bluuebunny/crossref_metadata_2025_split huggingface dataset:
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. [Table: see text]
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.