bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of anti-CD19 BiTE blinatumomab on complete remission rate and overall survival in adult patients with relapsed/refractory B-precursor ALL.
Authors: Topp Max , Goekbuget Nicola , Zugmaier Gerhard , Viardot Andreas , Stelljes Matthias , Neumann Svenja , Horst Heinz-August , Reichle Albrecht , Marks Reinhard , Monika Brueggemann , Ritgen Matthias , Klappers Petra , Mergen Noemi , Goebeler Marie-Elisabeth , Einsele Hermann , Hoelzer Dieter , Bargou Ralph 
Published: March 2020

6500^ Background: Blinatumomab is a bispecific T-cell engaging (BiTE) antibody that directs cytotoxic T-cells to CD19 expressing target cells. Methods: In adult patients with relapsed/refractory B-precursor ALL, a phase II dose ranging trial is being conducted to evaluate efficacy and safety of blinatumomab. The primary endpoint is the rate of hematological complete remission (CR) or CR with partial hematological recovery (CRh*) within 2 cycles of blinatumomab treatment. Blinatumomab is administered by continuous intravenous infusion for 28-days followed by a 14-day treatment-free interval. Responding patients can receive 3 additional cycles of treatment or proceed to bone marrow transplantation. Three dose levels were explored as shown in the table. Results: In total 36 patients have been enrolled, 25 are currently evaluable. Seventeen out of 25 treated patients (68%) reached a hematological CR/CRh* and a minimal residual disease (MRD) response (MRD level <10-4) within the first 2 cycles. Five out of 17 responders (29%) showed a CRh* due to partial recovery of platelets. For the first 18 patients, response duration is 7.1 months and the median follow-up time for overall survival (OS) is 9.7 months (median not reached). Six cases of relapses have been recorded of which 3 were CD19+, and 3 CD19-. As final dose 5 µg/m²/day in week 1 and 15 µg/m²/day for the remaining treatment (cohort 2a and 3) was selected. In these cohorts (n=12), the most common treatment emergent adverse events (TEAEs, all grade 1-2) were pyrexia (67%), headache (33%) and tremor (33%). TEAEs of grade ≥3 (7 in 5 patients, no grade 4), irrespective of relationship, were infections, confusion, epilepsy, hypertension and thrombocytopenia. Conclusions: The final dose was well-tolerated and produced an exceptionally high complete remission rate. A global phase 2 study to confirm these data is underway. [Table: see text]
The Bruton's tyrosine kinase (BTK) inhibitor PCI-32765 (P) in treatment-naive (TN) chronic lymphocytic leukemia (CLL) patients (pts): Interim results of a phase Ib/II study.
Authors: Byrd John C. , Furman Richard R. , Coutre Steven E. , Burger Jan Andreas , Blum Kristie A. , Sharman Jeff Porter , Flinn Ian W. , Grant Barbara W. , Heerema Nyla A. , Johnson Amy J , Navarro Tasheda , James Danelle Frances , Hedrick Eric , O'Brien Susan Mary 
Published: March 2020

6507 Background: Fludarabine based therapy, while effective, carries significant risk of morbidity and mortality in the elderly pts. As such, older CLL pts represent a high priority for new therapeutic approaches. PCI-32765 (P) an oral, selective, irreversible inhibitor of BTK inhibits CLL cell proliferation, migration and adhesion. A multi-cohort Phase Ib/II trial evaluated 2 doses of single-agent P in both TN and relapsed/ refractory (R/R) CLL/SLL pts. Mature follow-up of the TN pts is reported. Methods: Pts >65 yrs old with active CLL requiring Tx by IWCLL guidelines were treated with oral P at doses of 420 mg or 840 mg administered daily for 28-day cycles until disease progression (PD). Response was evaluated according to 2008 IWCLL criteria. Results: 31 pts were enrolled- 26 pts (420mg) and 5 pts (840 mg). The 840 mg cohort was terminated after comparable activity and safety between doses was shown in R/R pts. Median age 71 yrs (range 65-84) with 74% of pts >70 yrs. 19/31 (61%) had baseline cytopenias (Hgb < 11g/dl or plts <100,000). Unmutated IgVH was present in 43% of pts. The majority of AEs have been Gr<=2 in severity, most commonly diarrhea, nausea, and fatigue. Gr >3 non-heme AEs potentially related to P in 19% of pts. 10% of pts experienced Gr >3 infections or cytopenias. With a median follow-up of 10.7 mos on 420 mg cohort 73% (19/26) achieved a response by IWCLL criteria with 65% partial responses (PR) and 8% complete remissions with no morphologic evidence of CLL on marrow. An additional 12% (3/26) of pts achieved nodal responses (NR) with lymphocytosis. Median follow-up in the 840 mg cohort is 4.6 mo, at 2 cycle assessment 2/5 achieved a PR and 1 pt with a NR. ORR was independent of high risk factors. 84% of pts remain on study, reasons for discontinuation = AE (3), investigator decision (1) and PD (1). There have been no deaths. Estimated 12 mo median PFS for the 420 mg cohort is 93%. Conclusions: PCI-32765 is highly active and well tolerated in elderly TN CLL pts. The high ORR, including marrow clearance and very low PD rate with the single agent suggests that P warrants further study as a first-line treatment approach in elderly pts.
Reductions in JAK2V617F allele burden with ruxolitinib treatment in COMFORT-II, a phase III study comparing the safety and efficacy of ruxolitinib to best available therapy (BAT).
Authors: Vannucchi Alessandro M. , Kiladjian Jean-Jacques , Gisslinger Heinz , Passamonti Francesco , Al-Ali Haifa Kathrin , Sirulnik L. Andres , Stalbovskaya Viktoriya , Squires Matthew , Hunter Deborah S. , Burn Timothy , Knoops Laurent , Cervantes Francisco , Barbui Tiziano , Barosi Giovanni , Harrison Claire N 
Published: March 2020

6514^ Background: Ruxolitinib is a potent and selective JAK1/2 inhibitor approved for the treatment of myelofibrosis (MF) based on results of the phase 3 COMFORT studies. Ruxolitinib demonstrated rapid and durable reductions in splenomegaly and improved MF-related symptoms and quality of life of patients (pts) with MF. Since one measure of efficacy is molecular response, this analysis correlates changes in mutant allele burden (%V617F) with spleen size reduction in COMFORT-II. Methods: COMFORT-II is a randomized, open-label, phase 3 study comparing ruxolitinib 15 or 20 mg twice daily (BID) with BAT. The primary endpoint was a ≥ 35% reduction in spleen volume from baseline (BL) at week 48. Change in %V617F was measured by allele specific qPCR. Pts were stratified by reduction in %V617F (< 10%, 10-20%, > 20%) and results were correlated with achievement of the primary endpoint. Results: More pts in the ruxolitinib arm had ≥ 10% V617F reductions compared with BAT (41% vs 5%; P = .01; Table). The majority of reductions > 20% were gradual and progressive over the course of the study; 2 pts had rapid reductions from 48% to 1% and 45% to 9% over 48 weeks. In the ruxolitinib arm, significantly more pts with a > 20% V617F reduction achieved the primary endpoint compared with pts with a < 10% reduction (79% vs 30%; P = .004); in each group, gender did not affect spleen response. For pts with < 10% reductions (15 mg BID, n = 16; 20 mg BID, n = 24), the average total daily dose (TDD) was ruxolitinib 29.6 mg; pts with > 20% reductions (15 mg BID, n = 3; 20 mg BID, n = 11) had a TDD of 35.3 mg. Conclusions: Pts who received ruxolitinib had larger reductions in JAK2V617F allele burden compared with BAT. %V617F reductions were gradual over the course of the 48-week study; longer follow-up is needed to determine the extent of allele burden reduction. [Table: see text]
Pretreatment prognostic factors associated with outcomes for first-line FCR-based treatments in previously untreated CLL.
Authors: Wierda William G. , O'Brien Susan Mary , Faderl Stefan , Ferrajoli Alessandra , Burger Jan Andreas , Estrov Zeev , Tambaro Francesco Paolo , Kadia Tapan M. , Lerner Susan , Kantarjian Hagop , Keating Michael J. 
Published: March 2020

6517 Background: First-line chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) demonstrated improved outcomes, including survival, for fit patients (pts) with CLL. Modifications of this regimen, including intensified rituximab (FCR3), addition of mitoxantrone (FCMR) or addition of alemtuzumab fir high-risk CLL (CFAR), were evaluated but did not improve outcomes in historic comparisons. Methods: We correlated outcomes, including complete remission (CR), time-to-treatment failure (TTF) and overall survival (OS), with new and traditional pretreatment prognostic factors to identify high-risk pts. Results: All pts (N=473) had an NCI-WG indication for treatment and received a first-line FCR-based regimen on trial; the intended treatment was 6 courses. Patient characteristics correlated with outcomes are presented in the table. Factors not associated with outcomes included absolute lymphocyte count; platelet count; performance status; spleen size; liver size; and number of involved lymph node sites. Conclusions: We identified the following as high-risk pretreatment features for patients going on first-line FCR-based therapy: advanced age, presence of 17p del, high B2M (≥4mg/l), and unmutated IGHV gene. Pts with these features should be pursued with new treatment modalities and novel agents in order to improve outcomes. [Table: see text]
A phase I/II study of the selective phosphatidylinositol 3-kinase-delta (PI3Kδ) inhibitor, GS-1101 (CAL-101), with ofatumumab in patients with previously treated chronic lymphocytic leukemia (CLL).
Authors: Furman Richard R. , Barrientos Jacqueline Claudia , Sharman Jeff Porter , De Vos Sven , Leonard John , Coutre Steven E. , Schreeder Marshall T. , Wagner-Johnston Nina D. , Boyd Thomas E. , Fowler Nathan Hale , Flinn Ian W. , Boccia Ralph V. , Holes Leanne , Lannutti Brian Joseph , Johnson Dave , Jahn Thomas Michael , Miller Langdon L. 
Published: March 2020

6518^ Background: PI3Kδ is expressed in cells of hematopoietic origin where it regulates the survival and proliferation of malignant B-cells. GS-1101 is an orally bioavailable, small-molecule inhibitor that selectively targets PI3Kδ and is highly active in patients with hematologic malignancies. Methods: This Phase 1/2 study evaluated repeated 28-day cycles of GS‑1101 in combination with ofatumumab. GS-1101 (150mg BID) was co-administered with a total of 12 infusions of ofatumumab over 24 weeks (300mg initial dose either on Day 1 or Day 2 (relative to the first dose of GS-1101), followed 1 week later by 1,000mg weekly for 7 doses, followed 4 weeks later by 1,000mg every 4 weeks for 4 doses). Thereafter, each subjects received single-agent GS‑1101 as long as the subject was benefitting. Results: Accrual is complete with 21 subjects enrolled and 11 evaluable. Six subjects started ofatumumab treatment on Day 1 and 5 on Day 2. Median [range] age was 63 [54‑76] years. The majority (9/11; 82%) of patients had bulky adenopathy. The median [range] number of prior therapies was 3 [1‑6], including prior exposure to alkylating agents (10/11; 90%), rituximab (9/11; 82%), purine analogs (8/11; 72%), alemtuzumab (3/11; 28%) and/or ofatumumab (2/11;18%). At the data cutoff, the median [range] treatment duration was 5 [0‑7] cycles. Almost all subjects (9/11;82%) experienced marked and rapid reductions in lymphadenopathy within the first 2 cycles. The lymphocyte mobilization that is expected with PI3Kδ inhibition was significantly reduced in magnitude and duration and persisted past Cycle 1 in only 1 patient. Early follow up data support a favorable safety profile and confirm a lack of clinically significant myelosuppression. Elevated baseline levels of CCL3, CCL4, CXCL13, and TNFa were significantly reduced after 28 days of treatment. Conclusions: GS-1101/ofatumumab offers a well-tolerated noncytotoxic combination regimen with substantial activity in previously treated patient with bulky adenopathy. Data on the complete cohort of 21 subjects will be presented.
Evaluation of the first-in-class antimitochondrial metabolism agent CPI-613 in hematologic malignancies.
Authors: Pardee Timothy S. , DeFord-Watts Laura M , Peronto Erica , Levitan Denise A. , Hurd David Duane , Kridel Steven , Harrelson Robin , Manuel Megan , Lyerly Susan , Powell Bayard L. 
Published: March 2020

6524^ Background: Altered metabolism is a hallmark of cancer, including hematologic malignancies. Most tumor cells use glycolysis even under aerobic conditions (the Warburg effect). This altered metabolism is a possible therapeutic target. The novel lipoate derivative CPI-613 is a first-in-class agent that targets a key mitochondrial enzyme, pyruvate dehydrogenase complex (PDH). Methods: CPI-613 was tested against leukemia cell lines in vitro and in vivo. It is also the subject of a phase I clinical trial for patients with hematologic malignancies. Results: CPI-613 was active against HL60, Jurkat, and K562 cells, with an average IC50 value of 14 μM (range 12.2 – 16.4). CPI-613 was synergistic with doxorubicin, with Combinatorial Index (CI) values of 0.478 to 0.765. CPI-613 sensitivity increased with knockdown of p53 or MN1 expression, despite their increased resistance to standard therapy. CPI-613 was synergistic with nilotinib against BCR-ABL-expressing cells and with sorafenib against Flt3 ITD-expressing cells. CI values for nilotinib + CPI was 0.059 (+/-0.002) and for sorafenib + CPI was 0.581 (+/-0.052). In vivo, CPI-613 synergized with doxorubicin; median survival improved from 12 days with doxorubicin to 16 days with CPI-613 plus doxorubicin (p=0.0001). In the phase I clinical trial, 7 of 13 evaluable patients had a response of stable disease or better, for an overall response rate of 54% (see table). CPI-613 was well tolerated, with no evidence of marrow suppression and no dose limiting toxicity identified. Conclusions: The novel agent CPI-613 has activity against a variety of hematological malignancies, including acute leukemias. The therapeutic index appears high, with only minor toxicities observed. [Table: see text]
Clinical trial and compassionate use experience with glucarpidase for methotrexate toxicity.
Authors: Widemann Brigitte C. , Jayaprakash Nalini , Howard Scott C. , Daugherty Claire , Chauhan Nikhil , King Thomas , Rush Janet 
Published: March 2020

6530 Background: High dose methotrexate (MTX) is used to treat acute lymphoblastic leukemia (ALL), osteogenic sarcoma, non-Hodgkin lymphoma (NHL), and other cancers. MTX-associated renal impairment with delayed MTX elimination develops after 2 to 10% of treatment cycles, exposing patients to elevated MTX concentrations with potential for enhanced MTX toxicity and prolonged hospitalization. Glucarpidase, a recombinant form of carboxypeptidase G2, rapidly hydrolyzes MTX into inactive metabolites and provides an alternate way of clearance in patients with delayed MTX elimination. Methods: From November 1993 to June 2009, 492 patients experiencing renal toxicity and delayed elimination of MTX were treated with glucarpidase (50 U/kg intravenously) in compassionate use trials conducted in the US and EU. Their outcomes are presented here. Results: The median age of the 492 patients was 18 yrs (range: 5 wks to 85 yrs). Sixty-three percent were male. Forty-one percent had NHL, 30% osteogenic sarcoma, 23% ALL, and 7% other malignancies. The median pre-glucarpidase MTX concentration was 17 µmol/L. Seventy-six percent of patients received 1 dose of glucarpidase, 22% received 2 doses, and 2% received 3 doses. The first dose of glucarpidase was given at a median of 3 days after MTX administration. One-hundred and fifty-six patients had MTX concentrations determined by HPLC. At the first measurement (median 15 minutes post-glucarpidase) MTX was reduced by a median of 99% relative to the pre-glucarpidase baseline. At the last measurement (median 40 hrs post-glucarpidase) median MTX reduction remained at 99% compared with baseline. In 410 patients with pre-glucarpidase renal impairment measured as CTCAE Grade 2 or higher, 64% recovered to Grade 0 or 1 after a median of 12.5 days post-glucarpidase. Glucarpidase was well-tolerated overall; adverse events included paresthesia (2.0%), flushing (1.8%) and headache (1.0%). Eight percent of patients died within 30 days of glucarpidase administration of causes unrelated to glucarpidase, as judged by the treating physician. Conclusions: Glucarpidase is well-tolerated and reduces MTX concentrations by 99% within 15 min of administration in patients with impaired renal clearance of MTX.
Impact of ATG on new HLA groups for unrelated donor allogeneic stem cell transplantation.
Authors: Lee Soo Jung , Kim Jong Gwang , Chae Yee Soo , Kang Byung Woog , Moon Joon Ho , Sohn Sang Kyun , Baek Jin Ho , Cho Yoon Young , Lee Yoo Jin , Choi Jun Young 
Published: March 2020

6536 Background: The outcomes of unrelated donor transplantation have improved with refinements in HLA testing. Recently, grouping of HLA matching for unrelated donor was suggested, defining by well-matched, partially-matched, and mismatched. In the current study, the role of ATG for each group was evaluated. Methods: A total of 92 patients diagnosed as hematologic diseases and received allogeneic stem cell transplantation (SCT) from unrelated donor were retrospectively analyzed. Results: Nineteen patients were classified as well-matched, 42 as partially-matched, and 31 as mismatched. Among them, 57 patients received anti-thymocyte globulin (ATG) as graft-versus-host disease (GVHD) prophylaxis. The overall survival (OS) rate was higher for well-matched group (83%) compared to partially-matched (54%) and mismatched (34%, p=0.076). For partially-matched group, the OS was significantly improved with ATG (83.3% vs. 38.6%, p=0.018). But, the OS was not different between groups with or without ATG for well-matched (87.5% vs. 66.7%, p=0.487) and mismatched (32.4% vs. 41.7%, p=0.215). ATG decreased the cumulative incidence of grade 3-4 acute GVHD (10% vs. 40.2%, p=0.068) and severe chronic GVHD (21.2% vs. 52.2%, p=0.037). The use of ATG (HR=0.248, p=0.029) was related with favorable OS for partially-matched group. However, the favorable effect of ATG was not observed in well-matched and mismatched groups. Conclusions: ATG effectively improved survival rate for partially-matched group in unrelated donor transplantation. However, the positive effect of ATG was not observed in well-matched and mismatched group.
Effect of IL-22 on intestinal stem cells, GVHD-related tissue damage, and GVL.
Authors: Hanash Alan M. , Van Den Brink Marcel R. M. , Hua Guoqiang , Kolesnick Richard , Blazar Bruce R. 
Published: March 2020

6539 Background: Intestinal graft vs. host disease (GVHD) is a major complication of allogeneic bone marrow transplantation (allo-BMT). Strategies to limit GVHD by selective promotion of epithelial regeneration in the absence of immunosuppression are largely unknown. Methods: We investigated the role of IL-22 in allo-BMT by utilizing wild type and IL-22 knockout (KO) mice as donors or recipients in allo-BMT. Results: We found that administration of an anti-IL-22 neutralizing antibody to allo-BMT recipients during the first month post-BMT led to increased GVHD mortality, indicating that IL-22 functioned to reduce GVHD severity post-BMT. In contrast, use of IL-22 KO donor T cells did not impair their ability to eliminate A20 lymphoma cells upon tumor challenge, thus indicating that IL-22 was not essential for donor T cells to mediate graft vs. lymphoma (GVL) responses. BMT with WT donors and recipients indicated that IL-22 levels in small and large intestine were increased after BMT and after radiation injury (RI) without BMT. IL-22 upregulation after RI was dependent on the presence of IL-23p40. Although intestinal IL-22 levels were increased after T cell-depleted (TCD) BMT, intestinal IL-22 was reduced by GVHD, as IL-22 production was mediated by host-derived innate lymphoid cells (ILC) that were eliminated by GVHD. Furthermore, host-derived IL-22 was critical for reduction of GVHD morbidity, mortality, and intestinal pathology. GVHD in IL-22 KO mice led to increased apoptosis in epithelial crypts where the intestinal epithelial stem/progenitor cell niche is located. Immunohistochemistry and immunofluorescence demonstrated IL-22 receptor expression on intestinal stem cells (ISC) and progenitors. Allo-BMT in Lgr5-LacZ reporter mice indicated that ISC were targeted by GVHD, and GVHD in IL-22 KO mice led to dramatic ISC depletion. Conclusions: IL-22 is critical for protection of host epithelium during GVHD and critical for protection of ISC, and it does not contribute to donor T cell GVL responses. These findings may have broad relevance for protection of ISC and intestinal epithelium in clinical GVHD and other inflammatory intestinal diseases, and may be useful for clinical separation of pathologic GVH and therapeutic GVL responses.
Outcomes of second allogeneic hematopoietic stem cell transplantation (SCT) for patients with acute lymphoblastic leukemia (ALL).
Authors: Poon LM , Bassett Roland , Rondon Gabriela , Worth Laura L , Cooper Laurence , Popat Uday R. , Nieto Yago , De Lima Marcos J.G. , Champlin Richard E. , Kebriaei Partow 
Published: March 2020

6540 Background: Disease relapse is the major cause of failure after allogeneic hematopoietic stem cell transplantation (SCT) for acute lymphoblastic leukemia (ALL). Treatment options for these patients (pts) are limited and only a second SCT provides a realistic chance for long term disease remission. Methods: We retrospectively analyzed the outcomes of 31 pts with ALL who relapsed following their first allogeneic SCT, and went on to receive a second allogeneic SCT. Univariate analysis was used to assess for risk factors which influenced treatment-related mortality (TRM), and progression free survival (PFS) following second SCT. Results: 31 pts were evaluable for response with 2 early deaths within 30 days of SCT. The median age of the pts was 26 years (range 7- 49), and the median duration between their first SCT (SCT1) to relapse was 9.5 months (range 2.2-32.6 months). 39% of pts were transplanted in active disease (n=12). The complete remission (CR) rate post SCT was 89%; 83% of pts transplanted with active disease attained CR. With a median follow-up of 3 years among survivors, PFS, and OS rates at 1 year were estimated at 23%. The TRM rate was 41% at 12 months. We did not identify any factors that impacted TRM through univariate analysis. We found a significant relationship between the time to progression following SCT 1 and PFS following SCT 2 (p=0.02, HR=0.93/month). Conclusions: In summary, a second transplant remains an effective method for achieving response in a highly refractory patient population. Pts with longer PFS following SCT1 have a better PFS following SCT2. While long-term survival is limited, a significant proportion of pts remain disease-free for up to one year following SCT2, providing a window of time to administer preventive interventions. Notably, our 4 long-term survivors, received novel therapies in the form of a single umbilical cord blood unit in addition to the PBSC to augment the immune response (n=2), a change in the stem cell source for the SCT from cord to mismatched adult unrelated (n=1), and post SCT maintenance therapy with 5-azacytidine (n=1), underscoring the need for a fundamental change with the methods for the second transplant to improve outcome.