bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II study of nilotinib administered to imatinib resistant and intolerant patients with chronic myelogenous leukemia (CML) in chronic phase (CP)
Authors: Rosti G. , le Coutre P. , Bhalla K. , Giles F. , Ossenkoppele G. , Hochhaus A. , Gattermann N. , Haque A. , Weitzman A. , Baccarani M. , Kantarjian H. 
Published: March 2020

7007 Background: Nilotinib is a highly selective Bcr-Abl tyrosine kinase inhibitor that is 30-fold more potent than imatinib. The objective of this phase II open-label study was to evaluate the safety and efficacy of nilotinib in imatinib-resistant or -intolerant CML-CP pts Methods: Imatinib-resistance was defined using standard criteria and had failed imatinib >/= 600mg/day. Imatinib intolerance was defined as intolerant symptoms and lack of MCyR. Primary endpoint was MCyR determined by conventional ITT analysis. Planned nilotinib dose was 400mg BID with escalation to 600mg BID for inadequate responses Results: 316 pts were enrolled and included for safety analysis; efficacy results are from 279 pts with at least 6 mos of follow up. 221 (70%) pts were imatinib-resistant and 95 (30%) were imatinib- intolerant. Median duration of CML was 58 mos; median prior imatinib use was 33 mos. 227 (73%) pts had prior imatinib dose >/= 600mg/day. Treatment with nilotinib is ongoing for 221 (70%) pts. 95 (30%) pts have discontinued treatment (41 for AEs, 32 for disease progression). Median duration of nilotinib exposure was 247 days; overall median average dose intensity was 797mg/day. Median cumulative duration of dose interruptions was 19 days. MCyR was achieved in 145 (52%), 96 (34%) were complete and 49 (18%) partial. Median time to MCyR was 2.8 mos. CHR was achieved in 137/185 (74%) pts without baseline CHR. Median time to CHR was 1.0 mos. Response rates were similar in imatinib- resistant and -intolerant pts. After 10 mos of follow up, the median duration of CHR and MCyR has not been reached. The most frequent Grade 3/4 laboratory abnormalities included thrombocytopenia in (29%), neutropenia in (28%), and asymptomatic lipase elevation in (15%) pts. Rare (<1%) pleural effusion, pericardial effusion, or pulmonary edema were observed. Requirements for growth factors and platelet transfusions were minimal. Conclusions: Nilotinib resulted in significant response rates in pts with imatinib-resistant or -intolerant CML-CP and excellent tolerability as indicated by high dose intensity, favorable rates of myelosuppression, and no serious episodes of fluid retention. No significant financial relationships to disclose.
Salvage therapy following failure or relapse after FCR chemo-immunotherapy as initial treatment for chronic lymphocytic leukemia (CLL)
Authors: Keating M. J. , Wierda W. , O'Brien S. , Tam C. , Lerner S. , Kantarjian H. 
Published: March 2020

7009 Background: CLL treatment evolved from single agents to combination chemotherapy to chemo-immunotherapy e.g. fludarabine and rituximab (FR) or with cyclophosphamide (FCR). Reports usually describe initial response, time-to-treatment failure (TTF), and survival. Follow-up of relapsed/failed patients (pts) is rarely reported. This report summarizes our experience with such pts after FCR. Methods: 300 pts initially treated with FCR were analyzed. 15 pts failed, 6 died in remission, six developed Richter's transformation (RT) or another malignancy (14) or relapsed (77). Ten have not required therapy. Results: 67 pts received first salvage therapy (S1) with a variety of regimens. The median age was 59 years and 70% were male. Most pts were Rai stage III - IV (56%). Median TTF after initial FCR was 31 months. Initial FCR responses were CR (36 pts), NPR (10 pts), PR (14 pts), and failure (7 pts). Following S1 therapy, CR was obtained in 17%, NPR (8%) and PR (14%). Initial FCR response of CR or NPR, Rai stage, and β2-microglobulin significantly predicted S1 response. The initial TTF did not predict salvage response. OR rate for FCR-based regimen alone or with alemtuzumab (A) or lumilixamab was 62%, rituximab (R) regimens (31%) and A + R (6/9, 67%). Median survival after S1 therapy was 30 months (28 deaths) and was significantly longer for CR/NPR pts (46 months) than PR/Fail (10 months) P<.001. Duration of initial FCR response, β2-microglobulin level and Rai stage predicted survival (P<.01) but the S1 regimens did not. 9/13 pts who eventually received an allogeneic transplant (allo SCT) are still alive (8 in CR). Conclusions: The results of salvage therapy following FCR initial treatment are unsatisfactory. Patients who failed to obtain a CR or NPR to FCR or S1 therapy should be considered for allo SCT. No significant financial relationships to disclose.
Prognostic significance of initial clinical and molecular genetic features of acute promyelocytic leukemia (APL): Results from the North American Intergroup Trial, C9710
Authors: Stock W. , Moser B. , Powell B. L. , Appelbaum F. R. , Tallman M. S. , Larson R. A. , Feusner J. H. , Bloomfield C. D. , Willman C. , Gallagher R. E. 
Published: March 2020

7016 Background: The impact of previously defined prognostic variables can change with advances in treatment. Thus, the significance of initial clinical and molecular genetic features of APL were explored in the context of the first randomized trial designed to evaluate the potential benefit of adding As2O3 consolidation into front-line all-trans retinoic acid (ATRA)-based therapy of APL (Powell et al, ASCO 2007). Methods: We evaluated pre-treatment white blood cell (WBC) and platelet count, age, PML-RARA transcript level and isoform type in the first 180 untreated APL patients (pts) who underwent molecular analysis on C9710 and explored their relationship to disease- free (DFS) and overall survival (S). PML-RARA transcripts were measured using real-time quantitative RT-PCR and expressed as a normalized quotient (NQ) of PML-RARA/GAPDH. Results: Using a multivariate proportional hazard model, pre-treatment PML-RARA level and WBC count were independently associated with DFS; p = 0.0073 and p = 0.05, respectively. Pre-treatment WBC count was the only feature significantly associated with S; p<0.0001. With a median follow-up of 29 months, neither median DFS nor S have been reached and only 30 DFS events have been reported among these 180 pts. Pts with higher presenting WBC > 10K/μl had both shorter DFS and S with hazard ratios (HR) of 2.3 and 5.5, respectively. The relationships between treatment arm and pre-treatment WBC and PML-RARA transcript level were explored by categorical analyses. For non-As2O3-treated pts, a striking difference was observed in DFS at 2.5 years between those above or below cut-off values: WBC <10K, 78%; WBC >10K, 50%; NQ <median, 87%; NQ >median, 60%. For As2O3-treated pts smaller and the reverse differences were observed: WBC <10K, 94%; WBC >10K, no DFS events reported; NQ < median, 93%; NQ >median, no DFS events reported. Conclusion: These preliminary results (based on analysis of 31% of total C9710 pts) indicate that pre-treatment PML-RARA transcript level and WBC are prognostic variables for newly diagnosed APL pts in first remission treated with standard ATRA-based chemotherapy but suggest that they may not apply in pts receiving two 25-day courses of As2O3 as first consolidation. No significant financial relationships to disclose.
PR1 peptide vaccination for patients with myeloid leukemias
Authors: Qazilbash M. H. , Thall P. F. , Wang X. , Wieder E. , Rios R. , Kant S. , Estey E. H. , Cortes J. E. , Komanduri K. , Champlin R. E. , Molldrem J. J. 
Published: March 2020

7017 Background: PR1 is a nanomeric HLA-A2-restricted peptide derived from the myeloid leukemia-associated antigens proteinase 3 and neutrophil elastase. Methods: Sixty-six HLA-A2+ patients with acute myeloid leukemia (42), chronic myeloid leukemia (13) or myelodysplastic syndrome (11) were treated with PR1 peptide vaccine. The first 54 patient received three vaccinations, and the last 12 patients were given six vaccinations. The vaccine was injected subcutaneously, at 3 week intervals at one of three dose levels: 0.25, 0.5 or 1.0 mg per vaccination. Immune response to the vaccine was defined as a ≥ 2-fold increase in PR1-specific cytotoxic T lymphocytes. Results: Fifty-three patients had measurable disease (MD) and 13 were in complete remission. The vaccine was well tolerated, with toxicity limited to grade I and II injection site reactions. Forty-four of the 53 patients with MD were evaluable for both immune and clinical responses. PR1-specific immune response was observed in 35/44 (57%) of the evaluable patients. Clinical responses were observed in 10 of the 25 immune responders versus 2 of the 19 immune non-responders (p=0.04). PR1 vaccine-induced immune response was associated with a longer event-free survival, 8.7 months vs. 4.1 months in immune non-responders (p = 0.17). Older age and high blast count were associated with short event-free survival (p=0.01 and <0.001). Conclusion: PR1 peptide vaccine-induced immune response is associated with a superior overall clinical response and a trend towards longer event-free survival in patients with persistent myeloid leukemia. [Table: see text]
Phase I trial of intermittent administration of sorafenib (BAY 43–9006) for patients (pts) with refractory/relapsed acute myelogenous leukemia (AML)
Authors: Quintas-Cardama A. , Kantarjian H. , Andreef M. , Faderl S. , Wright J. , Zhang W. , Konopleva M. , Verstovsek S. , Borthakur G. , Cortes J. 
Published: March 2020

7018 Background: Fms-like tyrosine kinase 3 (FLT3) mutations, both internal tandem duplication (ITD) and point mutations, occur in approximately 30% of pts with AML and confer poor prognosis. Sorafenib is an oral multi-kinase inhibitor highly potent against mutant FLT3 (IC50 1–3 nM). Based on preclinical data, this study was initiated to assess two intermittent administration schedules of sorafenib. Methods: This phase I trial evaluated the safety and efficacy of sorafenib in 15 pts with refractory/relapsed AML (n=14) or high-risk myelodysplastic syndrome (n=1). Pts were randomized to sorafenib for 5 days per week (arm A; n=8) or for 14 days every 21 days (arm B; n=7). In both arms, dose level (DL) 1 was 200 mg twice daily in 21-day cycles. Successive DLs were 600, 800, and 1,200 mg daily on a standard 3+3 design. Pre- and post-treatment peripheral blood (PB) and bone marrow (BM) samples were obtained for evaluation of FLT3 status and phospho and total FLT3 and ERK expression. Results: 10 (67%) of 15 pts (all with AML) received at least 1 cycle of sorafenib (5 in arm A, 5 in arm B) and 5 discontinued sorafenib (3 in arm A, 2 in arm B): 3 due to disease progression, and 2 due to infectious complications. Pts who received at least 1 cycle were treated at DL-1 (n=4) or DL-2 (n=6). Median age was 61 years (range, 51–81), number of prior therapies 4 (range, 1–6), and time from diagnosis to sorafenib 9 months (range, 5–46). Sorafenib was well tolerated; the MTD has not been reached. Six (60%) of 10 pts receiving at least 1 cycle of sorafenib (3 in arm A, 3 in arm B) responded. Responses were transient and only occurred in pts with FLT3-ITD mutation. The median blast percentage before and after sorafenib start was 59% and 0% in PB (p=0.008) and 66% and 32% in BM (p=0.03). Serial determinations of phosphorylation status following sorafenib (at 0, 2, 24,120 hours) in pts with FLT3-ITD, demonstrated inhibition of phospho-FLT3 in 3/3 and phospho-ERK in 5/5 pts. Conclusions: Sorafenib is safe in AML and has encouraging activity at the relatively low doses tested thus far, particularly in pts with FLT3-ITD mutation. Clinical studies of sorafenib in combination with chemotherapy or other targeted agents are warranted in pts with AML expressing this abnormality. [Table: see text]
The impact of leukocytosis on survival, leukemic transformation, and thrombosis in polycythemia vera
Authors: Gangat N. , Strand J. , Li C. Y. , Pardanani A. , Mesa R. , Tefferi A. 
Published: March 2020

7029 Background: A leukocyte count of > 15 ×109/L has recently been associated with myocardial infarction in polycythemia vera (PV). In the current study, we examine the impact of such degree of leukocytosis on survival, leukemic transformation (LT), and thrombosis in a large cohort of PV patients from a single institution Methods: Data was abstracted from the medical records of a consecutive cohort of patients with PV defined by the World Health Organization criteria. Results: i. Patient characteristics The study cohort included 459 patients (median age, 60 years). Median follow-up was 64 months. ii. Survival In a multivariable analysis, advanced age, leukocyte count of = 15 × 109/L, and arterial thrombosis at diagnosis were significantly associated with inferior survival. A prognostic model based on age = 60 years and leukocyte count = 15 × 109/L separated low-risk, intermediate-risk, and high-risk patient groups with respective median survivals of 272, 162, and 108 months (p<0.0001). iii. Leukemic transformation In a multivariable analysis, only leukocyte count was significantly associated with LT; median leukemia-free survival for patients with leukocyte count = 15 × 109/L was 273 months vs. not reached for those with lower leukocyte count (p<0.0001). iv. Thrombosis at diagnosis In multivariable analysis, arterial thrombosis at diagnosis was significantly associated with previous history of arterial thrombosis, hypertension, and tobacco use; venous thrombosis at diagnosis was significantly associated with previous venous event and splenomegaly. v. Thrombosis during follow- up In multivariable analysis, arterial thrombosis during follow-up was significantly associated with previous arterial event, hypertension, and tobacco use; venous thrombosis during follow-up was significantly associated with previous venous event, diabetes mellitus, advanced age, and leukocyte count = 1,500 × 109/L. Conclusions: The current study for the first time identifies leukocytosis as a risk factor for inferior survival, LT risk, and venous thrombosis in PV. No significant financial relationships to disclose.
Clinical correlates of JAK2V617F allele burden in essential thrombocythemia
Authors: Kittur J. , Knudson R. A. , Lasho T. L. , Finke C. M. , Gangat N. , Wolanskyj A. P. , Li C. , Wu W. , Ketterling R. P. , Pardanani A. , Tefferi A. 
Published: March 2020

7030 Background: JAK2V617F occurs in approximately 50% of patients with essential thrombocythemia. Qualitative studies of mutation analysis have previously reported an association between JAK2V617F and advanced age, higher hemoglobin level, higher leukocyte count, and lower platelet count. A possible association with thrombotic complication has also been considered. Methods: Allele-specific, quantitative PCR analysis for JAK2V617F was performed on 176 patients with ET, using genomic DNA from archived bone marrow, which was collected within one year (n=72), between 1 and 5 years (n=64), or after 5 years (n=40) of diagnosis. Results: JAK2V617F was detected in 96 patients (55%), in whom mutant allele burden ranged from 1% to 100% (median 6.3%). Neither mutational frequency (p=0.37) nor mutant allele burden (p=0.62) was affected by the timing of bone marrow sample collection. Presence of JAK2V617F was significantly associated with higher hemoglobin level (p<0.0001), lower platelet count (p=0.001), higher leukocyte count (p=0.008), increased incidence of venous thrombosis occurring after diagnosis (p=0.02), and older age at diagnosis (p=0.03). All but age retained significance in multivariable analysis. In mutation-positive patients (n=96), JAK2V617F allele burden clustered between 1% and 22% in 94 cases, in whom it correlated directly and significantly with platelet and leukocyte counts, palpable splenomegaly at diagnosis, and venous thrombosis occurring after diagnosis. Conclusions: JAK2V617F allele burden imparts additional phenotypic effects in ET. No significant financial relationships to disclose.
Safety and efficacy of eculizumab in paroxysmal nocturnal hemoglobinuria evolving from patients with myelodysplastic syndrome and aplastic anemia
Authors: Brodsky R. A. , Hillmen P. , Schubert J. , Luzzatto L. , Socié G. , Mojcik C. F. , Rother R. P. , Young N. S. 
Published: March 2020

7033 Background: Myelodysplastic syndrome (MDS) and aplastic anemia (AA) have been reported to be associated with the development of the acquired clonal hemolytic and bone marrow failure disorder, paroxysmal nocturnal hemoglobinuria (PNH). Two recent phase 3 clinical studies have demonstrated significant benefit of the complement inhibitor eculizumab (Soliris) in a heterogeneous population of patients with PNH (n=140). Methods: To investigate whether eculizumab was safe and effective in PNH patients with a history of MDS or AA (n=37), efficacy parameters were examined in the MDS/AA patient subpopulation. Results: Intravascular hemolysis, as assessed by plasma levels of the enzyme lactate dehydrogenase (LDH), was reduced from a mean of 1871 ± 159 U/L at baseline to 300 ± 21 U/L at week 26 in patients with a history of MDS or AA (p<0.001, signed rank test; normal range 103–223 U/L). Anemia was improved as packed RBC transfusion requirements were substantially reduced with eculizumab in these patients from a median of 8 units per patient in the 6 months before treatment to 0 units per patient during eculizumab treatment (p<0.001, signed rank test). Despite history of bone marrow failure, eculizumab treatment markedly improved fatigue with an 11.6 point increase over baseline using the FACIT-Fatigue instrument (p<0.001, signed rank test; a 3 or more point increase in this instrument has been shown to be clinical meaningful). Fatigue was similarly improved with the fatigue scale of the EORTC QLQ-C30 instrument (p<0.001, signed rank test). Eculizumab appeared to be well tolerated when administered to PNH patients with a history of MDS or AA. The significant clinical improvements in hematologic and quality of life outcomes with eculizumab treatment in PNH patients with a history of MDS or AA were similar to the clinical improvements demonstrated the overall PNH patient population. Conclusions: These analyses show that eculizumab treatment may provide important clinical benefit when administered to PNH patients with a history of bone marrow failure. No significant financial relationships to disclose.
Impact of prognostic factors on outcome in a phase III study comparing alemtuzumab to chlorambucil as first-line therapy for B-cell chronic lymphocytic leukemia (BCLL)
Authors: Mayer J. , Robak T. , Skotnicki A. , Jaksic B. , Dmoszynska A. , Sirard C. , Hillmen P. 
Published: March 2020

7035 Background: CAM307 is a phase III, open-label, randomized controlled trial comparing alemtuzumab (CAM) with chlorambucil (CHLO) for previously untreated B-CLL. Methods: The trial enrolled 297 previously untreated patients requiring therapy according to NCI-WG criteria. Patients were randomized 1:1 to CAM (n=149) vs CHLO (n=148) using standard dosing regimens. Diagnosis, Rai stage, response and disease progression were confirmed by an independent response review panel. In the overall study population, CAM demonstrated significantly higher overall response rates (ORR) than CHLO (83 % vs 55%) and a significant improvement in PFS (p= 0.0001) with manageable toxicities1. Outcomes according to Rai stage and cytogenetics have been previously reported.1,2 A pre-specified subgroup analysis of response rates (RR) and progression-free survival (PFS) by prognostic factors was performed. Results: Additional analyses revealed statistically significant PFS advantage in favor for CAM vs. CHLO for patients with β-2 microglobulin =3 mg/L (p<0.0001) or marrow infiltration =90% (p=0.0001). Conclusions: CAM is significantly superior to CHLO relative to overall and complete RR and PFS in the overall study population of previously untreated patients with CLL, and in patients < 65 years of age, < 70 years of age, maximum lymph node size < 5cm, and, performance status <2. Campath deserves further study in patients with age = 70, patients with massive lymphadenopathy, and in those with poor performance status. 1. Hillmen, P et al, Blood 108(11), abstract 301 2. Robak, T et al, Blood 108(11), abstract 2092 No significant financial relationships to disclose. [Table: see text]
Combination therapy with alemtuzumab and pentostatin is effective and has acceptable toxicity in patients with T-lymphoid neoplasms
Authors: Aribi A. , Kantarjian H. , O'Brien S. , Koller C. , Verstovsek S. , Faderl S. , Keating M. , Ravandi-Kashani F. 
Published: March 2020

7037 Background: The development of effective therapeutic strategies for T-lymphoid neoplasms has been difficult partly due to the paucity of clinical trials. These neoplasms are generally refractory to traditional chemotherapy regimens. Alemtuzumab and pentostatin have response rates of 50% to 65% when used individually to treat various T-cell leukemias and lymphomas. However, most responses are partial and of limited duration. Methods: We have treated 20 patients (pts) with T-lymphoid malignancies (11 T-PLL, 1 ATL, 1 PTCL, 2 T- ALL, 3 γd-T cell hepatosplenic lymphoma, 2 T-LGL) with a combination of alemtuzumab 30 mg IV, 3 times weekly for up to 3 months and pentostatin 4 mg/m2 weekly×4 followed by alternate weekly administration for up to 6 months. Prophylactic antibiotics were administered during the treatment and for 2 months after its completion. Results: The median age of pts was 57 yrs (range, 22 –79 yrs), median WBC was 43.9×109/L (range 0.6 –279.5 x109/L), and median serum β2M was 4.1 mg/L (range, 1.7 –10.8 mg/L). Four pts had splenomegaly, and 6 lymphadenopathy. Thirteen had prior therapy (median 2). Twelve pts have responded (10 CR, 2 PR) for an overall response rate of 60% (including 8 of 11 T-PLL, 1 of 1 ATL, 0 of 2 T-ALL, 2 of 3γd-T cell hepatosplenic lymphoma, 0 of 1 PTCL and 1 of 2 T-LGL). Monoclonal T-cell receptor chain gene rearrangements were detected by PCR in 18 pts and became negative in 5 of 7 evaluable pts in CR. Median response duration has not been reached (range, 0 to 78 weeks). 3 pts have proceeded to allogeneic stem cell transplant, 4 (1 with ATL, 2 with T-PLL, and 1 with T-LGL) have died from disease progression after a response, and 8 were refractory to therapy. Opportunistic infections included reactivation of CMV in 7 pts, reactivation of HSV in 1 pt, recurrence of pre-existing Serratia pneumonia in 1 pt and Aspergillus pneumonia in 2 pts. Unexplained, marked and sustained pancytopenia occurred in 2 pts. Other toxicities were mainly grade 1 and 2 and included nausea, fever, edema, and shortness of breath. Conclusions: The combination of alemtuzumab and pentostatin is feasible and effective in T-cell neoplasms. Although infections including CMV reactivation are a concern, they may be minimized with adequate prophylactic antibiotic therapy. No significant financial relationships to disclose.