bluuebunny/crossref_metadata_2025 huggingface dataset:
Fludarabine Plus I-131 Tositumomab as Initial Treatment for Follicular Lymphoma: Half of Patients In Remission at Over 10 Years Median Followup.
Authors: Martin Peter , Coleman Morton , Furman Richard R. , Vallabhajosula Shankar , Kim Dong Sun , Edelstein Andrew , Morrison Julia , Elstrom Rebecca , Ruan Jia , Goldsmith Stanley J. , Leonard John P.
Published: October 2019

Abstract 1785

Background:

The sequential combination of chemotherapy and radioimmunotherapy has been shown to be effective front-line treatment for patients with follicular lymphoma (FL). We report ten-year followup results of a phase II trial of abbreviated fludarabine followed by tositumomab and I-131 tositumomab in patients with untreated follicular lymphoma.

Methods:

Patients with untreated follicular lymphoma received fludarabine 25 mg/m2/d for five days every five weeks for three cycles followed in six to eight weeks by tositumomab and I-131 tositumomab.

Results:

Thirty-eight patients were enrolled. One patient was withdrawn due to ineligible histology. The median age of eligible patients was 53 years, median time from diagnosis was 3.5 months, and 43% of patients had a high-risk FLIPI score. Two patients did not receive radioimmunotherapy; one patient had a myocardial infarction during fludarabine and was not evaluable, and one patient had persistent cytopenias following three cycles of fludarabine. All 35 patients that completed the regimen responded (ORR 100%). With a median follow-up of 128.5 months for all 37 eligible patients, the 10-year intent-to-treat overall survival is 69% and the progression-free survival is 51%. Seventeen patients have progressed (range 2–102 months). Sixteen patients remain in remission with no evidence of disease more than ten years from enrollment. Only four patients have relapsed beyond five years. Four patients have developed MDS (range 16–84 months), one of whom evolved to AML.

Conclusions:

Fludarabine followed by tositumomab and I-131 tositumomab is very effective at inducing long-lasting complete remissions in FL. The efficacy and long-term safety of sequential chemotherapy plus radioimmunotherapy should continue to be evaluated in the context of the range of therapeutic options for the initial treatment of follicular lymphoma.

Disclosures:

Furman: GSK: Speakers Bureau. Leonard:GSK: Consultancy.
Age-Dependent Influence of TNF-α Polymorphism on Progression Free Survival of ASCT In Multiple Myeloma Patients
Authors: Buda Gabriele , Martino Alessandro , Orciuolo Enrico , Maggini Valentina , Lapi Francesco , Galimberti Sara , Barale Roberto , Rossi Anna Maria , Petrini Mario
Published: October 2019

Abstract 1829

Proinflammatory cytokines are suspected to play a role in the pathogenesis of multiple myeloma (MM). TNF-a, a potent mediator of inflammation, is involved in the malignant transformation of plasma cells and plasma cell proliferation. TNF-a determination was also reported to be a good parameter for monitoring therapy outcome during treatment with different protocols. Variation in TNF-a levels can be related to gene expression, which is regulated at transcriptional level, as well as to genetic polymorphism (SNP). Specifically, a G to A substitution at position -308 is associated with higher levels of TNF-a.

From September 2006 to April 2010 we selected 202 MM patients and 234 control cases matched for age and sex. TNF-a SNP at position -308 was determined on genomic DNA extracted from blood samples. These genotypes frequencies obtained were in Hardy-Weinberg equilibrium. Our results indicate that the cytokine TNF-a gene SNP do not confer differences in the susceptibility of MM. Then, we studied the correlation between the SNPs of TNF-a -308 and the outcome of 91 MM patients that underwent to autologous bone marrow transplantation (ASCT) after a similar induction therapy (DAV or TAD). Melphalan 200 mg/mq (or 100 mg/mq, for the elderly patients) was used as conditioning regimen (table I).

In the MM carrying the rarest A allele of TNF-a the overall response to chemotherapy and outcome to ASCT were similar to patients carriers G allele. On the contrary TNF-a seems to be an independent factor to predict the outcome in patients affected by MM modifying the progression free survival age related, if patients are > 60 yrs (p= 0.02). In particular pts > 60 years carrying the G/G genotype showed a better progression free survival compared to the same age patients carrying A/A or G/A genotypes (table II and table III ). Previous studies demonstrated that an higher plasma TNF-a concentration is significantly associated with advancing age and the combination of TNF-a and melphalan results in high response rates. Several mechanisms could be responsible for this, in particular a direct effect of TNF-a on the anti-tumour activity of melphalan. In our population the high dose of melphalan used in the youngest population is able to mask the role of TNF-a, but in the elderly patients it is clear as the impact of polymorphism plays a role in the better PFS of patients carrying the G/G genotype. To conclude we confirm the interesting role of TNF-a SNP in the outcome of MM in particular in the subset of pts characterized by a physiological high production of TNF-a.

Disclosures:

No relevant conflicts of interest to declare.
The BH3 Mimetic, ABT-737, Overcomes Stromal-Mediated Pro-Survival Signals and Synergizes with PHA-767491, a Dual Cdc7/CDK9 Inhibitor, In Acute Myeloid Leukaemia
Authors: Morrell Ruth C , Szegezdi Eva , Halpin-McCormick Anna , Cawley Karen , Samali Afshin , O'Dwyer Michael
Published: October 2019

Abstract 1841

ABT-737 is a small molecule inhibitor of Bcl-2 and Bcl-xL with reported activity in pre-clinical in-vitro and in-vivo studies of acute myeloid leukaemia(AML) but to date no data has been reported on its activity in an AML co-culture model. To address this, we examined the effects of co-culture of AML cell lines (MOLM-13, ML-1, KG-1, OCI-AML2) with HS5 cells, a human stromal cell line, on sensitivity to Ara-C and ABT-737. All cell lines cultured in the presence of HS-5 stroma demonstrated a significant reduction in Ara-C-induced apoptosis (% relative reduction - OCI-AML2:80%; ML1:65%; MOLM-13:53%; KG-1:55%) as compared to cells cultured in suspension in normal complete media, with the effect on expression of Bcl-2 family members being currently under evaluation. In contrast, in the presence of ABT-737, HS-5 co-culture did not provide any protective effect whatsoever to AML cells, with IC50 ranging from 0.1 to 0.3μM in the cell lines noted above, regardless of the presence of stroma. OCI-AML3, an AML cell line known to express high levels of Mcl-1 was resistant to ABT-737 in both normal suspension cultures and co-culture. Indeed Mcl-1, an important pro-survival protein in haematopoietic cells is thought to be a key factor promoting resistance to ABT-737 and it has recently been reported that transcriptional upregulation of Mcl-1 may follow exposure to ABT-737. Thus, the combination of ABT-737 with strategies to deplete Mcl-1 is particularly attractive. Cdk9 inhibition is such a strategy. Since Cdk9 phosphorylates RNA polymerase II affecting the rate of transcription, inhibition leads to a depletion of proteins with short half-lives, such as Mcl-1. Here we report that resistance of OCI-AML3 cells to ABT-737-induced apoptosis can be overcome by combination with PHA-767491, a novel dual Cdc7/CDK9 inhibitor. OCI-AML3 cells were treated with increasing concentrations of ABT-737, PHA-767491 or both. Co-administration resulted in a strong synergistic apoptosis-inducing effect as assessed by AnnexinV staining, with combination indices, as calculated by Chou et Talalay, for a range of doses of both drugs of <1 (range 0.3–0.9). Importantly, the sensitising effect of PHA-767491 was seen only at concentrations (≥ 2μM) that resulted in significant downregulation of Mcl-1 protein expression, implicating Mcl-1 downregulation as a possible cause of synergy. We are currently investigating the precise role of Mcl-1 in this regard. In conclusion, taken together, these studies support that ABT-737, possibly in combination with agents to deplete Mcl-1, represents a promising therapeutic strategy for AML and warrants further evaluation.

Disclosures:

No relevant conflicts of interest to declare.
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 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 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 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 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 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 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 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 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.
Radiotherapy in Stage I and II Extranodal Marginal Zone B-Cell Lymphoma of Mucosa-Associated Lymphoid Tissue (MALT): Analysis of the Surveillance, Epidemiology, and End Results (SEER) Database
Authors: Olszewski Adam J. , Desai Amrita
Published: October 2019

Abstract 2053

Background:

External beam radiotherapy (RT) is the treatment of choice for many patients with localized (stage IE-IIE) MALT lymphoma, primarily based on single-institution case series. There are no specific factors favoring surgical management or addition of systemic therapy in these cases. The purpose of this study was to evaluate the association of RT used as the initial treatment strategy with survival outcomes in a population-based cohort.

Methods:

We analyzed 6,111 cases of st I/IIE MALT lymphoma of the most common anatomical locations included in the SEER database, diagnosed between 1998 and 2009. Cases identified through autopsy or death certificate only, as well as those with unknown stage or RT status were excluded. RT was recorded only if administered as part of the initial treatment strategy within 12 months of diagnosis. 5-year relative survival was summarized for treated and untreated patients. For multivariate regression, flexible parametric Royston-Parmar models for overall survival were fitted for each site, adjusting for clinical and socioeconomic confounders. Age and surgical excision of the primary site were always included as variables. No records of progression-free survival, alternative or subsequent systemic treatments or watchful waiting strategy were available.

Results:

There were significant differences in the rates of RT utilization, baseline clinical characteristics and survival outcomes. Median age varied from 57 years (cutaneous lymphoma) to 69 years (breast). In multivariate models, RT was associated with improved survival in patients with ocular, cutaneous or gastric localization with no significant association for the pulmonary, intestinal, salivary, mammary and thyroid sites. The hazard ratio in gastric MALT was non-proportional and increased from 0.45 at 6 months to 0.97 at 24 months form diagnosis. Long-term prognosis for ocular, salivary and cutaneous thyroid lymphomas was excellent, but was less favorable for the gastrointestinal or pulmonary locations.

Conclusions:

The survival benefits of RT in early-stage MALT lymphoma are most evident for ocular and cutaneous sites of origin, and this modality can be advocated for treatment. The relative survival of 99–100% in those anatomical subtypes may indicate curative potential in patients who receive RT. In gastric MALT lymphoma the benefit is limited to the early period of two years of follow up. Inferior survival despite local radiotherapy in pulmonary and intestinal locations may suggest higher rates of occult disseminated disease and potential value of systemic therapy.

Disclosures:

No relevant conflicts of interest to declare.
Thymocyte Reprogramming by the Scl, Lmo1 and Notch1 Oncogenes
Authors: Gerby Bastien , Tremblay Cedric Stevens , Tremblay Mathieu , Rojas-Sutterlin Shanti , Hoang Trang
Published: October 2019

Abstract 207

Normal thymic progenitors are devoid of self-renewal capacity, which is a distinctive stem cell property. These thymic progenitors progress into the thymus through several stages of differentiation (DN1, DN2-4, DP) before giving rise to CD4+ or CD8+ immunocompetent cells that are released into the periphery. Therfore, thymic output requires continuous seeding from stem cell-derived progenitors. T cell acute lymphoblastic leukemia (T-ALL) is a common cancer in children. Almost 25% of childhood T-ALL involve the SCL transcription factor and/or its nuclear partners LMO1/2 and more than 50% harbour gain of function mutations of NOTCH1. Using a transgenic mouse model that reproduces the human disease, we previously showed that activation of SCL, LMO1 and Notch1 in the thymus is sufficient to transform thymocyte progenitors and induce T-ALL (Tremblay M et al., 2010). Here, we explore the mechanism of transformation by these three oncogenes in primary thymocytes during the pre-leukemic stage. Our results indicate that the SCL and LMO1 oncogenes collaborate to confer an aberrant self-renewal potential to a subset of pre-leukemic thymocytes, via induction of a stem cell gene signature that also distinguishes primary T-ALL patient samples in which LMO2 is expressed. Furthermore, our clonality and functional analyses indicate that only a few clones of preleukemic thymocytes from Scl-Lmo1 mice are able to colonize the thymus of recipient mice in transplantation assays and produce mature T-cells during the pre-leukemic stage. Precisely, we show that self-renewal activity is enriched in DN3 thymocytes which eventually acquire Notch1 gain of function mutations and leukemia initiating activity. On the other hand, the Notch1 oncogene by itself does not confer self-renewal properties to thymocytes. Rather, we show that the Notch1 oncogene enhances the activity of the SCL-LMO1 oncogene to increase the frequency of pre-Leukemic Stem Cells (pre-LSCs) without modifying the clonal expansion of individual pre-LSC when transplanted at limiting dilutions. These results indicate that the Notch1 oncogene modifies the self-renewal activity enforced by the SCLtgLMO1tg oncogenes into a self-renewal of expansion, typical of a transformed state. Furthermore, NOTCH1 confers an invasive potential to SCLtgLMO1tg thymocytes that become thymus-independent and acquire the capacity to develop in peripheral organs. Therefore, our observations are consistent with the view that the SCL-LMO1 oncogenic transcription factors reprogram DN3 thymocytes to acquire self-renewal potential, thereby establishing a pre-leukemic state. Finally, NOTCH1 activation provides a strong signal that collaborates with the SCL-LMO1 oncogenes to induce T-ALL by favoring self-renewal divisions in pre-LSC together with an invasive capacity.

Disclosures:

No relevant conflicts of interest to declare.
Relationship Between vitamin D Deficiency and Bone Fragility in Sickle Cell Disease: A Cohort Study of 56 adults.
Authors: Arlet Jean-Benoît , Courbebaisse Marie , Chatellier Gilles , Eladari Dominique , Souberbielle Jean-Claude , Friedlander Gerard , De Montalembert Mariane , Prié Dominique , Pouchot Jacques , Ribeil Jean-Antoine
Published: October 2019

Abstract 2103

Background:

Recent studies suggest that patients with sickle cell disease (SCD) have profound vitamin D (VD) deficiency. Limited data exist on the effect of VD deficiency on bone fragility in these patients.

Objectives:

To assess the prevalence of VD deficiency in adults with SCD and its consequences on bone metabolism and fragility.

Methods:

This prospective study included 56 SCD adult patients (mean age 29.8 ± 9.5 years), in a clinically steady state. Clinical and laboratory data were recorded. Bone mineral density (BMD) was measured using dual X-ray absorptiometry. Fracture history, BMD, avascular osteonecrosis, H-shaped vertebra and markers of mineral metabolism were compared between two groups of patients presenting very low (≤6 ng/ml, n=26) (group 1) and low (>6 ng/ml, n=26) (group 2) 25(OH)D concentration, respectively.

Results:

Median 25(OH)D concentration was 6 ng/mL. VD deficiency (25(OH)D <10 ng/mL) was found in 42 out of 56 patients (75%) and secondary hyperparathyroidism in 40 (71.4%). History of fracture was documented in 17 patients (30.3%), osteopenia and/or ospeoporosis in 39.6% of patients. Overall, patients of group 1 were more likely to have sustained a fracture (42.8%) compared to patients of group 2 (17.8%) (p=0.04). These patients had also lower body mass index and significantly higher parathyroid hormone, C-terminal telopeptides of type I-collagen and bone-specific alkaline phosphatase serum levels. There was no difference between group for BMD, avascular osteonecrosis history, H-shaped vertebra, and disease severity markers.

Conclusion:

This study suggests that VD deficiency is a key feature in SCD-bone disease. It is highly prevalent and associated with hyperparathyroidism, bone resorption markers, and history of fracture. The optimal supplementation regimen remains to be determined.

Disclosures:

No relevant conflicts of interest to declare.
The Biological Effects and Mechanisms of Interleukin-34 in the U937 Human Leukemic Cell Model.
Authors: Booker Burthia E , Adunyah Samuel E.
Published: October 2019

Abstract 2155

Interleukin-34 (IL-34) is a cytokine consisting of a 39kD homodimer employing the Macrophage Colony Stimulating Factor (MCSF/CSF-1) receptor; recently identified through functional proteomics experiments. Among its physiological activities, IL-34 has been shown to promote monocyte viability and proliferation; promote the differentiation of bone marrow cells into macrophage progenitors and induce pro-inflammatory cytokines: IL-1β, IL-6, TNF-α, and GM-CSF in human whole blood. All of the published work on IL-34 involves its effects on hematopoietic and osteoclast progenitors; however, it is not known whether IL-34 has the ability to induce any of these physiological responses in cancer cells. The purpose of this study is to evaluate the biological effects of IL-34 in the U937 leukemia cell line while deducing the signaling mechanisms associated with these effects. Thus far, we have evaluated IL-34 on U937 cells for cell growth and proliferation, induction of cytokines, migration, differentiation and apoptosis. Congruently, we are also exploring the JAK/STAT and PI3K/Akt signaling pathways for activation. In U937 cells, we have noted that while IL-34 does not induce cell growth or proliferation, there is a reduction in cells in the S phase of the cell cycle at 48hours, post treatment. Additionally, we note a differential induction of a number of Th1/Th2/Th17 and pro-inflammatory cytokines, namely IL-1α, IL-1b, IL-6, IL-8 and G-CSF. Our results also show that IL-34 influences the migration of monocytes by the possible induction of chemoattractant cytokines in media. Furthermore, we report that IL-34 is able to differentiate the human leukemic cellular model, U937, from monoblastic precursor cells towards monocyte- and macrophage-like cells. Accompanying this differentiation appears to be a selective induction of apoptosis in undifferentiated U937 cells, supported by the induction of cleaved Caspase-3. To our knowledge, this is the first report that IL-34 induces differentiation in human leukemic cellular model, let alone any cancer model. Exploration of the JAK/STAT signaling pathway has identified TYK2 and JAK 1 as mediators of the IL-34 signal through in U937 cells, while identification of its associated STAT proteins is currently ongoing. Interestingly, the evaluation of the PI3K/Akt pathway has demonstrated a reduction of phosphorylated Akt, suggesting an influence of PTEN, which is currently being evaluated. This research may provide insight into the influence of IL-34 in the cancer microenvironment as compared to the normal cell microenvironment, resulting in potential therapies targeting its mechanistic actions.

Disclosures:

No relevant conflicts of interest to declare.
Cleaved High Molecular Weight Kininogen Induces Endothelial Progenitor Cell Senescence by Stimulation of JNK/FOXO4/MnSOD Pathway.
Authors: Zhu Xuemei , Colman Robert W. , Wu Yi
Published: October 2019

Abstract 2181

Objectives:

High molecular weight kininogen (HK) is a major component of plasma kallikrein-kinin system (KKS), and is cleaved to its active form (HKa) upon the activation of this system. Although the KKS activation is widely involved in a variety of pathological settings, the activities of its activation product HKa remain largely unknown. Recently we have reported that HKa accelerates the onset of endothelial progenitor cell (EPC) senescence by induction of reactive oxygen species (Arterioscler Thromb Vasc Biol. 2011;31:883), whereas the mechanism is not clear. In this study, we investigated whether HKa induces EPC senescence via stimulation of c-Jun N-terminal kinases (JNK)-related pathway.

Methods:

Human EPCs were treated with HKa in different concentrations for 72 hours, which were followed by the measurement of phospharylation of JNK at Thr183/tyr185 and transcription factor FOXO4 at Thr451, as well as expression of Mn-superoxide dismutase (MnSOD) at protein and mRNA level. To narrow down the functional domain of HKa, recombinant proteins of human HK heavy chain (HC, 19–380aa) and light chain (LC, 390–644aa) were generated for determining which domain(s) mediates the effect of HKa.

Results:

In a concentration-dependent manner, HKa treatment induced phosphorylation of JNK at Thr183/Tyr185, and its downstream phosphorylation of transcription factor FOXO4 at Thr451. Concomitantly, HKa upregulated the expression of MnSOD at protein and mRNA levels as measured by Western blot and real time RT-PCR. However, it did not affect the expression of catalase. Similar to HKa, the heavy chain (HC), but not the light chain, increased the percentage of senescent EPCs (63%±6.6 for HC v.s. 77.5%±6.02 for HKa). Moreover, HC at 100 nM increased FOXO4 phosphorylation at Thr451 and the expression of MnSOD in EPCs. Besides, both of HKa and its HC stimulated the production of intracellular H2O2.

Conclusion:

These above results demonstrate that HKa accelerates the onset of EPC senescence by stimulating JNK/FOXO4/MnSOD pathway, and its effect is mediated by the HC.

Disclosures:

No relevant conflicts of interest to declare.
Identification of a Novel Exosite (Glu634-Arg639) in the Spacer Domain of ADAMTS13 Required for Recognition of Von Willebrand Factor.
Authors: Casina Veronica , Hanby Hayley , Lyalenko Anastasia , Zheng X. Long
Published: October 2019

Abstract 2214

Exosite binding plays a key role in cleavage of VWF by ADAMTS13 (A Disintegrin And Metalloprotease with ThromboSpondin type 1 repeats, 13). Two exosites that are evolutionarily conserved from zebra fish to mammals have been identified in the spacer domain by sequence alignment. Previous studies have shown that exosite 3 in the spacer domain plays a critical role for substrate recognition (Blood 115:2300–10, 2010), and modification of this exosite generates ADAMTS13 variants with improved specific activity but reduced autoantibody binding (Blood 119:3836–43, 2012). In the present study, using a site-directed mutagenesis approach, we identified a novel exosite near exosite 3 in the spacer domain, termed exosite 4, a region between residues Glu634 and Arg639. A partial (ΔEx4a:deletion of Leu632-Asp635 or ΔEx4b:deletion of Arg636-Arg639) or complete deletion of the exosite (ΔEx4) significantly impaired proteolytic activity towards peptidyl VWF73 and multimeric VWF. Moreover, substitution of all surface exposed residues in Ex4A (LTED/AAAA) or Ex4b (RLPR/AAAA) with alanine had a similarly detrimental effect on proteolytic activity. Further studies demonstrated that the residues Asp635 and Arg636 in exosite 4 play a critical role for substrate recognition. We conclude that the region between residues Glu634 and Arg639 is a novel exosite necessary for recognition and cleavage of VWF.

Disclosures:

No relevant conflicts of interest to declare.