bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early and Sustained Response to Azacytidine in High-Risk MDS Patients with Monosomy 7 Correlates with Increased Apoptosis and Not CDKN2B Demethylation.
Authors: Raj Kavita K. , John Alison M. , Ho Aloysius , Thomas Nicholas Shaun B. , Mufti Ghulam J. 
Published: April 2020

Abstract
Disease progression in MDS is associated with CDKN2B (encodes p15INK4b) promoter methylation and an inhibition of apoptosis. We therefore studied predominantly high-risk MDS patients treated with azacitidine in order to determine whether clinical responses correlated with changes in CDKN2B promoter methylation and bone marrow apoptosis. In all, 24 patients (19 male) with a median age of 66.7 years were treated with azacitidine (75mg/m2/day x 7 days, every 28 days). Patients were FAB RA (n=2), RAEB (n=7), RAEB-T (n=13) and AML (n=2) with 18/24 having an IPSS risk of Int-2 or High. Cytogenetic abnormalities were present in 17 patients (4 patients with monosomy 7; 1 with der(7) as the sole cytogenetic abnormality and 1 as part of a complex karyotype; 4 with trisomy 8; 1 with 11q abnormalities; 1 with 5q-, 1 with 20q, 1 with iso 17p; and the remaining -y or misc). A median of 5 courses of azacitidine was administered (range: 1–13). Complete remission was achieved in 6 patients: 2 with trisomy 8, 3 with monosomy 7, and 1 with der(7). Haematological Improvement (HI) in Platelets occurred in 6 patients, HI-E in 2 patients, and HI-N in 3 patients. Five patients had a reduction in blast percentage. Importantly, even in complete cytogenetic remission bone marrow dysplasia persisted. All patients with monosomy 7/der(7) are in complete remission (median follow up of 10 months) whereas those with trisomy 8 relapsed their response at 2 and 5 months. CDKN2B promoter methylation in patients pre-treatment and at hematological remission was studied by bisulfite genomic sequencing (region: −263 to +243). There was no difference in CDKN2B methylation in CD34+ or CD33+ cells of responders and non-responders (both had low level, heterogeneous methylation patterns). However, CDKN2B was unmethylated in lymphocytes of responders and methylated in non-responders. Demethylation was not evident following treatment. Baseline bone marrow mononuclear cell apoptosis of 16 patients (12 RAEB, 2 RAEB T, 2 AML) analysed by PI/Annexin V staining (6% mean, 4.06% median); was not significantly different from normal controls (2%: mean, 0.77%; median, n=3) (2 sample T-test 0.103). From 12 treated patients, 8 patients responding to azacitidine (6 CR; 2 blast reduction with HI-E major and HI-N major, regardless of cytogenetic subtype), the mean apoptosis at the time of remission (11.61% mean; 9% median) was significantly higher than the mean apoptosis of 1.82% (median, 1.095%) in 4 non- responders (2 sample t-test p = 0.006). Azacitidine treatment induced sustained responses in all patients with monosomy 7, in whom the CDKN2B promoter is unmethylated. We propose that increased bone marrow apoptosis disrupts the leukaemic clone and leads to disease regression to an earlier stage.
Myelodysplastic Syndromes (MDS): An International Practice and Treatment Survey.
Authors: List Alan F. ,   for the MDS Foundation Inc.
Published: April 2020

Abstract
Results from The MDS Foundation’s 2004–2005 Practices & Treatment Survey, distributed to 102 Centers of Excellence (48 US and 53 international academic medical centers), indicate that the perceived incidence of MDS patients is increasing. 70% of the 70 responding centers that reported higher case loads in the last five years attributed the increase to rising participation in and interest in clinical trials (37%), improved diagnostics and treatments (27%), and increased awareness and referrals (16%). Although 83% of the respondents indicated that their institution uses the World Health Organization (WHO) classification system, only 28% of referred patients were categorized by WHO subtype. Analyses of treatment strategies revealed that an average of 41% of patients in Low and Intermediate-1 International Prognostic Scoring System (IPSS) risk groups received supportive care only (median, 50%), 34% received active treatment (median, 30%), and 25% are being followed expectantly (median, 25%). For IPSS Intermediate-2 and High risk groups, an average of 30% of patients received supportive care (median, 30%), whereas 63% received active treatment (median, 70%), and 7% are being observed (median, 10%). Survey responses showed a wide array of interventions including transfusions (94%, with 28% indicating transfusion as the only type of supportive care used), erythropoietin alone or with myeloid growth factors, G- or GM-CSF alone, cyclosporine, antibiotics, vitamins (B12, B6, folic acid), or corticosteroids. Median ranking of the current investigative agents for the treatment of MDS indicate that lenalidomide, decitabine, and oral iron chelation therapy are viewed as the most clinically useful agents for all IPSS risk groups; amifostine and calcitriol were viewed as being least useful; arsenic trioxide and thalidomide were viewed as somewhat useful. These survey responses from investigators associated with academic medical centers with clinical research or diagnostic programs in MDS suggest that more disparate MDS treatment approaches may be expected in the office-based setting. The epidemiologic and treatment survey responses indicate that there is an urgent need for establishing guidelines that would assist clinicians in effectively matching patient and disease characteristics with treatment options, particularly as a number of therapies are moving forward in clinical testing phases.
Darbepoetin Alfa for the Treatment of Anemia in Patients with Myelodysplastic Syndrome.
Authors: Giraldo Pilar , Nomdedeu Benet , Loscertales Javier , Requena Carmen , de Paz Raquel , Tormo Mar , Navarro Pilar , Benedit Patricia , Gasquet Jose Antonio ,   On Behalf of the ARM Study Group
Published: April 2020

Abstract
Background: Anemia is one of the main problems associated with myelodysplastic syndrome (MDS) leading to fatigue, increased red blood cell transfusions, and reduced quality of life. Erythropoiesis-stimulating proteins (ESPs) have been used to treat MDS-induced anemia. Darbepoetin alfa (Aranesp®) is a unique ESP that can be administered less frequently than recombinant human erythropoietin (rHuEPO) due to its longer serum half-life, increasing patient convenience and possibly enhancing treatment compliance.
Methods: We performed a retrospective analysis of medical records from anemic patients with confirmed MDS that had been treated with darbepoetin alfa in 2004 in 9 Spanish centers. Data were collected 16 weeks before and 16 weeks after the starting date of darbepoetin alfa treatment. Response to darbepoetin alfa was evaluated using the International Working Group criteria.
Results: This study included data from 81 patients. Median age was 70 years (range, 38.0 – 87.0) at diagnosis and 75 years (range, 39.0 – 91.0) at the beginning of treatment with darbepoetin alfa. The proportion of female patients was 56.8%. French-American-British (FAB) classification: 39.5% refractory anemia (RA), 46.9% RA with ringed sideroblasts (RARS), 9.9% RA with excess blasts (RAEB), 1.2% RAEB in transformation (RAEB-T), and 2.5% chronic myelomonocytic leukemia (CMML). International Prognostic Scoring System (IPSS) classification: 55.3% low; 36.2% intermediate-1 and 8.5% intermediate-2. ECOG status: 0–1 in 79% of patients. Median baseline hemoglobin level was 8.9 g/dL (range, 8.4 – 9.1). Previous treatment with recombinant human erythropoietin (rHuEPO) occurred in 44.4% of patients and time from last rHuEPO dose to initiation of darbepoetin alfa treatment was lower than 1 week in 53.1% of patients (average of 16.7 weeks; range, 0.0–159.0). Starting darbepoetin alfa dose was 150 mcg/week in 69.1% and 300 mcg/week in 29.6% of patients. Darbepoetin alfa dose was increased in 18.5% and reduced in 9.9% of patients. Median time until dose adjustment was 8 weeks. Granulocyte colony-stimulating factor (G-CSF, Filgrastim) support was required in 6.5% of patients and this percentage was maintained during the 16-week followup. A total of 69 patients (34 rHuEPO-naïve and 35 rHuEPO-treated) were evaluable for efficacy analysis (Hb and transfusion data available). Erythroid response was achieved in 55% of patients (29% major and 26% minor) with 65% of rHuEPO-naïve responders and 46% of rHuEPO-treated responders. A total of 66% responses were achieved before or at week 8.
Conclusion: These results indicate that darbepoetin alfa treatment appears to be effective in patients with MDS regardless of whether or not they had received previous treatment with rHuEPO.
Bortezomib in Combination with High-Dose Dexamethasone and Continuous Low-Dose Oral Cyclophosphamide for Relapsed Multiple Myeloma.
Authors: Kropff Martin , Bisping Guido , Liebisch Peter , Sezer Orhan , Einsele Hermann , Straka Christian , Kroeger Nicolaus , Metzner Bernd , Engelhardt Monika , Lang Nicola , Hentrich Marcus , Wolf Hans , von Schilling Christoph , Salwender Hans , Berdel Wolfgang E. , Kienast Joachim 
Published: April 2020

Abstract
Single agent bortezomib treatment yields ≥ partial responses (PR) in 24% of patients with relapsed, refractory multiple myeloma (MM) and 38% of patients who had received 1 – 3 previous therapies. Dexamethasone (DEX) adds to anti-myeloma activity of bortezomib. The present phase II trial was intitiated to study bortezomib combined with DEX and continuous low-dose oral cyclophosphamide (CY).
50 patients with advanced MM were scheduled to receive bortezomib 1.3 mg/m2 IV days 1, 4, 8, and 11 q 3 weeks for 8 cycles in combination with DEX 20 mg PO on the day of bortezomib injection and the day thereafter, and CY 50 mg PO daily; followed by 3 cycles bortezomib 1.3 mg/m2 IV days 1, 8, 15, and 22 q 5 weeks in combination with corresponding DEX and CY schedules. Patient characteristics included median age 63 years; B2M &gt; 3,0 mg/L, 64%; CRP &gt; 3,0 mg/L, 25%; deletion of chromosome 13, 46%; median number of prior regimens, 2 (range 1 – 9), and prior standard therapy &gt; 12 mo, 94 %. 78% of patients had relapsed after high-dose melphalan. The EBMT criteria were used for definition of response. Five patients (10%) achieved a complete response, 33 (66%) a PR, and 6 (12%) a minor response (MR) resulting in an overall response rate (≥MR) of 88%. On an intention-to-treat basis, median event-free survival (EFS) with this combination was 10 months. After a median follow-up of 10 months, median overall survival has not been reached. Notably, chromosome 13 deletion was predictive of a favorable outcome (higher response rate, longer EFS) in this setting.
The median number or treatment cycles given was 6. 56% of the patients terminated study treatment prematurely, mainly for disease progression (10%) or adverse events (34%). Grade 4 neutropenia during at least one treatment cycle occurred in one patient (2%), grade 4 thrombocytopenia in 17%; one thrombocytopenic bleeding. Grade 3/4 non-hematologic toxicities requiring dose or schedule modifications included infections (26%), peripheral neuropathy (25%), fatigue (15%), herpes zoster (13%), and cardiovascular events (11%). One patient succumbed to infection without predisposing neutropenia.
Bortezomib in combination with DEX and CY appears to be a highly active regimen without increased toxicity compared to a single agent treatment with bortezomib. Maintenance treatment might be required for prolonged EFS.
Doxil, Vincritine, Reduced Frequency Dexamethasone in Combination with Thalidomide (DVd-T) Is Associated with Higher Overall and Progression Free Survival as Compared to DVd in Patients with Multiple Myeloma (MM).
Authors: Almhanna Khaldoun , Suppiah Revathi , Baz Rachid , Karam Mary Ann , Faiman Beth , Reed Janice , Hussein Mohamad 
Published: April 2020

Abstract
Background: Although initially responsive to chemotherapy, multiple myeloma ultimately relapses. Replacing Adriamycin with pegylated liposomal doxorubicin in the VAD regimen results in a regimen with better safety profile (less neutropenia, alopecia, fewer hospital and clinic visit). DVd resulted in normalizing the angiogenic process however this did not improve PFS or OS. Thalidomide because of its antiangiogenic, immunomodulatory effects and chemo-sensitizing activity through modulating integrins was added to the DVd regimen. Adding the thalidomide to the DVd regimen resulted in an overall response rate of 89% with a CR/NCR rate of 49 % as compared to 60% and 18 % respectively for the DVd. At this stage it is not clear if the quality of response affects outcome in multiple myeloma patients receiving conventional dose therapy. To better assess the prognostic implication of improved quality responses and to define the role of up front Thalidomide, we compared the DVd to the DVd-T regimen by retrospectively reviewing the two trial data, the follow up for both trials is mature. It is still not clear whether thalidomide is more appropriately used up front or in the management of relapse.
Methods: we recruited a total of 68 patients in our DVd trial versus 105 patient in the DVd-T trial. A total of 155 patients in both groups were evaluable for follow-up and response (58 received DVd and 97 received DVd-T). Patients were matched for age, disease prognosticators, disease stage, and bone marrow involvement. The newly diagnosed patients were comparable in both groups except for the b 2 microglobulin which was higher in the DVd-T group as compared to the DVd (3.2 vs. 5.0; respectively. p0.05). In the relapsed/refractory group of patients, all variables were comparable.
Results: The median follow up was 5 years for the DVd group and 2 years for the DVd-T group. Median age for the DVd was 62 years, which was similar to the DVd-T. For the DVd vs. the DVd-T group of patients achieving complete and near complete remission was 17% vs. 49.5% respectively with a p value of 0.001. Progression free survival was significantly longer for the DVd-T regimens vs. the DVd (28 vs. 13 months p= 0.0002) Figure 1., and for over all survival the median is not reached for the DVd-T vs. 28 months for he DVd (p=0.006).
Conclusion: we conclude that the addition of thalidomide significantly improved the quality of response and this appears to translate in to a PFS and OS benefit. While, recently published SWOG data suggests that the overall survival is determined by the duration of the PFS and not the quality of the response, this discrepancy could be related to the small number of patients in our study or the lack of use of biologic immune modulators among SWOG patients.
Figure Figure
Weekly Bortezomib with or without Glucocorticosteroids Is Effective in Patients with Relapsed or Refractory Multiple Myeloma.
Authors: Suvannasankha Attaya , Smith Gina G. , Abonour Rafat 
Published: April 2020

Abstract
Well-tolerated, effective and simple regimens are warranted in multiple myeloma (MM). Bortezomib is an active novel agent for MM therapy. A phase III randomized trial in patients with relapsed and refractory MM demonstrates bortezomib to be superior to dexamethasone in time to progression and overall survival. The FDA approved schedule of bortezomib (days 1, 4, 8 and 11 infusion of a 21-day cycle) is rather inconvenient. We investigated the synergy between weekly bortezomib and glucocorticosteroids in order to the frequency of patients’ clinic visits.
Methods: Patients with relapsed or refractory MM referred to Indiana University Cancer Center were offered bortezomib 1.3 mg/m2 by intravenous push and methylprednisone 500–2000 mg by intravenous infusion over 30 minutes. Treatments were given on days 1, 8 and 15 of 28-day cycles. Therapy was maintained as long as subjects’ diseases were responding and side effects were minimal. Both efficacy and tolerability of the regimen were evaluated.
Results: Thirty patients were treated on the protocol. Twenty six received bortezomib in combination with methylprednisone, while 4 received single agent bortezomib. Patient age ranged from 50–79 years (median 62); there were 15 females and 15 males. Twenty-one patients (70%) had prior high dose chemotherapy and stem cell transplantation, including 2 with prior allogeneic stem cell transplantation. Thirteen patients were in third relapse or higher. The response was evaluable in 28 patients. Eighteen patients achieved clinical response (60 %), including 1 (3%) complete response, 1 (3%) near complete response, and 16 (53%) partial response. Five (17%) had stable disease, and 5 (17%) had progression. The median number of treatment cycles was 5 (range 2 to 12). Among responders, the median number of cycles given to achieve the best response was 3 cycles (range 1–8 cycles). Major adverse effects included neuropathy (2 grade III), gastrointestinal side effects (1 grade III) and congestive heart failure (1 grade III). The updated time to progression and overall survival will be presented at the meeting.
Conclusion: Weekly bortezomib with or without steroid is a convenient and efficacious therapy for patients with heavily pretreated relapsed and refractory MM and should be further explored in a larger patient cohort.
JAK2 V617F Mutational Status in Myelofibrosis at and before Disease Progression Including Leukemic Transformation: A Longitudinal Study in 68 Patients.
Authors: Mesa Ruben A. , Powell Heather , Lasho Terra , Tefferi Ayalew 
Published: April 2020

Abstract
Background: An acquired point mutations of JAK2 (V617F) was recently described in a substantial proportion of patients with myeloproliferative disorders (MPD), including myelofibrosis with myeloid metaplasia (MMM). The current study examines i) JAK2 V617F mutational status at time of leukemic transformation (LT) of MMM and its clinical correlates, ii) the possibility of changes over time in mutational status in MMM patients that have either undergone leukemic transformation (LT) or experienced disease progression.
Methods: Mutation analysis for JAK2 V617F was performed in DNA derived from either peripheral blood mononuclear cells (PBMC) (i.e. fresh specimens) using genomic DNA amplified by PCR, or extracted from cytogenetic pellets in archived specimens. Fluorescent dye chemistry sequencing was performed using the same primers used for amplification.
Results: The study population consisted of 68 patients including 33 patients with disease transformation into AML.
i. MMM patient cohort with LT (n=33). The JAK2 V617F mutant allele was detected in 21 of the 33 patients (64%; homozygous in 6%) at the time of LT. As expected, PPMM was over-represented in the group with the mutation but the presence of the mutation affected neither the clinical presentation at time of LT or overall outcome. Furthermore, in 9 patients (7 heterozygotes and 2 with wild-type allele), archived bone marrow that was collected at a median of 23 months (range, 3–105) before LT was available and disclosed no change in mutational status.
ii. MMM patient cohort with disease progression without LT (n=35; 19 AMM, 9 PPMM, 7 PTMM): Each patient in this group had at least two bone marrow or peripheral blood samples that were collected at two different time points separated by a median of 18.2 months (range (3–82). Of the total 35 patients in this group, 32 (91%) showed no change in JAK2 V617F mutational status over time including 3 patients in whom the first sample was collected before they transformed into MMM from antecedent PV or ET. In the remaining 3 patients, a switch from wild-type to heterozygous state (1 patient), and heterozygous to homozygous (2 patients), was documented after 78, 43, and 83 months, respectively.
Conclusions: In most instances, JAK2 V617F mutational status in MMM remains unchanged over time including during leukemic transformation. Furthermore, the presence of the mutation in MMM-related LT does not appear to affect clinical outcome. These observations undermine the role of JAK2 V617F in either disease progression or LT in MMM.
Thrombocytopenia Is a Strong Adverse Feature in Transplant-Eligible Patients with Myelofibrosis: Utility for an Improved CBC-Based Scoring System.
Authors: Dingli David , Schwager Susan M. , Mesa Ruben A. , Li Chin-Yang , Tefferi Ayalew 
Published: April 2020

Abstract
Background: Allogeneic hematopoietic stem cell transplantation is potentially curative in agnogenic myeloid metaplasia (AMM) but is associated with substantial mortality and morbidity that necessitates accurate identification of patients in whom benefit outweighs risk. The current single institutional study investigates prognostic variables in transplant-eligible patients with AMM with the main objective of improved discrimination between intermediate- and high-risk patient categories.
Methods: Patients diagnosed with AMM before the age of 60 years and seen at Mayo Clinic were identified and the diagnosis confirmed. Relevant demographic, clinical and laboratory characteristics were abstracted and the impact of various parameters on overall survival was evaluated with univariate and multivariate analysis.
Results: A cohort of 159 patients (median age 52 years, range 18–60; 89 males) with AMM is described. Median follow-up from initial diagnosis was 63 months (range 0–300). During this period, 102 patients have died; overall median survival 79 months. Multivariate analysis of parameters measured in all study patients at diagnosis identified thrombocytopenia (platelet count &lt; 100 x 109/L) as the strongest predictor of inferior survival (p=0.002). In addition, a hemoglobin level of &lt;10 g/dL (p=0.003), white blood cell count of either &lt;4 or &gt;30 x 109/L (p=0.03), and older age (p=0.02) were also found to be independent indicators of poor prognosis. However, when the analysis included parameters that were measured in variable proportion of the study population, the independent prognostic factors for poor survival were thrombocytopenia (p=0.0001), anemia (p=0.01), and the presence of unfavorable cytogenetic abnormalities (0.001).
Based on the above findings, we constructed a new complete blood count (CBC)-based prognostic scoring system (Figure 1) that performed better than the Dupriez scoring system in discriminating intermediate- from high-risk patient categories(Figure 2).
Figure Figure
Conclusions: Thrombocytopenia is a strong predictor of poor survival in transplant-eligible patients with AMM. The incorporation of platelet count into the Dupriez prognostic scoring system might allow the construction of an improved, CBC-based scoring system that can accurately identify high-risk as well as intermediate-risk patients with AMM.