bluuebunny/crossref_metadata_2025 huggingface dataset:
Sustainable improvement in quality indicators in Ontario's surgical oncology program (SOP)
Authors: Stern H. , Fung-Kee-Fung M. , Urbach D. , Smith A. , Brouwers M. , Langer B.
Published: March 2020

6638

Traditional approaches to quality improvement (QI) have in general utilized performance data against benchmarks, and pay for performance to drive quality. In 2002 the SOP of Ontario, Canada, population 12 million, combined such a QI strategy with philosophical, cultural change aimed on the development of a workforce capable of setting and implementing improvements through communities of practice (CoPs) and application of evidence. The objective was to facilitate implementation of a rigorously developed set of performance indicators, guidelines and standards of care. The most tangible examples of early success include the reduction in operative mortality of pancreatic cancer and the improvement in harvesting lymph nodes in colorectal cancer. A series of indicators, guidelines and standards for colorectal, prostate, thoracic, and hepatobiliary cancers, were developed in partnership with the program in evidence-based care utilizing a rigorous and transparent methodological framework. A value-based purchasing contract (volume-based funding dependent on submission of wait time data). Health service delivery research to identify gaps and evaluate success. CoPs approach to engaging surgeons in solving quality gaps, including opinion leaders, workshops, multidisciplinary teamwork and website tools. Significant improvements have been seen in colorectal and pancreatic caancer indicators. In pancreatic cancer they include a reduction in 30 day operative mortality, in Ontario from a mean of 10.2% in 1988–1996 to 4.5% in 2002–2004, a reduction in numbers of surgeons and hospitals performing pancreatic surgery, and an increase in volumes performed in high volume institutions. In colorectal cancer the compliance with the NCI guideline of 12 lymph nodes harvested increased from 27% in 1997–2000 to 69% in 2005. Oncologists have been engaged in solving system gaps through participation in guideline and standard development and implementation using the CoPs approach. Our experience supports the hypothesis that guidelines, standards and performance indicators, value- based purchasing, and CoPs social influence elements are essential components that can change practice and improve quality in a large jurisdiction cancer system.

No significant financial relationships to disclose.
Post-radiation pulmonary epithelial regeneration from transplanted adult stem cells
Authors: Koratkar R. , Lakshmipathy U. , Jiang Y. , Kaur T. , Slater B. , Verfaillie C. M. , Jahagirdar B. N.
Published: March 2020

7022

Background: Pneumonitis and pulmonary damage are common toxicities of chest radiation therapy (RT), which may be reduced by transplantation of stem cells that differentiate into pulmonary epithelium. Multipotent Adult Progenitor Cells (MAPC) are adult bone marrow (BM) derived cells, which after IV injection in NOD-SCID mice, differentiate into epithelial and hematopoietic tissues (Nature 418:41). Here we tested the ability of mouse (m) MAPC to regenerate epithelia after RT, in Fanconi Anemia C (FAC) mouse model, which inherently has DNA repair defects and is over sensitive to DNA-cross linking agents. Methods: One million, enhanced-green fluorescent protein (eGFP)- expressing, wild-type mMAPC were injected IV in FAC mice, 4–24 hours after 7.5 Gy (followed by mitomycin C {MMC} 0.1mg/kg/week X 4 in a subset) or 11 Gy RT. Non-eGFP expressing BM was co-transplanted after myeloablative (11 Gy) RT. BM, lungs, intestine and liver of the recipients were analyzed 3–10 months post-transplant for eGFP+ cells and epithelial (CK+) or hematopoietic (CD45+) differentiation using flowcytometry (BM) & immunohistochemistry. Control FAC mice were identically treated but without MAPC. Results: MAPC engraftment (>1% eGFP+ cells) was absent in all control mice. Following 7.5 Gy RT, autologous BM recovery occurred in all (N=10) mice and 1 mouse had 2.7% donor-derived hematopoietic (eGFP+/CD45+) cells after MMC. In both recipients of 11Gy RT, analyzed 9–10 months post-transplant, 5–7% of all CD45+ BM cells were donor MAPC-derived. No donor MAPC-derived epithelial cells were seen in the intestine or liver. However, lungs of most recipients had clusters of donor MAPC-derived epithelial cells, estimated to comprise 1–8% of all pulmonary epithelial cells, consistent with homing of MAPC in lungs following IV injection and their epithelial differentiation in the post-radiation, regenerative, pulmonary micro- environment. The highest degree of MAPC-derived pulmonary regeneration was seen following 11Gy RT that was persistent at 10 months post- transplant. Conclusions: Following radiation, IV injected mMAPC differentiate into hematopoietic and pulmonary epithelial cells that persist long-term. MAPC transplantation has the potential for reducing radiation-induced pulmonary toxicity.

No significant financial relationships to disclose.
Efficacy of dasatinib in chronic phase chronic myelogenous leukemia patients after imatinib failure according to baseline BCR- ABL mutations
Authors: Hochhaus A. , Branford S. , Radich J. , Mueller M. C. , Shah N. , Erben P. , Ernst T. , Acevedo M. , Nicaise C. , Hughes T.
Published: March 2020

7023

Background: Dasatinib is an oral, multi-targeted BCR-ABL and SRC kinase inhibitor with preclinical activity against 20/21 imatinib (Im) resistant BCR-ABL mutations. Clinical efficacy was demonstrated in phase I, II, and III studies in patients (pts) with chronic myelogenous leukemia (CML) in all phases of the disease and BCR-ABL positive acute lymphoblastic leukemia (ALL). We sought to establish a relationship between type of BCR-ABL mutations associated with Im resistance and efficacy of dasatinib in chronic phase (CP) CML pts. Methods: Between 10/03 and 03/06, dasatinib was commenced in 1,093 CP-CML pts recruited for three consecutive trials and administered for a median of 8.7 months (range <1–25.9). BCR-ABL mRNA was screened for mutations of amino acids 207–517 by D-HPLC and/or regular sequencing and data are available from 961 cases (88%). ABL polymorphisms K247R and E499E were excluded from analysis. Results: Prior to dasatinib, 75 different BCR-ABL mutations involving 56 amino acids were detected in 18/240 Im intolerant (7.5%) and 324/721 (45%) Im resistant pts. 267 pts showed one, 53 pts two, 16 pts three, and six pts four mutations. In Im resistant pts, response was not different between 370 pts with and 351 pts without baseline mutations: Complete hematologic response (CHR) was achieved in 89% vs 92%; major cytogenetic response (MCR) in 48% vs 52% being complete (CCR) in 38 vs 36%, respectively. Response dynamics were associated with preclinical activity of dasatinib: classifying mutations for IC50 values <2, 2–20 and >1,000nM (T315I), CHR was achieved in 93, 85 and 28%; MCR in 48, 42 and 0%; and CCR in 37, 35 and 0% of cases, respectively. During follow up, new mutations were detected in 30 cases, predominantly T315I (n=10), Y253H/F (n=4), and F317L (n=3). Conclusions: We conclude that dasatinib is capable of inducing hematologic and cytogenetic remissions in a significant proportion of Im resistant pts associated with BCR-ABL mutations, except T315I, but also in pts with BCR-ABL independent causes of resistance. Quality of response depends on the individual type of the mutation which is consistent with preclinical observations.

No significant financial relationships to disclose.
Response dynamics to nilotinib depend on the type of BCR-ABL mutations in patients with chronic myelogenous leukemia (CML) after imatinib failure
Authors: Mueller M. C. , Branford S. , Radich J. , Kim D. W. , Martinelli G. , Saglio G. , Hughes T. , Shou Y. , Weitzman A. , Baccarani M. , Hochhaus A.
Published: March 2020

7024

Background: Nilotinib (AMN107) is an oral, aminopyrimidine-derivative, selective inhibitor of the BCR-ABL tyrosine kinase with improved potency and specificity compared with imatinib. In preclinical models, activity of nilotinib was also demonstrated in 32/33 imatinib- resistant mutant cell lines. We sought to explore the efficacy of nilotinib in vivo according to the type of preexisting BCR-ABL mutations associated with imatinib resistance. Methods: We have investigated peripheral blood samples from 101 chronic phase (CP) and 41 accelerated phase (AP) CML patients (pts) who had been enrolled in a phase II study investigating the efficacy and safety of 400mg nilotinib bid after imatinib failure. Screening for BCR-ABL mutations was performed by D-HPLC combined with DNA sequencing. The analysis covered amino acids 207–517 of the BCR-ABL tyrosine kinase domain. Results: Prior to nilotinib, 24 different BCR-ABL mutations involving 20 amino acids were detected affecting 44% CP and 61% AP pts. After 6 mo of therapy, complete hematologic response was achieved in 59%, major cytogenetic response (MCR) in 25% being complete (CCR) in 16% of pts with mutations vs 81%, 51% and 33% of pts without mutations, respectively. Response dynamics were associated with preclinical activity of nilotinib: MCR was reached in 10/18 pts with mutations associated with preclinical IC50 to nilotinib of <100nM, 2/9 pts with IC50 of 100–1,000 nM, and 0/4 pts with mutation T315I demonstrating virtual resistance to imatinib and nilotinib. In AP pts, hematologic response was achieved in 56% and 31%, MCR in 24% vs 19%, and CCR in 24% vs 13% of pts with or without mutations, respectively. Conclusions: Nilotinib is efficacious in pts with BCR-ABL mutations, except T315I, as well as in patients with BCR-ABL-independent resistance. Time to response may depend on the individual type of the mutation and correlates with the IC50 to nilotinib. Thus, nilotinib may have an important therapeutic role in imatinib resistance as well as in frontline CML therapy to prevent emergence of resistant clones.

[Table: see text]
Dasatinib 140 mg QD compared to 70 mg BID in advanced-phase CML or Ph(+) ALL resistant or intolerant to imatinib: One-year results of CA180–035
Authors: Pasquini R. , Ottmann O. G. , Goh Y. T. , Kim D. , Dorlhiac Llacer P. E. , DiPersio J. F. , Khoury H. J. , Van Tornout J. M. , Damokosh A. , Kantarjian H. M.
Published: March 2020

7025

Background: Dasatinib, an oral multi-targeted kinase inhibitor of BCR-ABL and SRC family kinases, has been shown to be safe and effective at 70 mg BID in advanced phase CML and Ph(+) ALL resistant or intolerant to imatinib. QD and BID schedules were equipotent in Phase I which led to this dose-optimization study. Methods: In this Phase-III, open-label, prospective study, patients with imatinib-resistant or intolerant advanced phase CML or Ph(+) ALL were randomized to dasatinib 140 mg QD or 70 mg BID. The primary objective compared the major hematologic response (HR) rate between the 2 regimens. Dose escalation was allowed for inadequate response and dose reduction for drug toxicity. Results: From June 2005 through March 2006, 611 patients (56% male) were randomized (median age 55 years). 42% of patients received imatinib at doses >600 mg/d and 37% were treated for >3 y. Response rates, with a median follow-up of 6.5 mo (range <1 to 17 mo), are summarized in the table below. Median durations of HR and progression-free survival were 10.2 and 7.9 mo for the 140-mg QD regimen vs 12.3 and 11.7 mo in the 70-mg BID arm. Drug-related toxicities in 140-mg QD (n=304) vs 70-mg BID (n=305) arms, respectively, listed as all grades (grade 3–4), were: pleural effusion 16% vs 23%, P=0.024 (5% vs 6%); peripheral edema 6% vs 13%, P=0.004 (<1%/1%); pericardial effusion <1% vs 4%, P=0.012 (0% vs 1%); neutropenia 85% vs 87% (65% vs 70%); thrombocytopenia 89% vs 92% (68% vs 70%). Dose reductions (24% vs 36%, P=0.002) and interruptions (47% vs 54%, P=0.105) were required less frequently for the 140-mg QD regimen, whereas dose escalations were more prevalent (33% vs 22%, P=0.005). Conclusions: Dasatinib 140 mg QD shows comparable hematologic and cytogenetic response and a trend for improved tolerability in relation to 70 mg BID. Further follow-up is ongoing to assess the long-term benefit of these two schedules in patients with ABP-CML or Ph(+) ALL; 1-year follow-up will be presented.

[Table: see text] [Table: see text]
Phase I/II study of SPC2996, an RNA antagonist of Bcl-2, in patients with advanced chronic lymphocytic leukemia (CLL)
Authors: Tilly H. , Coiffier B. , Michallet A. S. , Radford J. A. , Geisler C. H. , Gadeberg O. , Dalseg A. , Steenken E. J. , Worsaae Dalby L.
Published: March 2020

7036

Background: SPC2996 is a novel Bcl-2 mRNA antagonist, based on the high affinity RNA analogue, Locked Nucleic Acid (LNA), being developed by Santaris Pharma for the treatment of CLL. Bcl-2 expression is typically high in CLL cells and epidemiologic data suggest that over expression of Bcl-2 is associated with a less favourable outcome in this disease. Methods: The study was an international, multicenter, dose escalating phase I/II study. Included were patients with relapsed or refractory Chronic Lymphocytic Leukemia requiring therapy, with a screening blood sample showing circulating lymphocyte counts of > 5×109/L and expressing the phenotype CD5+CD20+CD23+. Number of patients: 3 at the first two dose levels and 6 at the following levels. The patients received 6 intravenous infusions over a 2 week period with a 6 months follow up period. Assessments included: physical examinations, ECG, CT-scan, flow cytometry, PK, mRNA Bcl-2, clinical chemistry and hematology. Results: A total of 25 patients have been treated with the last patient completing treatment on 29 September 2006. Final data will be presented at ASCO. Preliminary data show a patient population with mean age 63.6 years; 68 % male; median 6.5 years of disease; median 3 prior therapies. Dose escalation was stopped after group E (4 mg/kg/dose) due to 2 DLTs in this group. A decrease in lymphocyte count was observed in 6 out of 6 pts in group E, which started within 24 hrs of the first administration of the investigational drug. Four out of 6 pts showed a maximal reduction in lymphocyte count of = 50%. Lymph node data show a decrease in total lymph node SPD of = 50% in 1 out of 5 pt in group D (2 mg/kg) and 2 out of 4 pts in group E (4 mg/kg/dose). Conclusions: Treatment of CLL patients with SPC2996 gives promising results. In group E all patients responded with an immediate decrease in lymphocyte count after receiving the initial administration of 4 mg/kg. A new investigation has been started to explore other dosing regimens, giving a smaller number of higher doses.

[Table: see text]
Increased frequency and suppressive function of CD4+ CD25high regulatory T-cells in acute myeloid leukemia patients
Authors: Boyiadzis M. , Szczepanski M. , Strauss L. , Czystowska M. , Welsh A. , Foon K. , Whiteside T. L.
Published: March 2020

7054

Background: Regulatory CD4+CD25+ T cells (T reg) are critical regulators of immune tolerance. However, the functional role of T reg in human tumor immunity has been less well studied. The frequency of circulating Treg is increased in patients with solid malignancies. We evaluated the frequency, phenotype and suppressive function of T reg in patients with acute myeloid leukemia (AML). Methods: The frequency and phenotype of CD4+ CD25high T cells were investigated in the peripheral blood of fifteen newly diagnosed AML patients prior to any treatment and fifteen healthy donors by multiparameter flow cytometry. The suppressive function of Treg was evaluated using CFSE-labeled fresh autologous CD4+CD25- T cells activated with an anti-CD3 antibody. Results: The percentage of circulating CD4+ CD25high Treg was higher (p <0.001) in the AML patients (5.2 ± 1.3%, range 0.4 −7%) compared to healthy donors (1.1 ± 0.2%, range 0.8–1.5%). T reg expressing Foxp3, CTLA-4, CD45 RO, CCR4 and Fas receptor (CD95) were significantly elevated in the circulation of AML patients, but GITR expression on Treg was low. Suppression mediated by T reg co-incubated with proliferating autologous responders was also significantly higher (p<0.001) in AML than that mediated by control T reg (75 ± 6% vs 12%± 4%). Conclusions: These results indicate that T reg accumulate in the periphery of patients with AML and have vigorous suppressive functions. This high suppressive activity may impair the host anti-tumor responses and promote leukemogenesis.

No significant financial relationships to disclose.
Effect of hematologic improvement (HI) on survival in patients (pts) given targeted therapy (TT) as initial treatment of acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (HR-MDS)
Authors: Yanada M. , Huang X. , O'Brien S. , Garcia-Manero G. , Ravandi F. , Borthakur G. , Issa J. , Giles F. , Kantarjian H. , Estey E.
Published: March 2020

7059

Background: Recent years have seen the introduction of TT for pts with AML and HR- MDS (> 10% marrow blasts). New criteria, less stringent than those for CR, for response to these agents have been promulgated, giving rise to the response category HI. However, the effect of achieving HI on survival is uncertain. Methods: 180 pts, median age 73, with AML or HR-MDS received TT, most commonly decitabine (69 pts), from 2000–2006. Treatment-related death occurred in 11%, CR in 28%, CRp in 6%, and 55% (99 pts) were resistant. We examined survival in these 99 according to whether TT produced HI, blood count criteria for which were as defined by the International Working Group (IWG) for MDS. Initially, we, unlike the IWG, did not require any duration of HI, however; in subsequent analyses, we required durations of = 4 weeks (HI-4) and, like the IWG, = 8 weeks (HI-8). Results: Survival time dated from start of TT was similar in the 32 pts who achieved HI and the 67 who did not. However, the 13 pts with HI-8 lived longer than those with shorter or no HI (48% vs. 11% at 2 years, p=0.01) as did the 14 with HI-4 (p=0.01). Because HI-4 and HI-8 pts had to live long enough to achieve and maintain HI, we re-did the analysis including only the 84 pts who lived = 67 days from start of TT, the median time needed to observe HI-4. This analysis, which included HI-4, age, and cytogenetics as predictors of survival, indicated that HI-4 was the strongest predictor of longer survival (HR 0.34, 95% CI 0.13–0.86, p=0.02). Results were analogous when we limited the analysis to the 68 pts who lived at least 138 days, by which time 75% of HI-4 pts had achieved HI (p=0.06). Conclusions: Our results suggest that HI-4 (or HI-8 as defined by the IWG) following TT confers a survival benefit in AML or HR-MDS.

No significant financial relationships to disclose.
Phase II study of clofarabine and cytosine arabinoside in adult patients with relapsed AML and in elderly patients with untreated AML who are at high risk of anthracycline toxicity
Authors: Agura E. D. , Berryman R. , Cooper B. , Fay J. , Holmes H. , Maisel C. , Molina A. , Pineiro L. , Vance E.
Published: March 2020

7064

Purpose: To evaluate the efficacy/safety of a novel AML regimen in elderly patients with heart disease or in patients with a contraindication to ‘standard‘ anthracycline-containing regimens. Patients and Methods: Phase II, open-label design. Eligible pts had elderly de-novo or relapsed AML or would not benefit from 7+3 or simlar therapy. Treatment was CLOF 40 mg/m2, Ara-C 1,000 mg/m2. (d1–5). Results: Patients were accrued and treated from April 2005 through Oct 2006. All pts signed IRB-approved consents. The median age was 67 years (range 38–82 years). Twenty (67%) subjects had received at least one prior cytoxic regimen (excluding 5-AZA). Significant cardiovascular (history of MI, bypass grafting, cardiomyopathy) was present in 43% (13/30) prior to therapy. Thirty pts were enrolled and all recieved at least one day of therapy. 1 pt died within 24 hours of starting treatment due to disease progression. Of the remaining, 29/30 received at least one complete cycle of therapy and 5 received 2 cycles. None received more than 2 cycles. Toxicities were greater in those receiving a second cycle. Grade 4 neutropenia developed in all patients. There were no cases of regimen-related cardiac toxicity. Most patients had some degree of edema and third-spacing syndrome. Several developed a significant but reversible acral rash. 25 patients survived >28 days and are evaluable for hematologic response. The histologic response rate (RR) is 68% (17/25) consisting of 14 (56%) complete remissions (marrow blasts <5%) and 3 (12%) partial responses (PR). There were 13 subjects with known cytogenetic abnormalities, 1 favorable and 12 unfavorable. Complete cytogenetic remissions (CytoCR) occurred in 4 of those patients, by chromosome analysis and/or FISH. Durable remissions and low toxicity allowed some patients to proceed to nonablative allogeneic stem cell transplantation. Conclusion: Clofarabine and Ara-C is an active and well tolerated regimen in myeloid malignancies including “elderly AML” a distinct entity usually associated with poor response rate and high treatment-related toxicities. Other drug combinations with clofarabine are ongoing in hematopoietic transplant and other high risk subgroups.

No significant financial relationships to disclose.
Effect of low-dose cytarabine and aclarubicin in combination with granulocyte colony-stimulating factor priming (CAG regimen) on the outcome of elderly patients with acute myeloid leukemia
Authors: Qian S. , Li J. , Zhang S.
Published: March 2020

7067

Background: To evaluate the efficacy and toxicity of low-dose cytarabine and aclarubicin in combination with granulocyte colony-stimulating factor (G-CSF) protocol in elderly patients with acute myeloid leukemia (AML). Methods: A total of fifty-two elderly patients were enrolled. Twenty-eight patients were male, and 24 were female, with ages ranging from 60 to 81 years (median, 65 years). Complete remission (CR) had not been achieved in five patients after 2 courses of a standard induction regimen including daunorubicin and cytarabine or an equivalent anthracycline-based regimen. Cytogenetic analysis was performed in 40 patients, and unfavourable cytogenetic aberrations were showed in 10 patients. All patients were treated with CAG regimen including low-dose cytarabine (10 mg/m2 per 12 hours, days 1 to 14), aclarubicin (10 mg per day, days 1 to 8), and G-CSF priming (200 μg/m2 per day, days 1 to 14). Results: The overall response rate was 69.2%, and 29 of 52 (55.8%) patients achieved CR, including 23 of 35 (65.8%) patients with previously untreated AML, 6 of 17 (35.2% ) patients with refractory, relapsed and secondary AML, 4 of 9 (44.4%) patients aged over 70 years, 4 of 10 (40.0%) patients with unfavourable cytogenetic aberrations. The early death rate was 7.6%. The median overall survival duration 14 months. Myelosuppression was mild to moderate, severe nonhematologic toxicity was not observed. Conclusions: CAG priming regimen as the induction therapy is well tolerable and effective in elderly patients with AML.

No significant financial relationships to disclose.
Induction of remission in patients with acute myeloid leukemia without prolonged myelosuppression using diphtheria toxin-interleukin 3 fusion protein
Authors: Frankel A. E. , Weir M. A. , Hall P. D. , Holguin M. , Cable C. , Rizzieri D. A. , Hogge D. E.
Published: March 2020

7068

The recombinant diphtheria toxin fusion protein, DT388IL3, composed of the catalytic and translocation domains of diphtheria toxin (DT388) fused to human interleukin-3 (IL3) showed selective cytotoxicity to acute myeloid leukemia (AML) stem cells both in vitro and in vivo and was prepared for a phase I clinical study (Urieto, Protein Exp Purif 33, 123, 2004). FDA approval (BB IND#11314) and IRB approvals were obtained. Seventy-five AML patients were screened and thirty-one patients treated. The median age of treated patients was 62 years (range, 25- 81 years). There were sixteen males and fifteen females. Disease was de novo in three, first relapse in ten, second relapse in eight, and refractory in ten patients. Four patients had a history of MDS, and one had a history of secondary AML. One patient each had previously received an autologous or allogeneic stem cell transplant. Cytogenetics were unfavorable in ten, intermediate in nineteen, and not done in two. Seven patients were treated with 4 μg/kg, eight patients were treated with 5.3 μg/kg, thirteen patients treated with 7.1 μg/kg, and three patients treated with 9.4 μg/kg DT388IL3. Drug-related toxicities were mild to moderate and transient including fever, chills, hypotension, hypoxemia, and hypoalbuminemia. Consistent with an absence of toxicity to normal hematopoietic progenitors, responses occurred in the absence of prolonged myelosuppression. Among thirty evaluable patients, we have observed one CR of 8 months duration, two partial remissions (PRs) lasting one and three months and three minimal responses with clearance of peripheral blasts and marrow blast cytoreductions of 89%, 90% and 93% lasting one to two months. Dose escalation is proceeding.

No significant financial relationships to disclose.
Phase I study of s-trans, trans-farnesylthiosalicylic acid (FTS), a novel oral Ras inhibitor, in patients with refractory hematologic malignancies
Authors: Borthakur G. , Ravandi F. , O'Brien S. , Williams B. , Giles F.
Published: March 2020

7071

Background: Ras activation (mutational or non-mutational) is a key pathway for survival and proliferative advantage of leukemic cells. Farnesyl transferase inhibitors (FTI) that are thought to alter lipid modification of Ras and thereby alter its membrane targeting, are in clinical trial in hematologic malignancies but their target may not be specific for Ras. Toxicities of FTIs include diarrhea, skin rash and hepatic toxicity. FTS is an oral Ras inhibitor that causes dislocation of Ras from its membrane location by competing directly with farnesylated Ras to bind to its putative membrane binding proteins. FTS does not inhibit farnesyl transferase enzyme. Methods: We report on an ongoing phase I study of FTS in patients with relapsed/refractory hematologic malignancies in which FTS is administered orally twice daily on days 1–21 of a 28 day cycle in a “3+3” dose escalation design. Results: To date, 12 patients (pts) have been enrolled, with 11 pts treated (1 cycle=3, 2 cycles=5, 4cycles=1, 2= too early). Four pts were enrolled at dose level (DL) of 100 mg , 3 pts at each DL of 200 and 400 mg and 2 pts at DL of 600 mg. One pt enrolled at 100 mg DL was never treated. Median age was 74 years (range, 57 to 85 years), median ECOG status 1 (range, 0–2) and median no. of prior therapies 2 (range, 0–7). Diagnoses included: Acute myelogenous leukemia (AML) = 6 pts, myelodysplastic syndrome (MDS) = 4 pts, chronic myelomonocytic leukemia (CMML) = 1 pt and chronic myelogenous leukemia (CML) = 1 pt. Of 9 pts evaluable for response, 6 pts (3 MDS, 1 CMML, 2 AML) had hematological improvement (HI) (3 in two lineages, 3 in one lineage). Grade 1 diarrhea has been the only non-hematologic toxicity seen, observed in 8 of 10 (80%) pts evaluable for toxicity and is completely correctable with oral antidiarrheals. Conclusions: FTS shows promising activity in refractory hematologic malignancies and to date has minimal toxicity.

No significant financial relationships to disclose.
Prognostic value of low platelets in MDS patients with del(5q)
Authors: Galili N. , Ahmed A. , Quddus F. , Jandani S. , Gul Z. , Siddiki A. , Mumtaz M. , Mehdi M. , Devuni D. , Raza A.
Published: March 2020

7078

The most common (10–15%) chromosomal abnormality found in myelodysplastic syndromes (MDS) is an interstitial deletion of the long arm of chromosome 5 (del(5q)). The recent finding that lenalidomide is efficacious for MDS patients with del(5q) as either the sole abnormality or as part of a complex karyotype has focused renewed interest in the prognostic characteristics of these patients. We analyzed 189 patients with del(5q), 70 having isolated and 119 having additional chromosomal abnormalities. The median survival for the isolated del(5q) patient was 2.45 years and for those with complex abnormalities was 0.63 years (p=0.001). Each of these groups was then divided by IPSS category; median survival for Low/Int1 (n=56) was 2.46 years and 0.49 years for Int2/High (n=10, p=0.019).Thus our median survival times match previously published results and we have a representative dataset. Since 5q- syndrome patients with normal to high platelets have the best survival, platelet count may be of prognostic significance. We determined the median platelet count for our dataset to be 115,000 and analyzed median survival for patients with greater (n=89) or less (n=88) than the median value. Survival for those with higher platelet counts was 2.6 years, but dropped to 0.54 years with lower counts (p=0.0001). We then analyzed each of these two groups independently for survival based on IPSS, blast % and karyotype. Median survival for patients with >115,000 platelets and either Low/Int1-risk (n=62), <5% blasts (n=46) or an isolated del(5q) (n=46) was 2.95–3.0 years. The survival of these patients dramatically decreased (0.63 years) if they had Int2/High IPSS (n=19) or >10% blasts (=11). The presence of additional chromosomal abnormalities decreased survival to 1.85 years (n=28). A different range of survival times occurred with patients that had <115,000 platelets. Their median survival based on Low/Int1 IPSS (n=20), <5% blasts (n=18) or isolated del(5q)(n=20) was only 0.68–0.84 years. Int2/High IPSS (n=64), >5% blasts (n=50) or additional chromosomal abnormalities (n=68) lowered survival to 0.44–0.49 years. Thus lower platelet counts in del(5q) MDS patients with favorable IPSS (median survival 0.84 years), <5% blasts (median survival 0.68 years) or isolated del(5q) (median survival 0.74 years) appear to have poor prognosis.

No significant financial relationships to disclose.
Validation of IPSS criteria in more than 1,600 MDS patients
Authors: Quddus F. , Ahmed A. , Naqvi S. , Hasan K. , Mumtaz M. , Galili N. , Raza A.
Published: March 2020

7079

Myelodysplastic syndromes (MDS) are a diverse group of clonal stem cell disorders characterized by bone marrow failure, dysmyelopoiesis and peripheral cytopenias and affecting predominantly an elderly population. The International Prognostic Scoring System (IPSS) incorporates the number of peripheral cytopenias, percentage of bone marrow blasts and chromosomal abnormalities and assigns a score to predict survival and risk of disease progression to AML. Using the extensive MDS database at the University of Massachusetts we analyzed survival time in relation to IPSS scoring and also its various individual components, i.e. blast percentage, number of cell lines involved and the number of karyotype abnormalities in 1,200+ patients. The overall median survival time in 1,424 MDS patients as a group was 2.9 years. IPSS low group had the longest median survival time of 7.5 years with IPSS Int-1 3.6 years. There was minimal difference in the median survival time between IPSS Int-2 and IPSS high risk group 1.2 and 1.1 years respectively. These results were significant for a P value of <0.0001. The median survival time for blasts <5% was 5.3 years and blast 5–10% was 1.7 years. Interestingly, there was minimal survival difference between median survival time for blasts 11–20% and blasts >20% showing 1.2 years and 1.3 years respectively. Again, these results were significant for a P value of <0.0001. The median survival time for the number of cytopenias involved was also calculated with 0, 1, 2 and 3 numbers of cytopenias showing 6.4 years, 4.4 years, 2.6 years and 1.8 years respectively, with P value of <0.0001. The median survival time for normal karyotype versus one or two karyotype abnormality was 4.9 years, 2.6 years and 2.4 years respectively. Three or more karyotype abnormalities showed a median survival time of 0.8 years. The P value was again significant (<0.0001). Our results not only validate the prognostic value of IPSS scoring system as a whole but also its various individual prognostic indicators.

No significant financial relationships to disclose.
Phase II trial of decitabine in myelofibrosis with myeloid metaplasia
Authors: Odenike O. , Godwin J. E. , van Besien K. , Huo D. , Stiff P. J. , Wade J. L. , Lester E. , Klekowski N. , Larson R. A. , Stock W.
Published: March 2020

7088

Background: DNA hypermethylation of promoter-specific CpG islands has been implicated in the pathogenesis and progression of disease in MMM. We are evaluating Decitabine, a DNA methyltransferase inhibitor in patients (pts) with MMM. Methods: This is a single stage Phase II trial: planned accrual of 20 pts. Pts had to have MMM with anemia and/or splenomegaly. Decitabine is given subcutaneously (SQ) at a dose of 0.3 mg/kg/d on days 1–5, and days 8–12; cycles are repeated every 6 weeks, in the absence of dose limiting toxicities. Response is determined every 12 weeks as an improvement in cytopenias and/or splenomegaly. CD34+ cells are measured by flow cytometry in peripheral blood at baseline, and at days 5 and 12 of therapy; elevated levels are associated with advanced stage and evolution to blast phase in MMM. Results: Pt characteristics: M/F: 6/4, median age 67 (range 42–89), median absolute CD34+ cell count 116 × 106/L (11–4,959), Dupriez score of 2, 1 and 0 in 50%, 30% and 20% respectively. Median number of cycles administered: 3 (range 1- 9). Median WBC and platelet (plt) count: 5.2 K/uL (1.5–29), and 171 K/uL (47–465 K/uL); 5 pts were red cell transfusion dependent. Grade 4 neutropenia (ANC) occurred in all pts, and grade 3/4 plts in 6 pts. 7 pts have developed febrile neutropenia. Grade 3–4 non-hematologic toxicities include a variceal bleed in a patient with baseline portal hypertension and a splenic infarct occurring in another pt. 7 pts are evaluable for response: 3 pts have responded including 1 pt with a CR (normalization of blood counts and transfusion independence), and 1 pt with a PR (Hb increase of > 2 g/dL). A third pt in the blast phase of the disease had a hematological improvement as evidenced by a normalization in plts (from 62 K/uL to 219 K/uL) associated with a significant decrease (from 2.58 K/uL to 0.03 K/uL) in circulating blasts. The other 4 pts have had stable disease. There was a reduction in CD34+ levels: mean decrease of approximately 75% at day 12 of therapy (p<0.0001). Conclusions: Low dose SQ decitabine is feasible in MMM and is associated with a significant decrease in CD34+ cells. There is preliminary evidence of clinical activity. Myelosupression is significant, though reversible and requires close monitoring. These findings must be validated in a larger group of pts. Sponsored by NCI grant NO1-CM-62201

No significant financial relationships to disclose.
Response to azacitidine in patients with myelodysplastic syndrome with marrow fibrosis
Authors: Juvvadi R. , Rossetti J. M. , Shadduck R. K. , Kaplan R. B. , Kennedy M. , Kramer W. , Lister J.
Published: March 2020

7089

Background: The Myelodysplastic syndrome (MDS) is characterized by aberrant hematopoietic progenitor cell maturation resulting in ineffective hematopoiesis, cytopenia and progression to acute myeloid leukemia. Some individuals with MDS also have fibrosis within the marrow. MDS with marrow fibrosis appears to be biologically and clinically distinct from myeloproliferative disorders with marrow fibrosis such as agnogenic myeloid metaplasia. While azacitidine (AZA), a DNA methyl transferase inhibitor has known activity in MDS, little is known about its efficacy in patients with MDS with marrow fibrosis. Methods: The records of 41 patients with MDS with marrow fibrosis treated with AZA were reviewed. The degree of fibrosis was determined by reticulin staining and ranged from 1+ to 3+. Patients who received at least 2 cycles were considered evaluable for response. All patients were evaluated for toxicity. The International Working Group standardized response criteria for MDS were used for evaluation of response. Results: Patients had a median age of 69 years (range = 44–84). All FAB subtypes were represented (RA = 16, RARS = 6, RAEB = 5, CMML = 8, RAEB-t = 6). The mean International Prognostic Scoring System score was 1.3 and ranged from 0–3.5.. The overall response rate was 63% (26/41): CR = 7% (3/41), PR = 20 % (8/41), major hematological improvement (MHI) = 29% (12/41), and minor hematological improvement (mHI) = 7% (3/41). The response rates did correlate with FAB subgroup or IPSS score. Treatment was well tolerated. The most common side effects were nausea, vomiting, diarrhea and cytopenia. Conclusions: Azacitidine appears to be effective and well tolerated in patients with MDS with marrow fibrosis. Results of this study demonstrate a response rate similar to that reported in previous studies treating MDS regardless of marrow histology. There does not appear to be a material difference in response to AZA between MDS patients with and without marrow fibrosis.

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IL-21 enhances chemoimmunotherapy mediated death of chronic lymphocytic leukemia cells
Authors: Gowda A. C. , Ramanunni A. , Cheney C. , Roda J. , Kindsvogel W. , Henderson D. , pallavur S. , Carson W. , Muthusamy N. , Byrd J. C.
Published: March 2020

7094

Chemoimmunotherapy with fludarabine and rituximab has demonstrated promising clinical activity in CLL. We hypothesized that the IL-21 might enhance the efficacy of this regimen and play a role in immune mediated clearance of CLL cells. Expression of IL21R-a was present (>20% cells +) in 13 of 16 (81%) pts. IL-21 induced direct cytotoxicity of CLL cells (>20% apoptosis) in subset of patients (n=9, 40% ± 15.9, p<0.0001) that directly correlates with expression of surface IL-21 receptor-a (p=0.001). This direct apoptotic effect is time dependent with maximum cytotoxicity observed at 72 hours post treatment at 25ng/ml. IL-21 induced phosphorylation of STAT-1tyr- 701 and STAT-3tyr-705 was seen in cells with apoptosis >20% whereas phosphorylation of STAT-1tyr-701 was not seen in cells failing to undergo apoptosis. In contrast to this, responder and non responder cells exhibited comparable levels of STAT-1, STAT-3 and constitutive Ser727 phosphorylated STAT-3 levels. Further, IL-21 induced upregulation of Bim was observed in the cells undergoing apoptosis. Interestingly, IL-21 enhanced additively, the direct apoptosis by either antibody (rituximab or alemtuzumab) or fludarabine therapy (Pretreatment of CLL cells with IL-21 for 18–20 hours). In contrast to the enhanced fludarabine mediated direct cytotoxic death of B cells, IL-21 failed to enhance the fludarabine mediated death of T cells (n=5, % alive 56±15 vs 58±16 with IL-21) suggesting that this immunotherapeutic strategy will not augment the immunosuppressive effect of fludarabine. IL-21 also enhanced innate immune activation as demonstrated by killer inhibitory receptor matched autologous natural killer cell mediated antibody dependent cellular cytotoxicity against rituximab coated CLL cells by 33% (E: T ratio 25:1, 42% ± 4.4 versus 28% ± 3.1, p<0.0001). In conclusion, our data demonstrates that IL-21 1) enhances autologous CLL NK cell function against rituximab coated tumor cells 2) mediate direct apoptotic signaling that correlates with STAT1 signaling and BIM up-regulation, and 3) enhance sensitivity to both fludarabine and rituximab mediated direct apoptosis. These results provide strong support for future clinical investigation of IL-21 as a single agent and as part of chemoimmunotherapy regimens for CLL.

No significant financial relationships to disclose.
Association of MBL2 genotypes wtih infections and outcome after allogeneic stem cell transplantation
Authors: Papanicolaou G. A. , Mihu C. , Kadeishvili K. , Doll M. , Stokar D. , Buchbinder A. , Hsu K. , O'Reilly R. , Pamer E. G. , Satagopan J.
Published: March 2020

7100

Background: Low MBL2 concentration and MBL2 genotype variants have been associated with an increased risk of infection. Our objective was to correlate MBL2 genotypes with specific infections and outcome of HSCT. Methods: 125 non- consecutive, non-selected HSCT were examined. Patients were classified as high or low risk group based on status of underlying disease. Antifungal prophylaxis consisted of fluconazole 400 mg daily. Patients on steroids received mould prophylaxis. There was no routine antibacterial prophylaxis. Microbiologically confirmed infections were recorded. Genotype was determined by PR-Melting Curve Analysis on blood or buccal swab specimens. MBL genotype was classified as wild-type: A/A (MBL-sufficient, MBL-S) or variant-type: A/O, O/O (MBL deficient, MBL- D). Patients were followed for up to 2 years. Analyses of categorical variables were performed using the Fisher exact test and the Log-Rank test for time to event. Results: Seventy-one (58.2%) patients were homozygous for wild-type MBL2 (AA), 43 (35.3%) were heterozygous (A/0) and 8 (6.5%) were homozygous for variant genotypes (OO). MBL-D group had higher incidence of fungal infections (20% vs 7%, p=0.05), and in particular Aspergillosis (12% vs 3%, p=0.05). MBL-D was associated with a trend for higher rates of bacterial infections (63% vs 46%, p=0.10) and total number of bacterial infections (p=0.10). Rates of respiratory and enteric viral infections or CMV were similar in MBL-D and MBL-S groups (41% vs 38%, p=0.9 and 58% vs. 54% p=1.0 respectively). Patients with MBL-D genotype were at a disadvantage in relapse-free (RFS) and overall survival (OS), (p<0.01 and p=.08). This disadvantage was also observed when stratified by disease risk groups. The estimated 2-year relapse-free survival rate was 30% compared to 53% for MBL-D vs. MBL-S patients (p<0.01). Conclusions: 1) Patients with variant MBL genotype (MBL-D) had a trend for increased incidence and number of bacterial infections. 2) MBL-D genotype and graft versus host disease were risk factors for aspergillosis. 3) MBL-D genotype was associated with worse overall survival and relapse free survival post HSCT. These data suggest that MBL-D patients have impaired immune function compared with MBL-S patients and is consistent with animal data.

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r-HuEPO 40,000 U one time/week before high-dose melphalan allows a tandem autologous peripheral stem-cell transplantation without red blood cell transfusion in multiple myeloma patients: A pilot study
Authors: Martino M. V. , Console G. , Massara E. , Moscato T. , Callea I. , Gatto F. , Pucci G. , Dattola A. , Spiniello E. , Iacopino P.
Published: March 2020

7103

Purpose: To decrease red blood cell (RBC) transfusion requirements during a tandem high-dose melphalan (HDM) for multiple myeloma (MM) patients (PTS), we conducted a pilot study to assess the effect of high-dose of recombinant human erythropoietin (rHuEpo) started during chemotherapy before the first HDM and autologous peripheral blood stem-cell transplantation (APBSCT). Patients and Methods: After induction chemotherapy with VAD, 14 consecutive PTS with MM, stage III, median age 58 years (range 42–62), were mobilized with cyclophosphamide (3–4 g/m2) to collect peripheral blood stem cells (PBSC) and entered a study consisting of two HDM (200 mg/m2) with APBSCT. Enrolled patients received rHuEpo (40,000 U subcutaneously one time/week) as soon as their hemoglobin (Hb) level fell <11 g/dl during induction chemotherapy. rHuEpo was continued at the same dose during PBSC collection and was reintroduced at the time of discharge after the first transplant up to the admission for the second one. If the Hb level exceeded 13 g/dl at any time, rHuEpo was withheld until the concentration decreased to <11 g/dl, at which time it was restarted. Results were compared to those of 20 tandem HDM and APBSCT performed in 15 consecutive historical MM controls matched for hematological parameters. Results: rHuEpo increased the hemoglobin (Hb) level from 10.1 ± 2.5 g/dl at diagnosis to 12.8 ± 2 g/dl at the time of the first HDM; no major adverse effects occurred. Compared to historical controls (46.6%, 7/15), RBC transfusion requirements were significantly lower for rHuEpo recipients (6.6%, 1/14) (P=0.00001). After the tandem HDM and APSCT, fewer RBC transfusions were needed: 3.3 and 1 RBC units for controls and rHuEpo recipients, respectively (P=0.006). Conclusion: The administration of high dose of rHuEpo during induction chemotherapy and interval beetween the first and second HDM cycle permit the realitazion of tandem chemotherapic program with a reduction of blood product support.

No significant financial relationships to disclose.
Efficacy and safety of axitinib (AG-013736; AG) in patients (pts) with advanced non-small cell lung cancer (NSCLC): A phase II trial
Authors: Schiller J. H. , Larson T. , Ou S. I. , Limentani S. A. , Sandler A. B. , Vokes E. E. , Kim S. , Liau K. F. , Bycott P. W. , Olszanski A. J.
Published: March 2020

7507

Background: A correlation between vascular endothelial growth factor (VEGF), microvessel density, and prognosis has been reported in pts with NSCLC. AG is a small molecule inhibitor of the receptor tyrosine kinases, with picomolar potency against VEGFR 1, 2 and 3 and nanomolar potency against PDGFR-β and KIT. This is an open-label, multicenter phase II study examining the efficacy and safety of AG in pts with advanced NSCLC. Methods: Pts with stage IIIB or metastatic NSCLC received AG 5 mg BID. Eligibility criteria included measurable disease and ECOG performance status of 0 or 1. A Simon 2-stage minimax design was used with 18 pts in the first stage plus an additional 14 in the second stage if 1/18 pts responded. The primary endpoint was response rate (RR) according to RECIST. Results: A total of 32 pts were enrolled: median age was 66 yrs (39–80); histologies were adenocarcinoma (75%), squamous cell carcinoma (9%), and not otherwise specified (16%); 56% male/44% female; 72% received prior chemotherapy, 47% prior surgery, 47% prior radiotherapy, 9% investigational therapy, 3% immunotherapy, and 13% were treatment-naïve. Mean duration of treatment was 93 days (1–271). Three (9.4%) investigator confirmed responses were reported with a 95% confidence interval (CI) of 2, 25. Median duration of response was 9.4 months (mo). Median survival was 12.8 mo (95% CI: 9.9 mo, undefined) and progression-free survival was 5.8 mo (95% CI: 3.8 mo, 10.2 mo). 26 (81%) pts discontinued treatment: lack of efficacy 19 pts (59%), adverse events 5 pts (16%), death 1 pt (3%), and withdrawal of consent 1 pt (3%). Grade 3/4 toxicities (=5%) were fatigue (22%), diarrhea (6%), hypertension (6%) and hyponatremia (6%). Conclusions: AG demonstrates single- agent activity in pts with advanced NSCLC. Therapy is well tolerated with manageable toxicity in this population. Further investigation in this setting is warranted.

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