bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of the total cost of FNAC as a diagnostic tool in patients with thyroid nodules
Authors: Borget I. , Vielh P. , Allyn M. , Schlumberger M. , De Pouvourville G.
Published: March 2020

6628

Background: The prevalence of thyroid nodules in the general population ranges from 4 to 7% and fine-needle aspiration cytology (FNAC) is a widely used diagnostic procedure. As the final diagnosis is based on post-surgical pathology of the lesion, a number of patients with nodules classified as benign or indeterminate by cytology may have a postponed final diagnosis, impacting the procedure cost. This study aims to determine the total cost of FNAC, by taking into account of diagnostic mistakes (false-positive and false-negative), failures of FNAC (indeterminate results) and the follow-up of non operated patients. Methods: A Markov model was built to describe the management of patients through time, from the first FNA-t. We derived estimates for diagnostic accuracy values and follow-up from a retrospective study, including all patients who had their first FNAC from 2003 to 2005 at Institut Gustave Roussy. Costs were computed from the viewpoint of the hospital. A microcosting study was performed to determine the unit cost of FNAC. Sensitivity analyses were performed. Results: Out of the 624 patients who had FNAC, 15 were cytologically classified as malignant, 57 as suspicious and 171 as indeterminate. Surgical excision was carried on in 155 cases. The unit cost of FNAC was 121 €. Markov modelling showed that the mean total cost of a true diagnosis including unnecessary surgeries, repeat FNAC and follow-up was 1,145 Euros. The number of false negative and false positive cases had little impact on total cost, whereas it was significantly affected by the percentage (27%) of unsatisfactory specimens. The absence of such specimens would reduce the total cost to 738 Euros (35%). Conclusions: The cost of FNAC exceeds its unit production cost. It depends on the performance of the cytologist and on the rate of indeterminate results that might be reduced by routine ultrasound-guidance.

No significant financial relationships to disclose.
Establishing a research network in Scotland more than doubles trial recruitment
Authors: Cassidy J. , Bonner-Shand S. , Nicoloson M. , Cameron D. , McLaren R. , Gordon A.
Published: March 2020

6630

Background: Scotland has a population of 5.4 million people with 26, 000 new cases of cancer per annum. In 2002 the Scottish Executive established a research network covering all of the country with the objective of doubling recruitment to cancer trials within 3 years. Methods: A grant of £1million (circa $2 million) was provided to establish a network covering all of Scotland. The network was centred on 3 of the main cancer centres. Support staff consisting mainly of data managers and research nurses were employed in each region. Clinical trials were selected by interested clinicians from the existing NCRI portfolio in the UK. These trials were then opened in centres and regional units with the intention of recruiting patients locally. Each trial was approved by appropriate local university and NHS ethics, research and development boards. Recruitment numbers were collated by trials co-ordinators and compared with baseline figures derived from 2001–2 Results: 31 members of staff were recruited and trained. These were a mix of data managers and research nurses. In 2001, 927 patients were entered in trials which is 3.5% of all cases. In 2005 this had risen to 3557 (13.7% of all cases). These ranged across all the major common solid and haematological malignancies. In portfolio includes therapy studies in phase 1–3 including large scale RCTs, screening and prevention studies. The breakdown of patients treated within the cancer centres versus those in regional units indicated that the biggest impact on recruitment was in the latter. The network has introduced streamlined procedures for multiple ethics and R+D submissions which has facilitated recruitment in cancer units. Web based tools have been piloted to allow patient screening to be performed remote from the cancer centres. A breakdown of recruitment by trial and tumour type will be presented. Conclusions: Investment in infrastructure support in a targeted manner can very significantly improve trial recruitment.

No significant financial relationships to disclose.
The NCI pediatric central institutional review board (PedCIRB) initiative: Progress and impact
Authors: Anderson B. D. , Goldberg J. , Adler J. , Covington L. , Olson D. , Gordon B. , Reaman G. , Everett J. , Smith M. , Christian M.
Published: March 2020

6632

NCI has developed a central IRB (PedCIRB) to review NCI-sponsored pediatric clinical trials conducted by the Children's Oncology Group (COG). COG comprises ∼200 U.S. medical institutions and protocol activation traditionally requires separate protocol review by each local IRB (LIRB) and, subsequently, a review of each protocol amendment and significant adverse event. The PedCIRB model seeks to increase patient protection by improving the expertise of protocol reviewers and making their review available to all PedCIRB participating institutions. The PedCIRB consists of experts in pediatric oncology, pediatric medicine, nursing, pharmacy, bioethics, biostatistics, as well as patient advocates and childhood cancer survivors. The PedCIRB model also eliminates redundant reviews, reduces administrative burdens on local COG investigators and LIRBs, and can accelerate the pace of local protocol activation, thus increasing the availability of clinical trials to children with cancer. The PedCIRB conducts a full board protocol review that is available via a confidential website to participating LIRBs. LIRBs can choose to perform a facilitated review, using PedCIRB materials, that focuses on local concerns, rather than a full LIRB protocol review. If the LIRB accepts the PedCIRB review, the PedCIRB becomes the IRB of record for that protocol and takes responsibility for the review of subsequent protocol amendments, adverse events and continuing reviews. Since starting in November 2004, the PedCIRB has reviewed 59 protocols. Initial reviews resulted in 44 approvals pending modification and 15 protocols being tabled for further information. The time from protocol submission to final approval by the PedCIRB has ranged from 3 to 28 weeks with an average time of 16.9 weeks during year one and 12.7 weeks during year two of the project. As of November 2006, 117 of a possible 197 U.S. COG institutions (59%) have signed on to the PedCIRB initiative and 70% of the participating institutions have conducted facilitated reviews (total 750) for the 30 protocols available on the PedCIRB website. The PedCIRB's influence on protocol development and patient accrual timelines will be discussed.

No significant financial relationships to disclose.
The European Medicines Agency (EMEA) guideline on oncology drug development
Authors: Palmeri S. , Bergh J. , Bergmann L. , Hansen S. W. , Moraleda J. M. , Marty M. , Schellens J. H. , Smyth J. , Therasse P. , van Oosterom A. , Jonsson B.
Published: March 2020

6636

Background: The scientific assessment and positive opinion of the EMEA is mandatory for the approval of new oncology drugs in the European Union. One of the tasks of the EMEA is to provide guidance on the conduct of the various tests and trials necessary for approval. The EMEA has recently revised its guideline on the clinical development of new anticancer drugs. The revised version includes specific guidance on the development of non-cytotoxic (i.e., cytostatic) agents ( http://www.emea.europa.eu/pdfs/human/ewp/020595en.pdf ). Specific guidance is given about methodological issues using progression-free survival (PFS) as primary endpoint in confirmatory trials for registration ( http://www.emea.europa.eu/pdfs/human/ewp/26757506en.pdf ). Methods: The key elements of the revised guideline are described with particular reference to requirements for approval. Results: The early stages of clinical drug development have to be tailored according to the assumed pharmacology of the individual compound as defined in non-clinical studies. The integration of information from exploratory (phase I-II) and confirmatory (phase III) studies is of primary importance. In general, phase III trials should be designed with the aim of establishing the benefit risk balance of the drug, in a well-characterized target population. These studies should be randomized controlled and, where possible, blinded or include blinded evaluation. Acceptable primary endpoints include overall survival (OS) and PFS or disease-free survival (DFS). It is acknowledged that there are situations where PFS can be considered as a primary endpoint that measures clinical benefit. Adherence to protocol-defined schedules for tumor assessments, typically by imaging techniques, is important and deviations should be reported. Independent, blinded review and confirmation of best tumor response and progression should be undertaken if PFS is the primary endpoint. Conclusions: The current revision of the EMEA guideline provides useful clinical regulatory guidance for the development of cytostatic agents. When recommended guidelines are considered suboptimal, sponsors are encouraged to seek regulatory scientific advice.

No significant financial relationships to disclose.
Unrelated donor hematopoietic cell transplantation (HCT) as treatment for acute myeloid leukemia (AML) in first remission
Authors: Pagel J. M. , Gooley T. , Sandmaier B. M. , Drouet L. , Petersdorf E. W. , Sorror M. L. , Hansen J. A. , Deeg H. J. , Martin P. J. , Storb R. , Appelbaum F. R.
Published: March 2020

7000

Background: Unrelated donor HCT has been used with increasing frequency for the treatment of AML patients in first remission. Methods: Between 1990 and 2005, 105 adult patients with AML [66 (62%) primary and 39 (38%) secondary] received T- cell-replete HCT from unrelated donors in Seattle. Results: Median age was 44 (range, 18–74) years. Seventy-nine patients received ablative conditioning for HCT (57% conditioned with cyclophosphamide plus total body irradiation (TBI), 43% with chemotherapy alone). Non- myeloablative doses of fludarabine (FLU; 25 mg/m2 daily for 3 days) and TBI (200 cGy) were delivered to 26 patients. Ninety-six percent of patients who underwent reduced-intensity conditioning received unrelated peripheral blood stem cells (PBSC) while 59% of myeloablative HCT patients received PBSC as their source of stem cells. For all patients, the leukemia-free survival (LFS) and non-relapse mortality estimated at 2 years were 53%, and 26%, respectively, as 27 patients died of transplant-related causes (pulmonary-6, cardiac-1, graft versus host disease (GVHD)-6, infection-5, and unknown-9). Twenty-two patients (21%) relapsed 2 to 83 months (median 5) post-transplant, and 56 patients are surviving disease-free 1 to 168 months (median 27) post-transplant. For 90 patients (86%) with intermediate-risk cytogenetics, 51 (57%) are surviving disease-free, with 16 (18%) relapsing. Fourteen patients (13%) were considered high risk based on unfavorable cytogenetics; 4 of these 14 (29%) are surviving disease-free and 6 (43%) have relapsed. The probability of grade 3/4 acute GVHD was 19% while the probability of clinical extensive chronic GVHD was 54% one year after transplant. Unfavorable cytogenetics (HR=2.16, p=.08), secondary leukemia (HR=1.71, p=.10), higher co-morbidity score (p<.0001), and HLA mismatching (HR=2.35, p=.02) were associated with an increased hazard of mortality. After controlling for these factors, non-ablative conditioning was not statistically worse than ablative conditioning (HR=1.21, p=.61). Conclusions: These data suggest that HCT using unrelated allografts has the potential to provide significant LFS for patients undergoing HCT for AML in first remission when an HLA family match is not available.

No significant financial relationships to disclose.
Bosutinib (SKI-606) exhibits clinical activity in patients with Philadelphia chromosome positive CML or ALL who failed imatinib
Authors: Gambacorti-Passerini C. , Brummendorf T. , Kantarjian H. , Martinelli G. , Liu D. , Fisher T. , Hewes B. , Volkert A. , Abbas R. , Cortes J.
Published: March 2020

7006

Background: Bosutinib (SKI-606) is an orally available, dual Src/Abl kinase inhibitor. To assess safety and preliminary clinical activity of bosutinib, we conducted a phase 1/2 study in patients (pts) with Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL) who were imatinib resistant/intolerant. Methods: In part 1, 18 pts with imatinib- relapsed/refractory chronic phase (CP) CML received bosutinib 400 mg/day (3 pts), 500 mg/day (3 pts), or 600 mg/day (12 pts). Part 2 was an expanded cohort of 51 pts with all phases of Ph+ CML and ALL dosed at 500 mg daily. Timed blood samples were collected on days 1–3, 15 for PK analysis. Results: Of 69 pts, median age was 59 yrs; 48 were CP; 90% imatinib resistant. Drug-related grade 1/2 adverse events (AEs) occurring in =10% of CP pts: diarrhea (69%), nausea (44%), vomiting (19%), abdominal pain (13%), rash (13%). Grade 3/4 AEs occurring in =5% of CP pts: rash (6%), thrombocytopenia (6%). 17 pts required dose reductions. In evaluable imatinib-resistant CP-CML pts with no prior exposure to other Abl inhibitors, 16/19 (84%) had complete hematologic response (CHR); 4/21 had partial and 7/21 had complete cytogenetic responses for major cytogenetic response (MCyR) rate of 52%. Of 58 pts evaluable for mutations, 13 different imatinib-resistant mutations were found in 32 pts. 12/14 CP pts with non-P-loop mutations and 3/3 with P-loop mutations achieved CHR. 5/11 CP pts with non-P- loop mutations and 1/1 with P-loop mutation achieved MCyR. 4/9 evaluable advanced leukemia pts had CHR, 2 had MCyR. After oral administration, steady state exposure of bosutinib was nearly 2-fold higher than single-dose exposure. Mean elimination half-life was approximately 22–27 hours, supporting a once-daily dosing regimen. Conclusions: Bosutinib was well tolerated in pts with CML, with primarily low-grade gastrointestinal and dermatologic AEs. Bosutinib showed clinical activity in imatinib-resistant pts with cytogenetic responses and CHR across a range of mutations. Durability of response continues to be assessed.

[Table: see text]
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, 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.

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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.
Does BCR-ABL transcript type predict cytogenetic response to imatinib mesylate in chronic phase, chronic myeloid leukemia patients?
Authors: Sharma P. , Kumar L. , Mohanty S. , Bose S. , Kochupillai V.
Published: March 2020

7043

Background: We prospectively studied BCR-ABL transcript type (b2a2, b3a2, e1a2 and e19a2 in 100 CML-CP patients treated with Imatinib mesylate therapy and studied their correlation with the cytogenetics responses. Methods: Between Aug, 2004 and Sep, 2006, 100 CML –CP patients (median age was 32 years, range, 11 to 62 years, M: F: 2.5: 1) were treated prospectively with imatinib mesylate 400 mg daily on outpatients. 70 patients were pre-treated with interferon Alfa. The mean duration of Gleevec treatment was 24 months (range 3 to 38 months). Patients were monitored closely for clinical, hematological, cytogenetic & molecular response as per standard guidelines. Bone marrow was studied at 3, 6, 9 then 4–6 months interval for cytogenetic response (CGR) and also for the presence of BCR-ABL transcript types by multiplex and nested RT-PCR technique. Results: 96% of patients achieved complete hematological remission (CHR); median time being 21 days, ranging from 7 to 110 days. 60% of patients achieved Major CGR (complete 32, partial CGR-28); median time 8 months, ranging from 6 to 22 months. Previously untreated patients had higher major (70% vs 55.7%) and complete (46.6% vs 25.7%) CGR compared to patients previously treated with interferon alfa. Analysis for BCR-ABL transcript type revealed - b2a2 in 38%, b3a2 -54% and both in 8% of patients. 28 of 38(74%) patients with b2a2 type acieved Major CGR compared to 24 of 54 (44%) patients with b3a2 transcript, p<0.002. Of remaining 40 patients with minor or no CGR, 10(25%) had b2a2 compared to 30 (75 %) b3a2 type, p<.002. However, there was no significant correlation between transcript type and pre-treatment characteristics e.g. spleen size (in cm), Hb (G/dl), WBC & platelets counts. Conclusions: Present study suggests that site of breakpoint in major breakpoint cluster region might be predictive of cytogenetic responses to Imatinib Mesylate in CML patients.

No significant financial relationships to disclose.
Discontinuation and dose modification of imatinib in clinical practice
Authors: Hamdan M. Y. , Sanders L. , Oliveria S. , Campbell U. , Willey V. , Hirji I. , Davis C. , Ulcickas Yood M.
Published: March 2020

7045

Background: Imatinib mesylate induces response in most patients with chronic myelogenous leukemia (CML). Although recent evidence shows benefit from a starting dose of 800mg/day, the recommended starting dose is 400 mg/day for chronic phase patients and 600 mg/day for accelerated phase/blast crisis patients. This study describes trends in imatinib dosing and reasons for dose changes in CML patients. Methods: Using medical and pharmacy claims in the HealthCore Managed Care Database, we identified all patients with CML from 1/1/00–3/31/04. Chart review supplemented claims and confirmed CML diagnosis, obtained phase, treatment, and clinical outcomes through 3/31/05. Results: Among 216 patients receiving imatinib, 87% were diagnosed in chronic phase, 5% in accelerated phase, 1% in blast phase; 7% were unable to be determined. Among 156 patients (72%) with a starting imatinib dose of 400mg/day, 21% had a subsequent dose reduction of at least 100mg/day. The most common reasons for dose reduction were neutropenia, anemia, and nausea/vomiting. Among 29 patients (13%) with a starting dose of at least 600mg/day, 59% had a subsequent dose reduction; the most common reasons for dose reduction in these patients were thrombocytopenia and gastrointestinal bleeding. Among 9 patients (4%) with a starting imatinib dose of at least 800mg/day, 67% had a subsequent dose reduction; the most common reason for dose reduction was myelosuppression. Imatinib therapy was suspended in sixty-two patients (29%), most often because of anemia (11%) or thrombocytopenia (11%); 46 patients (74%) restarted imatinib therapy following a median time of 21 days and the remaining 16 (26%) patients were permanently discontinued. Of the 64 patients (30%) who experienced a dose escalation of at least 100mg/day over starting dose, 34% patients had a subsequent dose decrease; the most common reason for dose reduction among these patients was neutropenia (18%). Conclusions: Among CML patients treated with imatinib, discontinuation and dose changes occurred frequently; the most common reason was myelosuppression. More than 50% of patients starting at higher doses required dose reductions and 1/3 of those receiving dose escalations did not remain on higher doses.

No significant financial relationships to disclose.
Imatinib (I) compared to I + cytarabine (Ara-C) for the frontline treatment of chronic phase (CP) chronic myeloid leukemia (CML)
Authors: Hurtado-Monroy R. , Vargas P. , Martinez A. , Cruz J. , Enriquez V. , Gutierrez O. , Candelaria M. , Aguayo A. , Cervera E.
Published: March 2020

7048

Background: Imatinib is now worldwide accepted as the standard frontline therapy of CP CML. Regardless of their impressive clinical results and low toxicity profile, a small proportion of CP CML patients could develop primary or secondary resistance. Main objective of present trial was to increase the hematological (HR) and major cytogenetical responses (MCR) with the addition of Ara-C to standard doses of I as a frontline therapy of CP CML. Methods: on September, 2003 we began this multicentric, phase III randomized, clinical trial, comparing I (400 mg/day) vs I (400 mg/day) plus subcutaneous Ara-C (10 mg/m2/day, for 10 days/monthly cycles), doses could be adjusted due to tolerance and toxicity. Inclusion criteria: newly diagnosed CP CML, not elective to allogeneic transplant. Primary endpoint was the acquisition and time to acquisition of HR, MCR by conventional criteria. Secondary endpoints were main toxicities, dead to progression and overall survival. Results: 61 patients were randomized with median follow-up of 850 days (range 85–1151) for entire group. Table 1 shows results for both treatment arms. Table 1 Both treatment arms were well tolerated and the toxicity profile was low and manageable. Statistical analysis (chi- square, paired T-student, Log-rank survival analysis) did not show significant differences among treatment arms. Conclusions: The addition of cytarabine to conventional I doses on frontline therapy CP CML does not produce significant benefit on HR or MHR. Larger I doses or other therapeutic options should be explored.

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Oral chemotherapeutic agents in elderly acute myeloid leukemia (AML) patients, a study from a developing country
Authors: Mukhopadhyay S. , Chitalkar P. , Gupta P. , Roy U. , Mukhopadhyay A.
Published: March 2020

7057

Background: Almost 60% of the patients with Acute Myeloid Leukemia (AML) are over the age of 60 years. Age is one of the strongest adverse prognostic factor for AML, both for induction remission and for survival. Studies have shown that elderly patients have reduced tolerance to aggressive chemotherapy especially the myelosupressive effects. Elderly patients with Leukemia who receive intensive treatment often die as a result of chemotherapy. Aggressive chemotherapy is also costly which the relatives in developing country are reluctant to spend for the elderly patients. The aim of our study was to see the outcome, tolerability and cost effectiveness of oral chemotherapeutic agents. Methods: We selected consecutive 100 patients more than 50 years of age in haemato oncology department of NCRI (Netaji Subhas Chandra Bose Cancer Research Institute) during the period from Jan 2004 to Dec 2006. The mean age of the patients was 65 (range 50 –71) years. There was male preponderance. The inclusion criteria were performance status more than 60% (Kornofsky), Morphological, Cyto-Chemical and Immunophenotyping diagnosis of Acute Myeloid Leukemia (AML), normal liver (billirubine < 2) and kidney function ( Creatinine <2%). After the incent consent all patient were started oral chemotherapeutic agents 6 Mercptopurine (6MP) 75mg/m2. Etoposide 70mg/m2 and Prednisolone 40mg/m2. All agents are given 3 weeks followed by 7 days gap every month and continued for 6 months. Bone Marrow was repeated after 3rd & 6th course of chemotherapy. Results: Fifteen (15%) and thirtyeight patients (38%) had complete hematological response after 3rd & 6th course of chemotherapy. Seven patients (7%) died because of grade III/IV Neutropenia. Median duration of Myelosupression was 18 days (2 to 48 days).12% required hospitalisation. With median follow up of 19 months (range 2–36 months) the disease free survival (DFS) and over all survival (OS) was 18 % and 32 % respectively. Conclusions: The combination of oral chemotherapeutic agents consisting of 6MP, Etoposide & Prednisolone were well tolerated by elderly patients with good induction remission, low mortality and median survival. It was cheaper and well accepted by the patients.

No significant financial relationships to disclose.