bluuebunny/crossref_metadata_2025_split huggingface dataset:
Infusions of HSV-TK genetically modified donor lymphocytes enable a wider use of partially mismatched allogeneic transplantation by reducing infection related mortality and improving survival in high risk acute leukemia
Authors: Ciceri F. , Bonini C. , Lupo Stanghellini M. , Santoro A. , Slavin S. , Apperley J. , Bruzzi P. , Toma S. , Gallo Stampino C. , Bregni M. , Bordignon C. 
Published: March 2020

6519 Background: Allogeneic transplantation from a haploidentical family donor (haplo-SCT) represents the ideal solution to offer to every and each patient with high risk leukemia the potential cure of allogeneic adoptive immunotherapy. However, the delayed immune reconstitution compromise haplo-SCT with a high rate of late mortality and relapse. Methods: In a phase II multicenter trial (MM TK007), we explored early add-backs of donor lymphocytes genetically engineered to express the herpes simplex thymidine kinase (TK-DLI) suicide gene after haplo-SCT, in inducing early immune reconstitution and selective control of GvHD by ganciclovir. Results: Thirty-one advanced age pts (median age 51, 17–64) were transplanted for high risk leukemia. No immune reconstitution and no graft versus host disease (GvHD) were observed in absence of TK-DLI. 17 pts received TK-DLI at a median dose of 107/kg with 1st infusion at d +42; 14 pts obtained a prompt and sustained immune reconstitution with CD3+ >100/mcl at a median time of 86 d (57–127) from SCT and 21 d (13–42) from TK-DLI. Six pts developed acute (GvHD), (grade I to IV) that was always completely abrogated by ganciclovir. In patients in remission of leukemia at time of SCT, who were alive at day +42 and received TK-DLI, overall survival was 65% at 2 years (intention-to-treat analysis: 46%).The cumulative incidence of TRM and relapse showed a 40% probability of mortality with a median time of death of 90 days and last event at day +166. The cumulative infectious mortality beyond day 100 post transplant was 12.5% in our population, versus 53% of historical data. These data correlate with rapid development of normalization of the T cell repertoire documented by spectratype, followed by detection of high frequencies of T cells specific for CMV and EBV by gIFN ELISpot. Conclusions: These results indicate that TK-DLI drastically reduces late mortality after CD34+ haplo-SCT in adults. Survival rates in patients treated with TK-DLI were superior to survivals of haploidentical SCT of EBMT registry database. A phase III randomized multicentric study will start in 2006 to validate prospectively the advantage of TK-DLI in haplo-SCT. [Table: see text]
Bcr-Abl mutations in imatinib-resistant CML and Ph+ALL patients (pts) enrolled in a phase I study of AMN107
Authors: Ottmann O. , Bhalla K. , Kantarjian H. , Hochhaus A. , Jones D. , Dawson K. , Rose K. , Alland L. , Dugan M. , Lilleburg S. , Giles F. 
Published: March 2020

6527 Background: AMN107 is a potent, highly selective, aminopyrimidine inhibitor which in vitro is 30-fold more potent than imatinib and active against 32/33 imatinib resistant Bcr-Abl mutations. Methods: The spectrum of mutations in Bcr-Abl was evaluated by direct sequencing of the kinase domain and surrounding regions on samples from pts with imatinib-resistant Ph+ CML or ALL in a phase I study of AMN107 (total daily dose range 50 to 1200 mg administered qd or bid). The template was created by semi-nested PCR using primers in the BCR and ABL regions of the gene. Mutations were correlated with clinical response. Results: Among 119 pts, 86 had both pre and post tx analyses: 39 (45%) had mutations at baseline, of whom 27 (69%) responded. 47 (55%) had no mutation at baseline, of whom 34 (72%) responded. The most common baseline mutations were G250E, E255K/V, E355G, F317L, H396R and M351T. New mutations were found during median follow-up of 112 (6 - 350) days in 37 pts (26 without baseline mutations). New mutations most commonly included F349V, E255K/V, E355G, G250E, M244V and T315I. Of the 37 pts, 30 had evaluations after mutations emerged, and 15 continued to respond for median of 160 (41–351) days. Fourteen mutations not previously reported occurred, 6 at codons with known imatinib resistance mutations resulting in novel amino acid substitutions. Novel mutations in multiple pts and/or multiple timepoints included E344G, F311I, E453K, E459Q and L248L. The T315I mutation was present at baseline in 1 pt who failed to respond and emerged in 4 pts, of whom follow-up was available for 3. Two continued to respond ≥ 80 days after developing the mutation and one progressed when the mutation emerged. Conclusions: AMN107 has clinical activity in pts with Ph+CML/ALL with nonmutated and mutated Bcr-Abl. At AMN107 doses used in this phase I study, new mutations often emerged, but were not a reliable predictor of clinical relapse. [Table: see text]
Natural killer (NK) cells are associated with reduced relapse without increased graft-versus-host disease (GVHD) after allogeneic hematopoetic stem-cell transplantation (HSCT)
Authors: Reddy V. , Levine J. B. , Mahmood S. S. , Schold J. D. , Meier-Kriesche H. , Dunbar E. M. 
Published: March 2020

6542 Background: Natural killer cells have potential for anti-leukemia activity after haplo-identical HSCT. However, the role of reconstituted NK cells in relapse and survival after matched HLA-identical HSCT is unknown. We investigated the correlation between NK reconstitution and death, relapse, and GVHD after HSCT. Methods: We prospectively studied NK reconstitution in 123 patients with predominantly high-risk hematologic malignancies. Peripheral blood absolute NK cell count (ANK) was determined by flow cytometry analysis of lymphocytes co-expressing bright staining CD56+ and CD16+. Cluster analysis distinguished patients at engraftment with high ANK (>12.2/mm3) (n=80) and low ANK (n=43), and at 60 days with high ANK (>20/mm3) (n=64) and low ANK (n=26). Primary study endpoints were death, relapse and acute grade II-IV GVHD with median follow up of 360 days (28–1967). A cox proportional hazard model was adjusted for important covariates, including age, transplant conditioning (myeloablative vs. non-myeloablative), graft source (peripheral blood vs. bone marrow), and donor-type (HLA-matched related vs. unrelated), dendritic cell level and absolute neutrophil count. Results: A low ANK at engraftment was significantly associated with death (p=0.03) after non-myeloablative HSCT. Using a selection model, only NK remained in the model, and a low ANK was associated with a 2.5 hazard ratio for subsequent death (p=0.04). Additionally, for the overall cohort, ANK at 60 days was strongly associated with time to death (92% in high vs 65% in low group; LR p=0.0007), at 310 days after HSCT. ANK level at 60 days was strongly associated with time to relapse (n=82, (LR p=0.0001). In a multivariate model, low ANK at 60 days was associated with a 4.2 fold relative risk (RR) of death (1.9, 9.1) and 8.6 RR for time to relapse (3.1, 24.3). Conclusions: High NK cell reconstitution is associated with reduced relapse and death without increased incidence of GVHD after HLA-identical HSCT. Our study suggests that NK may have both a potential anti-tumor effect, as well as be tolerogenic. Measuring NK after HSCT may have novel prognostic and therapeutic implications. No significant financial relationships to disclose.
Long-term outcomes of survivors of autologous hematopoietic-cell transplantation for refractory and relapsed Hodgkin’s Disease
Authors: Goodman K. A. , Serrano V. , Riedel E. R. , Gulati S. , Moskowitz C. H. , Yahalom J. 
Published: March 2020

6554 Background: With improvements in survival among refractory/relapsed Hodgkin’s Lymphoma (HL) patients after high-dose chemo-radiotherapy and autologous hematopoietic-cell transplant (AHCT), it is important to evaluate risk of late complications in this heavily treated population. Methods: From 1985–1998, 218 refractory/relapsed HL patients were treated on high dose chemo-radiotherapy and AHCT salvage protocols. 153 (70%) surviving ≥2 years after AHCT were analyzed. All received either radiotherapy with initial therapy or total lymphoid irradiation and involved field boost with the conditioning regimen (43%). Information from surviving patients was obtained through a self-administered questionnaire. The NDI was queried to determine vital status and cause of death. Primary endpoint was non-HL mortality, defined as mortality due to cardiac causes, infection or second malignancy (SM). Competing risk methods were used to calculate cause-specific mortality rates and examine its predictors. All events were calculated from 2 years post-AHCT to date of death/last follow-up. Results: Median follow-up time was 11 years. There have been 51 deaths, 32 due to HL and 19 due to other causes. Eleven deaths were due to SM: AML (3), MDS (2), NHL (2), NSCLC (2), gastric and colon cancer. There were 8 non-SM deaths: cardiac toxicity (4), infection, aplastic anemia, suicide, unknown causes (1 each). The 10 and 15-year overall survival (OS) rates are 64% and 57%, respectively. The 10-year cumulative incidence of death from HL and from non-HL causes were 22% and 13.5% ( table ). By univariate analysis, increased risk of death due to SM was associated only with higher age at AHCT (p=0.02). Conclusions: While HL initially accounts for the majority of deaths among patients surviving high-dose therapy, the HL mortality rate plateaus and risk of death from non-HL mortality increases after 5 years. Yet, even at 15-years, SM risk does not exceed that observed in patients treated with standard regimens. [Table: see text] No significant financial relationships to disclose.
Erythroid response (ER) rates in myelodysplastic syndromes (MDS) patients treated with epoetin alfa (EPO): A meta-analysis using the International Working Group criteria (IWGc) for MDS response
Authors: Moyo V. , Lefebvre P. , Duh M. S. , Bourezak A. , Yektashenas B. , Woodman R. C. , Mundle S. 
Published: March 2020

6572 Background: Refractory anemia is a clinical hallmark of MDS. The most consistently used therapy for this anemia is EPO. Prior to the introduction of IWGc in 1997, ER rates varied substantially between studies. The present meta-analysis was undertaken to compare ER rates in studies of EPO-treated patients in MDS when defined by either IWGc or non-IWGc. Methods: A systematic review and data extraction of studies published from 1990–2005 in MDS patients treated with EPO was performed and yielded 21 studies evaluating a total of 895 patients. Pooled estimates of ER rates, stratified by IWGc, were calculated using random-effects meta-analysis methods, which incorporated both between- and within-study variations. Univariate meta-regression analyses were conducted to identify study characteristics that were significant determinants of ER rate. Results: Ten studies (604 patients) used the IWGc to define ER (overall, major, minor), while 11 studies (291 patients) used other definitions. Mean age for all patients was 70.6 years; 45% women. Mean baseline (BL) serum erythropoietin level and proportion of patients with refractory anemia or refractory anemia with ringed sideroblasts were comparable between studies; however, the proportion of transfusion-dependent patients at BL was lower in the IWG studies vs the non-IWG studies (36% vs. 84%, respectively, p<.001). The pooled estimate of ER rate was significantly higher for the IWG studies compared to the non-IWG studies (50.5%, 95% CI: 38.6%-62.3% vs. 27.8%, 95% CI: 22.7%-32.8% respectively, p=.002). Among patients in the IWG studies who achieved an ER, 62% (188/305) achieved a major ER. Studies reporting mean BL serum erythropoietin level <400mU/mL, <65% of patients transfusion-dependent at BL and use of subcutaneous EPO were found to be associated with higher ER rates. Conclusions: This meta-analysis of MDS patients treated with EPO demonstrates significantly higher ER rates in studies utilizing IWGc. These findings may be due to more refined definitions of ER and MDS diagnostic criteria as well as improvement in the management of anemia. [Table: see text]
Transfusion independence in patients with myelodysplastic syndromes treated with azacitidine
Authors: Silverman L. R. , Peterson B. L. , Holland J. F. , Stone R. M. , Powell B. L. , Larson R. A. 
Published: March 2020

6576 Background: Patients (pts) receiving red blood cell (RBC) transfusions are exposed to various side-effects such as intolerance reactions, iron overload, and alloimmunization risks. Reduction in RBC transfusions plus improvement in quality of life was demonstrated in pts with MDS treated with azacitidine in the phase 3 randomized study (9221) conducted by the CALGB (JCO 2002;20:2429). Azacitidine also demonstrated beneficial effects on platelets and neutrophils. To further explore transfusion results in 9221, we compared RBC and platelet transfusion requirements in pts treated with azacitidine across 3 CALGB studies (phase 2 intravenous [IV] 8421, phase 2 subcutaneous [SC] 8921, and Phase 3 SC 9221). Methods: Baseline was defined as 90 days immediately prior to randomization or crossover, as appropriate. Transfusion independence was defined as maintaining independence for ≥56 days (IWG criteria). Duration of transfusion independence was defined as the date of last transfusion to the date of the next transfusion or date of censoring. Proportions of pts who became RBC or platelet independent during the study were compared, as were the median durations of independence. Results: Compared with pts treated with IV azacitidine, a greater percent of pts treated with SC azacitidine achieved independence ( Table ), but the IV study (8421) enrolled only pts with advanced MDS. Differences of 10% in proportions of pts registered or randomized to SC azacitidine who achieved transfusion independence were noted in the phase 2 and 3 studies for RBCs (8921: 35%; 9221: 45%) and for platelets (8921: 43%; 9221: 53%). Median duration of RBC independence in 8921 was 221 days, which was within 6% of that observed for pts randomized to azacitidine in 9221 (235 days). Conclusions: These results provide further support that azacitidine has beneficial effect on erythropoiesis and thrombopoiesis. Patients with MDS treated with azacitidine may develop RBC or platelet transfusion independence. [Table: see text] [Table: see text]
Clinical and hematological improvement in patients receiving liposome doxorubicin (Myocet) therapy for myelofibrosis with myeloid metaplasia (MMM)
Authors: Iuliano F. , Molica S. , Serra A. , Sterpone P. , Russo A. , Cilloni D. , Peta A. 
Published: March 2020

6593 Background: MMM is a chronic myeloproliferative disorder with bone marrow fibrosis, hepato-splenomegaly, extramedullary hematopoiesis,increase angiogenesis both in bone marrow and spleen. Myocet is a proprietary liposomal formulation of doxorubicin designed to enhance delivery of the drug to tumor cells and reduce side effects while maintaining equivalent anti-tumor efficacy. Liposomes are avidly removed from circulation by the macrophages of the RES or MPS and are taken up in the spleen, liver and bone marrow were show both a cytotoxic and antiangiogenic activity. Methods: We thus designed a phase II study for pts with MMM. The treatment program consisted of 25 mg total dose of Myocet given I.V. every two weeks for six months. Eligibility criteria included a histologically confirmed diagnosis, platelets ≥ 100 × 109/L, neutrophils ≥ 1 × 109/L, PS ≤ 2, LVEF > 45%, normal liver and renal function. Eight patients (median age, 66 years; range, 60–73) were enrolled to the trial. Median duration of disease prior to protocol treatment was 45 months (range, 24–144). All pts had received prior therapy for MMM, including thalidomide (37%) hydroxyurea (100%), interferon (25%), anagrelide (25%), erythropoietin (100%). 3 pts were RBC transfusion-dependent and 1 had severe constitutional symptoms. Baseline median (range) values for palpable spleen size, leukocyte count, platelet count, CD34 cell count, and serum lactate dehydrogenase (LDH) were: 10cm BCM (median, range 6 to 30), 8.5 × 109/L (3–36.2), 250 × 109/L (160–950), 151.1 × 106/L (1.9–3568), and 680 U/L (316–868), respectively. 8/8 pts had JAK2 V617F mutation. Results: 7/8 pts are evaluable (i.e., received six months of therapy), 1 pt discontinued for progression. Clinico-hematologic responses have been observed in 7/7 (100%) pts and were evaluated according to European Myelofibrosis Network criteria. These include CR in 1 pt, major response in 5/7 pts, minor response in one. The median time to response was 12 weeks (range, 4 to 18). Therapy has been well tolerated. Only a Grade 3 thrombocytopenia was seen. Conclusions: We conclude that Myocet has clinical activity in a subset of patients with myelofibrosis with an acceptable toxicity profile. No significant financial relationships to disclose.
AT-101, a small molecule Bcl-2 antagonist, in treatment naïve CLL patients (pts) with high risk features; Preliminary results from an ongoing phase I trial
Authors: James D. F. , Castro J. E. , Loria O. , Prada C. E. , Aguillon R. A. , Kipps T. J. 
Published: March 2020

6605 Background: CLL pts with early stage disease are often observed under a “watch and wait” approach. Unmutated immunoglobulin variable-region gene (IgVH); expression of zeta chain associated kinase (ZAP-70); CD38 expression; and cytogenetics abnormalities identify pts with a tendency for early disease progression. Whether pts with these high-risk features may benefit from early intervention warrants investigation in clinical trials. Gossypol, a naturally occurring compound in cotton seeds has been extensively studied in clinical trials and is well tolerated with a favorable safety profile. AT-101, a derivative of R-(-)-gossypol binds to Bcl-2 family proteins and induces apoptosis of CLL cells in vitro. Dysregulated expression of Bcl-2 proteins is critical for CLL leukemogenesis and is an attractive therapeutic target. Methods: We conducted a phase I study to evaluate the safety and tolerability of single agent AT-101 in treatment naïve CLL pts with high-risk features. Clinical activity, pharmacokinetics, and pharmacodynamics were assessed. Results: 7 pts were treated with AT-101 at doses of 20–40mg daily. Pt characteristics: median age 55, median Rai stage II, elevated ZAP-70 (57%), high CD38 (71%), unmutated IgVH (57%), trisomy 12 (43%), and loss of 17p (43%). AT-101 was well tolerated with no grade 4 toxicities, hospitalizations, deaths. Maximum toxicity in 6 evaluable pts was grade III transaminase elevation at week 7, with complete resolution following discontinuation of AT-101. Other most common adverse events, all Grade 1–2 include: elevated transaminases; nausea; fatigue; diarrhea; and hypokalemia. No hematologic toxicity was observed. 5/6 pts had decrease in lymphocyte count, 6/6 had reduction in lymphadenopathy, and 5/5 with palpable spleens had reduction in spleen size. Cmax for 30mg (n=3) and 40mg (n=2) dose of AT-101 was 570ng/ml and 660ng/ml at a Tmax of 4.3 and 4.4 hrs. Tmax correlated with in vivo apoptosis studies revealing maximum leukemic cell apoptosis occurring at 4hrs and poly(ADP-ribose) polymerase cleavage. Conclusions: AT-101 is safe and well tolerated, induces in vivo leukemia cell apoptosis, and may have clinical activity in previously untreated pts with CLL and high risk features. No significant financial relationships to disclose.
The combination of oxaliplatin, fludarabine (FLU), cytarabine (Ara-c), and rituximab (R) (OFAR) in patients with Richter’s Transformation and FLU-refractory CLL
Authors: Wierda W. , Tsimberidou A. , O’Brien S. , Ferrajoli A. , Faderl S. , Ravandi F. , Cortes J. , Kantarjian H. , Plunkett W. , Keating M. 
Published: March 2020

6608 Background: Patients with (FLU-ref) CLL and Richter’s transformation (RT) have a very poor prognosis. Oxaliplatin (OX), a platinum analog with a 1,2-diaminocyclohexamine carrier ligand, has a different activity and side effect profile from cisplatin. OX covalently binds DNA, inducing DNA intra- and inter-strand cross-links. FLU and Ara-c act synergistically to inhibit excision-repair of DNA cross-links, thereby providing the rationale for combining OX, FLU, Ara-c, and R (OFAR). Methods: The phase I portion of a phase I/II study of the OFAR regimen had increasing doses of OX. The OFAR regimen consists of OX 17.5, 20, or 25mg/m2, d1–4; fludarabine 30mg/m2, d2,3; Ara-c 1gm/m2, d2,3; and rituximab 375mg/m2, d3. Courses were given every 4 wks; patients received Neulasta 6mg each course and prophylaxis for tumor lysis, DNA virus’, and PCP. Results: 19 patients enrolled in phase I; 1 received no treatment, 8 had RT, and 10 had FLU-ref CLL. Patients received OX 17.5mg/m2 (3), 20mg/m2 (8), or 25mg/m2 (7). Patients receiving at least 1 course were evaluable for toxicity and could receive up to 6 courses. There were no dose-limiting toxicities, defined as any ≥ G3, non-hematologic, treatment-related toxicity. The major toxicity was hematologic and appeared OX-dose dependent. Neutropenia (G3–4) was experienced by 1/3, 6/8, and 7/7 patients treated at 17.5, 20, and 25mg/m2 OX levels, respectively. Thrombocytopenia (G3–4) was experienced by 2/3, 8/8, and 7/7 of patients treated at 17.5, 20, and 25mg/m2m OX levels, respectively. There were no treatment-related deaths. Five patients continue treatment on the phase I portion, and results will be evaluable, with 3 responders, including 2 complete, in the 7 evaluable patients with RT. Among the 10 FLU-ref patients, there are 5 PRs; treatment continues for 3 of them. Pharmacodynamic analyses demonstrate enhanced killing by OX in the presence of FLU and Ara-c. Conclusions: The OFAR regimen is safe and active for treating patients with RT and FLU-ref CLL. This trial continues to accrue patients to confirm efficacy. No significant financial relationships to disclose.