1.3 mg/m2once a week on days 1, 8, 15, cyclophosphamide orally at a dose of 50 mg daily on days 1–21, and dexamethasone orally or intravenously at a dose of 20 mg daily on days 1,2,8,9,15,16 in 4-week cycles. Total of 20 patients, including 12 newly diagnosed and 8 refractory, were treated with reduced-CyBorD and evaluated its efficacy and safety.

Results:
The median age was 72 years (range from 62 to 81). 14 patients were more than 70 year-old (70%). A half of the patients were female. According ISS, 3 patients were classified in stage I, 6 were in II, and 11 were in III. The overall response was 86.6 % with 26.7 % CR/nCR (1 CR, 3 nCR, 5 VGPR and 4 PR). Hematological adverse events were neutropenia (35%; G1/2 n=7), lymphocytopenia (35%; G1/2 n=1, G3/4, n=1), thrombocytopenia (10%; G1/2 n=2). Non-hematological adverse events were pneumonia (20%; G2 n=2, G3 n=2), VZV infection (15%; G2 n=3), cerebral infarction (5%; G2 n=1). Importantly, only three patients (15%) developed grade 1 PN, and no patient reduced or discontinued bortezomib due to PN.

Conclusions:
Reduced-CyBorD with three times once-weekly bortezomib retained high efficacy seen in standard and modified CyBorD (4 times bortezomib administration). Furthermore, it was found that this regimen obviously revealed less toxicity, especially BiPN compared with those previous regimens (See Table). Our results suggested that reduced-CyBorD might be safe and effective approach to the transplant ineligible patients, especially elderly frail patients with MM.

Disclosures:
No relevant conflicts of interest to declare.
Relapse Pattern After Bortezomib Based Salvage Therapy in Patients with Multiple Myeloma
Authors: Ahn Jae-Sook , Yang Deok-Hwan , Jung Sung-Hoon , Lee Se Ryeon , Kim Yeo-Kyeoung , Kim Hyeoung-Joon , Lee Je-Jung 
Published: October 2019

Abstract
Abstract 1869

Backgrounds & Aims:
More intensive and novel therapy options in multiple myeloma (MM) improve the treatment outcome. However, disease evolution, induced with long disease duration and extensive pretreatment, has resulted in changes in the biological behavior of MM and unusual relapse emergence. Therefore, we studied the relapse pattern after bortezomib based salvage treatment in patients with MM and also we analyzed the prognostic significance according to relapse pattern.

Methods:
We have retrospectively analyzed the relapse pattern. Eligibility criteria included primary refractory or relapsed MM patients who must have received previous chemotherapy and they also received at least 2 cycles of bortezomib based salvage treatment. Immunoglobulin M type of MM, primary amyloidosis and plasma cell leukemia were excluded in this study. For evaluation of disease response, International Myeloma Working Group (IMWG) uniform response criteria were used.

Results:
Between November 2004 and August 2011, 132 patients received bortezomib based salvage chemotherapy. In 132 patients, 91 (68.9%) patients showed the disease relapse. The pattern of relapse after bortezomib salvage treatment was heterogeneous, the 14/91 (15.4%) patients relapsed as a novel manifestation comparison with the initiation of bortezomib (plasmacytoma: 7 patients, light chain escape pattern: 4 patients and, plasma cell leukemia: 2 patients). There was no statistical difference in the duration from diagnosis to bortezomib treatment according to novel (group A) vs isoform (group B) relapse. In the group B, the median overall survival after relapse was 16.1 months (95% CI: 11.4–20.8) and the group A was 2.5 months (95% CI: 0.0–5.7)(p=0.000). The 27 out of 132 patients received the retreatment of bortezomib and 23 out of 27 patients showed the disease progression. The 4/24 (16.7%) patients relapsed as a novel manifestation (plasmacytoma: 2 patients, light chain escape pattern: 1 patients and intact immunoglobulin secretion from plasmacytoma type: 1 patient). In patients received retreatment of bortezomib, novel relapsed group showed the trend of poor survival without statistical significance (2.2 months vs 10.0 months) (p=0.30).

Conclusion:
Our report suggests that bortezomib treatment contribute as a selective pressure and it has culminated in novel relapse manifestation. The relapsed patients as novel pattern after bortezomib treatment show the extreme poor prognosis. These findings suggest that these patients may be worth consideration for intensive treatment or early clinical trials.

Disclosures:
No relevant conflicts of interest to declare.
Involvement of NFAT Signaling in Function and Anti-Tumor Reactivity of NK Cells
Authors: Wild Julia S , Schmiedel Benjamin J , Märklin Melanie , Kanz Lothar , Müller Martin R , Salih Helmut R 
Published: October 2019

Abstract
Abstract 1887
NK cells play an important role in anti-tumor immunity. They significantly contribute to the clinical success of allogeneic stem cell transplantation (SCT). Their reactivity as a consequence of an integrative response mediated by various activating and inhibitory surface receptors results in the induction of yet only partially defined signal transduction pathways. One of the major transcriptional regulators in lymphoid cells is NFAT (Nuclear Factor of Activated T Cells). While its role in T cell development and function is meanwhile well defined, surprisingly little is known on its function in NK cells. NFAT seems to be dispensable for NK cell development, but several lines of evidence clearly point to its involvement in NK reactivity and function. Cyclosporin A (CsA) and tacrolimus are immunosuppressive drugs that are widely used in transplant medicine. They mediate their immunosuppressive effects through inhibition of the serine/threonine phosphatase calci-neurin, which dephosphorylates and thereby activates NFAT. Here we studied the role of NFAT in NK cells and found that all five NFAT family members are expressed in NK cells with their levels being dependent on NK cell activation state. CsA and tacrolimus, but not mycophenolic acid which mediates its immunosuppressive effects by inhibiting inosine monophosphate dehydrogenase, reduced activation and degranulation of NK cells, resulting in impaired cytotoxicity and IFN-γ production in response to leukemia targets. NK reactivity was also suppressed by the specific NFAT inhibitors VIVIT and INCA-6, indicating that the calcineurin inhibitors CsA and tacrolimus in fact modulate NK reactivity by inhibition of NFAT proteins and not by potential “off target”-effects. These results provide evidence for the critical involvement of the transcription factor NFAT in NK cell reactivity and also indicate that potential effects on NK cell immunosurveillance should be considered upon choice and dosing of immunosuppressive treatment regimens after SCT.

Disclosures:
No relevant conflicts of interest to declare.
Phase II Multicenter Study of Busulfan-Fludarabine Conditioning Regimen for cord Blood transplantation in Pediatric Acute Myeloid Leukemia
Authors: Ju Hee Young , Kang Hyoung Jin , Lee Ji Won , Kim Hyery , Park Kyung Duk , Shin Hee Young , Lee Soo Hyun , Yoo Keon Hee , Sung Ki Woong , Koo Hong Hoe , Lee Jae Wook , Chung Nak Gyun , Cho Bin , Kim Hack Ki , Lee Young Ho , Park Eun Sil , Lim Jae young , Yoo Eun Sun , Ryu Kyung Ha , Koh Kyung Nam , Im Ho Joon , Seo Jong Jin , Park Sang Kyu , Jung Hyun Joo , Park Jun Eun , Lim Yeon Jung , Ahn Hyo Seop 
Published: October 2019

Abstract
Abstract 1928

Introduction.
Cord blood transplantation (CBT) has become an alternative transplantation for various diseases. CBT has comparable efficacy with unrelated transplantation, but higher transplantation related mortality (TRM) rate upto 50% in early results has been a major obstacle. To reduce TRM, we studied reduced toxicity myeloablative conditioning regimen with busulfan and fludarabine for CBT in pediatric acute myeloid leukemia (AML) patients.

Patients and methods.
This study was a phase II prospective multicenter clinical trial (NCT01274195) and 27 patients were enrolled who underwent CBT with upto 2 HLA mismatch cord blood. Conditioning regimen was composed of fludarabine (40 mg/m2 once daily iv on days -8 ∼ -3), busulfan (0.8 mg/kg every 6 hours iv on days -6 ∼ -3) and rabbit thymoglobulin (2.5 mg/kg once daily iv on days -8 ∼ -6). For GVHD prophylaxis, cyclosporine and MMF were used.

Results.
Nine patients received single unit cord blood, and 18 patients received double unit cord blood. Median dose of nucleated cells and CD34+ cells were 4.23×107/kg (0.5–16.4) and 2.58×105/kg (0.33–6.77), respectively. Primary graft failure developed in 5 patients, and secondary graft failure occurred in 1 patient. Acute and chronic GVHD occurred in 16 patients (59.3%) and 10 patients (37%), respectively. TRM developed in 5 patients (cumulative incidence 22.2%), which included chronic GVHD-associated complication (n=1), post-transplantation lymphoproliferative disease (n=2), pneumonia (n=2), and diastolic cardiomyopathy (n=1). Relapse incidence was 30.9%. The 5-year overall and event-free survival were 46.3% and 40.0%, respectively. Patients who received single unit cord blood showed survival rate of 44.4%, and those who received double unit cord blood showed survival rate of 50%. Univariate analysis revealed that low nucleated cell count (P=0.011), low CD34+ cell count (P=0.002) were independent prognostic factor for survival.

Conclusion.
Reduced intensity conditioning regimen containing fludarabine and iv busulfan showed lower TRM rate than previous studies with myeloablative conditioning regimens. However graft failure and relapse rate were not satisfactory, and further study for optimization of conditioning regimen is warranted.

Disclosures:
No relevant conflicts of interest to declare.
Metaphase Cytogenetic Abnormality (CA) Subtypes in Multiple Myeloma (MM) Treated with Front Line Total Therapy (TT) Protocols TT1, TT2, TT3, TT4 and TT5
Authors: van Rhee Frits , Sawyer Jeffrey R , Usmani Saad Z , Waheed Sarah , Heuck Christoph , Mitchell Alan , Hoering Antje , Barlogie Bart 
Published: October 2019

Abstract
Abstract 193
We have previously reported on the adverse prognostic implications of CA, independently contributing to clinical outcome prediction even in the era of gene expression profiling (GEP). The presence of hypodiploidy/deletion13 (CA13/hypo) was associated with a particular poor prognosis, whereas the absence of CA (no CA) imparted superior outcome; the remainder (other CA) had an intermediate prognosis. Here we provide an update of overall survival (OS) and progression-free survival (PFS) with TT1, TT2 control arm (TT2-), TT2 thalidomide arm (TT2+), TT3a, TT3b, TT4-light (TT4-L, fractionated melphalan + VTD), and TT4-standard (TT4-S). The backbone of protocols was tandem transplantation with melphalan 200mg/m2 (MEL-200). TT2 employed thalidomide during all phases of the protocol in a randomized fashion. TT3a introduced bortezomib and 3-yr maintenance with VTD for year 1 and TD for years 2 and 3; TT3b applied VRD with lenalidomide in all 3 years of maintenance; TT4-S used standard MEL-200 as conditioning, whilst in TT4 MEL-50 for 4 consecutive days was given. In addition, TT4L applied 1 instead of 2 cycles of induction and consolidation therapy. Both OS and PFS were consistently superior with “no CA” followed by “other CA” and “CA13/hypo” in all trials including TT4-S (Figure 1). However, there was a striking reversal of the benefit order with TT4-L: “no CA” fared worst, and both “CA13/hypo” and “other CA” had equally superior OS and PFS. The analyses were repeated for TT3 and TT4, limiting TT3 to the ∼85% of patients with GEP-defined low-risk MM, since TT4 was designed specifically for GEP70 low risk MM (Figure 2). In the “no CA” group, 2-yr OS and PFS were >90% in TT3a/b and TT4-S, compared to 75% in TT4-L (p=0.007 and 0.01 for TT3 and TT4-s, respectively). TT4-L patients had ∼90% 2-yr OS and PFS in case of “CA13/hypo” and “other CA”, contrasting with ∼60–80% 2-yr OS and PFS for the other protocols. It could be speculated that patients with “no CA” have more slowly cycling micro-environment dependent disease in which the well-recognized MEL dose response relationship is crucial. Conversely, the more genomically unstable “CA13/hypo”-type MM may benefit from the synergistic effect of repeated application of MEL and bortezomib, which could be related to the ability of bortezomib to disrupt protein metabolism required for repair of MEL-induced DNA damage. The basis for these finding is under investigation, but do support the need for further studies investigating novel conditioning regimens and their exact beneficiaries, which could further personalize myeloma care and may be related to bortezomib's presence in the fractionated melphalan transplant regimen in TT4-L.

Disclosures:
No relevant conflicts of interest to declare.
Comparative Analysis of the Value of Consolidation with Allogeneic Hematopoietic Stem Cell Transplantation (AHSCT) Versus High-Dose Cytarabine (HDAC) Based Chemotherapy in Patients (pts) with Acute Myeloid Leukemia (AML) with Chromosome Seven Abnormalities
Authors: Jabbour Elias J. , Kantarjian Hagop M. , Oran Betul , Ravandi Farhad , Ghanem Hady , Khouri Issa , Garcia-Manero Guillermo , Mathisen Michael S , Bashir Qaiser , Saliba Rima M , Khouri Maria , Pierce Sherry A. , Brandt Mark , Champlin Richard E. , De Lima Marcos 
Published: October 2019

Abstract
Abstract 2029

Background:
The karyotype of leukemic cells in pts with AML is one of the most pronounced prognostic factors determining response to therapy and overall outcome. Pts with AML and chromosome 7 abnormalities have poor prognosis and AHSCT is highly indicated for such pts.

Aims:
To determine to what extent AHSCT reduces relapses and improve survival in pts with AML with chromosome 7 abnormalities compared with alternative post remission therapy.

Methods:
We reviewed 2167 consecutive pts with AML referred to our department between 2000 and 2011. Among them, 325 were diagnosed with chromosome 7 abnormalities as a single abnormality (n=53, 16%) or complex (n=272, 84%). Of these, 126 pts (39%) were induced with IA based regimen and 49 (39%) of them achieved a complete remission (CR) or complete remission without platelet recovery (CRp) and pursued consolidation therapy. These pts were matched with 33 pts with available donors who were referred to receive an ASHCT in first CR.

Results:
Median age for pts receiving consolidation chemotherapy versus AHSCT was 56 (range, 19–78) and 49 (range, 22–71) years, respectively (<0.001). Of the 33 pts who received an AHSCT, 17 received their stem cells from related siblings, 15 from unrelated matched donors, and 1 from a haplo-identical donor. Conditioning regimen were fludarabine and busulfan in 26 pts and fludarabine and melphalan in 7 pts. Graft versus host disease (GVHD) prohylaxis consisted mainly of tacrolimus and short methotrexate. Median time to engraftment was 12 days for neutrophils (range, 9–20) and 19 days for platelets (range, 10–53). Acute Grade 3/4 and chronic GVHD were observed at the rate of 3% and 45%, respectively. With a median follow-up of 29 weeks (range, 14–239) for pts receiving consolidation chemotherapy and of 168 weeks (range, 5–454) for pts receiving AHSCT, the 4-year event-free survival (EFS) rates were 4% and 51%, respectively (p<0.001). The median EFS for pts receiving consolidation chemotherapy and AHSCT were 17 (range, 1–330) and 51 (range, 1–456) weeks (Figure 1), respectively. The 4-year OS rates were 7% and 62%, respectively (p<0.001), with the median survival being 35 (range, 1–568) and 389 (range, 1–456) weeks, respectively (Figure 2).

Conclusion:
AHSCT applied as a consolidation in first CR in pts with chromosome 7 abnormalities is associated with a significant reduction of the relapse rate and improvement of OS compared to alternative post remission therapy.

Disclosures:
No relevant conflicts of interest to declare.
Comorbidity and Outcomes for Patients Over Age 65 Years Treated with Allogeneic Stem Cell Transplantation for Acute Myelogenous Leukemia and Myelodysplastic Syndrome
Authors: Conter Henry J. , Nguyen Nhu-Nhu , Rondon Gabriela , Chen Julianne , Shpall Elizabeth J , Khouri Issa , Giralt Sergio A , Champlin Richard E. , DeLima Marcos 
Published: October 2019

Abstract
Abstract 2032

Background:
Acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) preferentially afflict patients 65 years of age and older. Patients in this age group are likely to have underlying comorbid conditions. These comorbidities affect treatment planning decisions and clinical outcomes. Here we report comorbidity-stratified outcomes of patients older than 64 treated at MD Anderson Cancer Center from 1996 until 2011, inclusive, treated with allogeneic stem cell transplant (ASCT).

Methods:
182 patients older than 64 received an ASCT for AML (n=143) or MDS (n=39). Patient charts were reviewed and comorbidity data abstracted using a standardized form. Burden of comorbidity was assessed using the Hematopoetic Stem Cell Transplant-Specific Comorbidity Index (HSCT-CI). Low-risk, intermediate-risk, and high-risk patients were categorised at 0, 1–2, and >=3 points as per the HSCT-CI. 157 patients were evaluable for pre-transplant comorbidity. Outcomes of interest were cumulative incidence of transplant-related mortality (TRM), cumulative incidence of relapse-related mortality (RRM), incidence of acute and chronic graft-versus-host disease (GVHD), and overall survival (OS). These were estimated from the date of transplantation.

Results:
The median age of transplanted patients was 67 (range 65–79), and 37 patients age 70 and older were treated. The majority of patients were intermediate-risk and high-risk patients (table), 9 patients had HSCT-CI scores of >=5. Median follow-up for alive patients was 12.6 months (n=63; range 0–118). Cumulative incidence of TRM was 6% at 100 days, 14% at 1 year, 23% at 2 years, and 36% at 5 years (figure). Cumulative incidence of RRM was 36% at 1 year, 42% at 2 years, and 47% at 5 years. HSCT-CI did not independently predict for either TRM or RRM (log-rank test p=0.95). The incidence of grade III and IV acute GVHD was 10% of all patients. The cumulative incidence of chronic GVHD was 25% at 1 year, 27% at 2 years, and 30% at 5 years, with no association between GVHD and HSCT-CI comorbidity.

Conclusion:
ASCT is a curative option for selected patients over age 64. HSCT-CI did not predict TRM or survival on this cohort of high-risk patients. Disease relapse was of greater concern than TRM, and so novel approaches to relapse prevention are needed.

Disclosures:
No relevant conflicts of interest to declare.