bluuebunny/crossref_metadata_2025 huggingface dataset:
International comparison on the factors influencing reimbursement of expensive cancer drugs.
Authors: Lim Carol Sunghye , Kwon Soonil , Lee Yun-Gyoo , Koh Youngil , Heo Dae Seog
Published: March 2020

6614

Background: Reimbursement policy for expensive cancer drugs is heterogeneous and inconsistent among countries. We compared the pattern of publically funded drug programs of ten countries. Methods: We investigated reimbursement policies of 19 indications with expensive cancer drugs (nilotinib, dasatinib, imatinib, pemetrexed, bevacizumab, sunitinib, temsirolimus, lapatinib, crizotinib, erlotinib, cetuximab, sorafenib and lenalidomide) in ten countries (Australia, Canada, England, France, Germany, Japan, Korea, Sweden, Taiwan, and the United States). Microarray analysis methodology is adopted to cluster the countries according to the pattern of reimbursement, based on incremental cost effectiveness ratio (ICER) and other variables of 19 indications. The earlier a country starts reimbursement for the indication, the higher reimbursement score (RS) is assigned to the country. Fairness index (FI) was determined for each country, depending on whether reimbursement decision follows ICER sequence. Results: Except for US, Japan and France were more likely to reimburse the indications (16/19), whereas Sweden and UK were less likely to reimburse them (5/19 and 6/19, respectively). From array analysis, we observed three separate groups: 1) France and Germany, 2) Korea and Japan, 3) UK, Sweden, Canada, Taiwan and Austrailia. The details of analysis will be presented. Regarding FI, Sweden (0.75), France (0.73) and UK (0.71) were the countries with high FI, in which health system was financed by general taxation and health technology assessment (HTA) was performed by government agency. Korea (0.34), Taiwan (0.40) and Germany (0.46) were the countries with low FI, in which social health insurance was financed by payroll tax or premium rather than general taxation. HTA was performed by non-government agency (Germany) or recently established government agency (2007 in Taiwan and 2009 in Korea) in these countries. Conclusions: Reimbursement policies for expensive cancer drugs are variable among the nations. Countries where health system is funded by general taxation and HTA is performed by government agency showed consistency of reimbursement policy based on ICER.
Underuse of cancer-directed care in Medicaid patients with esophageal cancer.
Authors: Revels Sha'Shonda L. , Reddy Rishinda , Wong Sandra L.
Published: March 2020

6637

Background: Among esophageal cancer (EC) patients (pts) there are significant disparities in the use of cancer directed-treatments. We examined the extent to which insurance status explains treatment choices and survival differences. Methods: Using the National Cancer Database Participant User File, we identified 94,399 EC pts (36% private insurance [PI], 51% Medicare, 6% Medicaid and 3% uninsured [UI]), treated at 1,586 hospitals, diagnosed 1998-2010. We evaluated variations in the use of chemotherapy, radiation and surgery with logistic regression. Cox proportional hazards regression was used to assess differences in survival. Models were adjusted for pt and tumor characteristics, as well as clustering. Results: Compared to PI pts, Medicaid pts were more likely to live in neighborhoods with low educational attainment (36 vs. 14%, p<0.01), have annual incomes <$30,000 (32 vs. 11% p<0.01) and present with stage III EC (37 vs. 17%, <0.01). Despite adjustment for pt, tumor and hospital characteristics, Medicaid pts with non-metastatic EC were less likely to undergo surgery (OR 0.43, 95% CI 0.37-0.50) and chemotherapy (OR 0.71, 95% CI 0.60-0.84) compared to PI pts. There were no differences in the use of radiation. Hospital resection rates were inversely related to Medicaid/UI case mix. The risk-adjusted resection rate for Medicaid pts at hospitals with relatively few Medicaid/UI pts was 42%, compared to 33% in hospitals with higher case mix (p<0.01). Pts at hospitals with higher Medicaid/UI case mix experienced poorer risk-adjusted survival (HR 1.16, 95% CI 1.11-1.23). Survival differences were attenuated after accounting for receipt of surgery (HR 1.09, 95%CI 1.04-1.15), but not for chemotherapy or radiation. Conclusions: Poorer survival among pts treated at hospitals with high Medicaid/UI case mix is, in part, related to the underuse of surgery. Reducing cancer deaths in disadvantaged populations will require stakeholders to gain an understanding of why these pts are less likely to get to the operating room. In addition, steps must be taken to assure that hospitals with higher Medicaid/UI case mixes are equipped to provide quality cancer care, particularly in light of upcoming Medicaid expansion.
Evaluating the impact of early versus late inpatient palliative care consultation for cancer patients.
Authors: Cassel Brian , Coyne Patrick J. , Skoro Nevena , Kerr Kathleen , Del Fabbro Egidio
Published: March 2020

6638

Background: Access to specialist palliative care (hospital-based or hospice) is a recognized measure of quality in cancer care. Most cancer centers do have palliative care consult services, although the availability of a comprehensive program that includes a palliative care unit and outpatient clinic (Hui 2010) is inconsistent. A simultaneous integrated model of palliative care that facilitates earlier access to a specialized palliative care team may improve clinical outcomes. Palliative care programs should measure the access, timing and impact of their clinical service. Methods: Hospital claims data were linked to Social Security Death Index (SSDI) data from the US Department of Commerce. 3,128 adult cancer patients died between January 2009 and July 2011 and had contact with our inpatient palliative care team in their last six months of life. We determined whether IPC earlier than 1 month prior to death had an impact on hospitalizations, in-hospital mortality and referral to hospice. Results: 27.5% of cancer decedents accessed IPC, median of 22 days before death. 13.2% were discharged to hospice, median of 13 days before death. Patients with IPC earlier than 1 month until death were more likely to have hospice and fewer in-hospital deaths but there was no association between early IPC and a 30-day mortality admission. Conclusions: Palliative care services are accessed by a minority of patients and typically in the last 2-3 weeks of life. Although in-hospital deaths were reduced by earlier palliative care consultation, 30 day mortality did not improve. Hospitals may need to implement other strategies including early integration of outpatient palliative care among cancer patients, to achieve an impact on 30-day mortality admissions. [Table: see text]
Allogeneic transplantation for myelofibrosis: Benefit of dose intensity.
Authors: Popat Uday R. , Bassett Roland , Chen Julianne , Alousi Amin Majid , Anderlini Paolo , Ciurea Stefan O. , Hosing Chitra , Jones Roy B. , Kebriaei Partow , Khouri Issa F. , Konoplev Sergej , De Lima Marcos , Nieto Yago , Oran Betul , Qazilbash Muzaffar H. , Rondon Gabriela , Shpall Elizabeth J. , Verstovsek Srdan , Andersson Borje , Champlin Richard E.
Published: March 2020

7011

Background: We did a prospective study of busulfan (bu) and fludarabine (flu) conditioning in patients with myelofibrosis. After observing a high relapse rate in the initial cohort, we increased the intensity of conditioning regimen for subsequent patients, hypothesizing that increased dose intensity delivered with PK guidance will reduce relapse rate without increasing non relapse mortality (NRM), thereby improving overall outcome. Methods: Patients with intermediate or high risk MF were eligible if they had adequate organ function and at least 9/10 matched related or unrelated donor. Of the 46 consecutive patients, 15 (bu low group) received IV busulfan 130 mg/m2 x 2 (day -3,-2). Of the remaining 31 (bu high group), 27 received IV busulfan dose to a target daily AUC of 4000 μmol.min x 4 (day -5 to -2) and 4 patients received a fixed dose of 100 mg/m2 x 4 (days -5 to -2). All patients received fludarabine 40mg/m2x 4 (day -5 to -2). Results: 23 males and 23 females with a median age of 58 years (27-74) had intermediate (25) or high-risk (21) disease. Donors were matched sibs (19), matched unrelated (23), or mismatched unrelated (4). With a median follow-up of 2.1 years (range 0.1-6 years), 3-year overall survival(OS), event-free survival (EFS), cumulative incidence (CI) of non-relapse mortality (NRM), and CI of relapse were 69%, 50% , 13%, and 37%, respectively. Multivariate Cox regression analysis showed that Bu-high dose (HR 0.41; p=0.04) and peripheral blood CD 34 count (HR 1.7; p=0.03) were significantly associated with EFS, and high CD-34 count was significantly associated with OS (HR 1.87; p=0.04). Table shows details of 3-year outcomes of low-dose and high-dose group. All patients engrafted with a median time to neutrophil engraftment of 13 (0-27) days and a median time to platelet engraftment of 24 (0-268) days. Cumulative incidence (CI) of grade II-IV, grade III, IV acute GVHD, and Chronic GVHD were 22%, 5%, and 39%, respectively. Conclusions: Higher dose busulfan, delivered with pharmacokinetic dose adjustment, reduces relapse without increasing non-relapse mortality, resulting in better EFS in patients with MF. Clinical trial information: NCT00475020. [Table: see text]
Efficacy and safety of cladribine: Subcutaneous versus intravenous administration in hairy cell leukemia.
Authors: Mohamed Tarek Yakout , El Gammal Mosaad , Namour Alfred Elias , Abdel Malek Raafat Ragaie , Khorshid Ola
Published: March 2020

7013

Background: Hairy cell leukemia (HCL) is rare B-cell lymphoproliferative disorder. Its treatment has evolved from splenectomy with time to failure (TTF) of 19 months to Cladribine that increased complete remission (CR) rate to 90%, with only small percentage of patients relapsing at 30 months. Cladribine (CDA) is originally administered intravenously as continuous infusion for 7 days; Subsequently, it was administered subcutaneously. This study aims at comparing efficacy and toxicity of Subcutaneous (SC) versus Intravenous (IV) administration of CDA in treatment of HCL. Methods: This retrospective study included HCL patients presented to National Cancer Institute and Nasser Institute, Cairo, Egypt, during period 2004-2010. Included patients received CDA as 1st or 2nd line with minimum follow up of 12 months. All files were reviewed for baseline clinical & laboratory parameters, route of administration, response, adverse events and survival. Results: This study included 49 eligible patients, 41 patients received CDA as 1st line treatment, while 8 patients as 2nd line. Eighteen patients were treated by continuous IV infusion whereas 31 patients by SC injections. Both groups were comparable regarding baseline clinical and laboratory parameters with no statistically significant difference. At median follow up period of 33.5 months, complete remission rate was 94% in IV group versus 97% in SC group (p=0.691); median TTF for IV group was 52.9 months while that for SC group was not reached (p=0.035). The median time to achieve CR in both arms was similar. By analyzing different factors affecting TTF using multivariate analysis, route of administration proved to be the only statistically significant factor (P=0.006). Regarding adverse events, there was no difference between both groups in hematological toxicities. IV route was associated with a significant higher incidence of mucositis (p=0.02) and viral infections (p=0.01). Hepatotoxicity and neurotoxicity were higher in SC group but difference was not statistically significant. Conclusions: SC administration of cladribine is an alternative route to IV in treatment of HCL with similar response rate, longer time to treatment failure and better tolerability.
A comprehensive prognostic index for patients with CLL.
Authors: Pflug Natali , Bahlo Jasmin , Shanafelt Tait D. , Eichhorst Barbara , Bergmann Manuela , Elter Thomas , Bauer Kathrin , Malchau Gebhart , Rabe Kari G. , Stilgenbauer Stephan , Dohner Hartmut , Jäger Ulrich , Eckart Michael , Hopfinger Georg , Busch Raymonde , Fink Anna-Maria , Wendtner Clemens M. , Fischer Kirsten , Kay Neil E. , Hallek Michael
Published: March 2020

7015

Background: Besides clinical staging, a number of biomarkers predicting OS in CLL have been identified. The multiplicity of markers, limited information on their independent value, and a lack of understanding of how to interpret discordant markers are major barriers to use in routine clinical practice. We developed an integrated prognostic index using the database of the German CLL Study Group (GCLLSG), which was subsequently validated in a cohort of untreated CLL patients (pts) from the Mayo Clinic. Methods: The analysis was based on a dataset collected between 1997 and 2006 in 3 GCLLSG phase III trials. The external validation was performed on a series of newly diagnosed CLL pts managed at Mayo Clinic. Results: The GCLLSG dataset (1,948 physically fit pts at early and advanced stage; median age: 60 yr (range 30-81); median observation time 63.4 mo) was used as a training dataset. 7 parameters were identified as independent predictors for OS: sex, age, ECOG status, del 17p, del 11q, IGHV mutation status, thymidine kinase and β2-microglobulin. By using a weighted grading a prognostic index was derived separating four different pts groups: low risk (score 0 - 2), intermediate risk (score 3-5), high risk (score 6-10) and very high risk (score 11-14) with significant different OS rates (95.2%, 86.9%, 67.7% and 18.7% OS after 5 yr for the low, intermediate, high and very high risk group respectively (p<0.001). This prognostic index was validated in a cohort of 676 newly diagnosed, untreated pts from the Mayo Clinic (median age 61.5 yr (range 32 - 89); median observation time 47.0 mo). The 4 risk groups were reproduced with 98.3%, 95.4%, 75.4% and 10.8% OS after 5 yr. The prognostic index predicts OS independent of Rai/Binet stage and provides accurate estimations regarding time to first treatment (TTF). C-statistic is 0.75. Conclusions: Using a multi-step process including external validation, we developed a comprehensive prognostic index combining clinical, serum, and molecular information into a single risk score for pts with untreated CLL. The prognostic index provides more accurate prediction of both TTF and OS. To our knowledge it is the first prognostic model in CLL to reach the C-statistic threshold (c > 0.70) necessary to have utility at the level of the individual.
Which treatment options impact outcomes in elderly chronic lymphocytic leukemia patients with high prevalence of comorbidity?
Authors: Satram-Hoang Sacha , Reyes Carolina M. , Hoang Khang , Momin Fayez , Guduru Sridhar , Skettino Sandra L.
Published: March 2020

7016

Background: Therapy selection in chronic lymphocytic leukemia (CLL) patients is based on disease severity as well as patient characteristics such as age and comorbidity. While treatment outcomes are mostly available from clinical trial data in younger patients, less is known about the effect of comorbidities on outcomes in elderly CLL patients in the real-world setting. Methods: The linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database was utilized in this retrospective cohort analysis of 3,366 first primary CLL patients. Patients were diagnosed between 1/1/1998-12/31/2007, were >66 years, continuously enrolled in Medicare Part A and B with no HMO coverage in the year prior to diagnosis and received first-line treatment with any oral or infused therapy. CLB is covered by Medicare Part D and data for its use were only available from 2007-2009 in the dataset. Cox regression with backward elimination and propensity score weighted Cox regression estimated the relative risk of death. Date of last follow-up was 12/31/2009. Results: There were 153 CLB, 606 R-mono, 702 R+IV Chemo, and 1,905 IV Chemo-only patients. CLB and R-mono patients were older at diagnosis with mean age of 77 compared to R+IV Chemo (73 years) and IV Chemo-only (76 years; p<.0001). Patients administered R-mono had a higher comorbidity burden and more advanced disease compared with other treatment groups. In the survival analysis we compared CLB to R-mono during the time period 2007-2009 and R+IV Chemo to IV Chemo-only during the time period 1998-2009. The adjusted multivariate survival analysis revealed a significant mortality risk reduction with R+IV Chemo compared with IV Chemo-only patients (HR, 0.72; 95% CI, 0.62-0.84) while a non-significant mortality risk reduction was noted with R-mono compared to CLB patients (HR, 0.47; 95% CI, 0.21-1.05). Older age and increasing comorbidity score were significantly associated with higher mortality. Conclusions: These findings suggest that chemo-immunotherapy is more effective than chemotherapy in an elderly population with a high prevalence of comorbidity. This extends the conclusions from clinical trials in younger, medically fit patients.
Effect of quizartinib (AC220) on response rates and long-term survival in elderly patients with FLT3-ITD positive or negative relapsed/refractory acute myeloid leukemia.
Authors: Martinelli Giovanni , Perl Alexander E. , Dombret Hervé , Kayser Sabine , Steffen Bjoern , Rousselot Philippe H. , Estey Elihu , Burnett Alan K. , Shah Neil P. , Gammon Guy , Trone Denise , Levis Mark J. , Cortes Jorge E.
Published: March 2020

7021

Background: Advanced age and FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD) in acute myeloid leukemia (AML) are associated with early relapse after standard chemotherapy and poor survival. Quizartinib (AC220), an oral FLT3 inhibitor active against ITD mutant and wild type FLT3, has shown promising activity in Ph 1 and 2 studies. Methods: Patients (pts) in a Ph 2 open label study (N = 333) of quizartinib monotherapy included 154 aged ≥60 y with known FLT3-ITD status and AML relapsed in <1 y or refractory to 1st line chemotherapy. Median duration of treatment was 14.2 wks (range 0.1–70.6 wks) for FLT3-ITD(+) pts and 9.5 wks (range 1.1–77.0 wks) for FLT3-ITD(-) pts. The composite complete remission (CRc) rate included complete remission (CR), complete remission with incomplete platelet recovery (CRp), and complete remission with incomplete hematologic recovery (CRi). Results: Of 110 FLT3-ITD(+) pts, 63 (57%) had a CRc (3 CR, 4 CRp, 56 CRi). Of 44 FLT3-ITD(-) pts, 16 (36%) had a CRc (2 CR, 1 CRp, 13 CRi). Median overall survival (OS) in FLT3-ITD(+) pts was 25.3 wks and 16/110 (15%) survived >52 wks. The median age of these pts surviving >52 wks was 69.5 y (range 66–80 y) and median OS was 76.3 wks (range 56.9–96.0 wks). All of these pts responded to quizartinib (2 CR, 2 CRp, 8 CRi, 4 partial remission [PR]). 2 pts were still alive >1 ½ y (OS 93.0 and 96.0 wks). Median OS in FLT3-ITD(-) pts was 19.1 wks and 6/44 FLT3-ITD(-) pts (14%) survived >52 wks. The median age of these pts was 70.0 y (range 65–77 y) and their median survival was 76.6 wks (range 54.9–98.4 wks). 5 of these pts responded to quizartinib (1 CR, 3 CRi, 1 PR). Conclusions: These data for an FLT3-targeted agent show encouraging survival in a subset of elderly pts with relapsed/refractory FLT3-ITD(+) AML. Clinical trial information: NCT00989261. [Table: see text]
Phase II study of combination of hyperCVAD with ponatinib in frontline therapy of patients (pts) with Philadelphia chromosome (Ph) positive acute lymphoblastic leukemia (ALL).
Authors: Jabbour Elias , Kantarjian Hagop M. , Thomas Deborah A. , Ravandi Farhad , Cortes Jorge E. , Faderl Stefan , Pemmaraju Naveen , Kadia Tapan M. , Garris Rebecca S. , Garcia-Manero Guillermo , Borthakur Gautam , Wierda William G. , O'Brien Susan Mary
Published: March 2020

7024

Background: Combination of chemotherapy with TKIs was evaluated and appears to be effective in Ph+-ALL. Ponatinib is a more potent inhibitor and suppresses the T315I clones, a common cause of relapse in pts with Ph+- ALL. Clinical trials of ponatinib have demonstrated its high activity and limited toxicity in pts with Ph+-leukemia failing 2-3 TKIs and in those with a T315I mutation. Combinations of chemotherapy regimens and ponatinib may be associated with better response rates and higher likelihood of eradication of MRD. Methods: In this phase II trial, pts with newly diagnosed Ph+ ALL receive ponatinib 45 mg po QD for the first 14 days of cycle 1 then continuously for the subsequent 7 cycles. Pts in CR receive maintenance with ponatinib 45 mg po QD and vincristine and prednisone monthly for 2 years followed by ponatinib indefinitely. MRD monitoring is conducted. Results: To date 20 pts with untreated Ph+ ALL have received a median of 6 cycles; 5 pts are receiving maintenance in CR. Median age is 49 years. Median WBC at diagnosis was 2.45 x 109/L. All pts were in CR after 1 cycle. 15 of the 17 pts (88%) known to be Ph+ by cytogenetic analysis at baseline achieved CCyR after 1 cycle; 1 had mCyR only and 1 had no cytogenetic analysis at CR, both of them achieved CCyR after cycles 2; 3 had a diploid karyotype at the start. To date, 17 pts (85%) have achieved MMR, of whom 11 (55%) have achieved CMR at a median of 10 weeks from initiation of treatment. MRD assessment by flow cytometry is negative in 18 (90%) pts at a median of 3 weeks. Median time to neutrophil and platelet recovery for cycle 1 was 18 and 22 days, and 16 and 22 days for subsequent cycles, respectively. Grade ≥3 toxicity included increase of LFT’s/hyperbilirubinemia in 8 pts, thrombosis in 3, skin rash in 2, pancreatitis in 1, and pericardial effusion in 1. With a median follow up of 6 months, 19 pts are alive and in CR; 1 pt died in CR from an unrelated cardiac event. 1 pt has undergone an allogeneic transplant. The 1-year PFS and OS rates were 100% and 95%, respectively. Conclusions: The combination of hyperCVAD with ponatinib is safe and highly effective in achieving molecular remissions in pts with Ph+ ALL. Clinical trial information: NCT01424982.
Costs of allogeneic hematopoietic cell transplantation using reduced intensity conditioning regimens.
Authors: Khera Nandita , Emmert Amy , Storer Barry , Sandmaier Brenda M. , Alyea Edwin , Lee Stephanie
Published: March 2020

7034

Background: Reduced intensity (RIC) conditioning regimens have allowed older patients and those with comorbidities to receive hematopoietic cell transplantation (HCT). Methods: We analyzed medical costs from the beginning of conditioning to 100 days after HCT for 484 patients who underwent a RIC allogeneic HCT at Fred Hutchinson Cancer Research Center (FHCRC; n=147) and Dana Farber Cancer Institute (DFCI; n=337) from 1/2008 to 12/2010. Costs up to 2 years after HCT were analyzed for DFCI (n=311) as most patients receive their post-transplant care there. Multiple linear regression was used to analyze the association between clinical variables and costs. Results: Disease distribution and transplant characteristics were comparable between the two sites, though significant differences were seen in age distribution (88% FHCRC patients ≥ 50 years vs. 80% at DFCI, p=0.04) and pre-transplant performance scores (63% patients with Karnofsky score≥ 90 at FHCRC vs. 47% at DFCI; p=0.006). Median costs for first 100 days in 2010 $ at FHCRC and DFCI were $129 000 (range 31,000-352,000) and $96,000 (3,000-614,000) respectively, p=0.0002, but differences were not significant in multivariate analysis. Inpatient costs accounted for 42% of early costs at FHCRC and 87% at DFCI.Significant predictors for early costs included a diagnosis of lymphoma/ myeloma (17% decrease in costs; p=0.01), donors other than matched related (50 -100% increase; p<0.001), relapse (17% increase, p=0.04) and ≥ grade II acute GVHD (37% increase; p<0.001). Median costs between d100 and 2 years were $39,000 (0-976,000) at DFCI. 39% of the 2 year costs occurred after first 100 days. There was no association of late costs with pre-transplant variables, and only death was associated with higher costs (138% increase; p=0.005). Conclusions: After adjustment for pre and post HCT variables, the overall costs of the RIC allogeneic transplants were similar between the two institutions despite different management approaches (inpatient vs. outpatient conditioning) and accounting methodologies. Use of unrelated/ alternative donors, relapse and acute GVHD were predictors for higher early costs while only death was associated with higher late costs.
Comparison of four different strategies of stem cell mobilization in patients with multiple myeloma.
Authors: Sivik Jeffrey Michael , Whaley Sesilya , Mierski Joseph , Castellani William J. , Lowe Mitzi , Zhu Junjia , George Melissa , Rybka Witold B. , Talamo Giampaolo
Published: March 2020

7039

Background: There is no consensus among institutions for the optimal strategy of peripheral blood stem cell (PBSC) collection for autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM). Methods: We retrospectively analysed the outcomes of PSBC collection in MM patients using the following mobilization regimens: cyclophosphamide 5,000 mg/m2 + etoposide 1,000 mg/m2 + G-CSF 5 mcg/Kg/day (Group A, n = 49); cyclophosphamide 2,000-3,000 mg/m2+ G-CSF 5 mcg/Kg/day (Group B, n = 25); G-CSF 16 mcg/Kg/day (Group C, n = 21); G-CSF 16 mcg/kg/day + plerixafor 0.24 mg/Kg (Group D, n = 128). Results: The median number of PBSC collected was 28.1 (range, 2.1-134), 4.5 (0.1-39.7), 4.0 (0-7.3) and 8.4 (0.2-41.2) million CD34+/kg in groups A, B, C and D, respectively (p <0.001). The mean number of collection days was 1.3, 2.2, 2.4, and 1.3 in groups A, B, C, and D, respectively (p <0.001). Febrile neutropenia occurred in 16 (32.7%), 1 (4%), 0, and 0 patients in groups A, B, C, and D, respectively. One patient who received CTX 3 g/m2 died of septic shock during the neutropenic phase. Failure to collect PBSC, defined as <2x106 CD34+ cells/Kg for a planned single ASCT or <4x106 for planned tandem ASCTs, was observed in 2/49 (4%), 5/25 (20%), 4/21 (19%), and 9/128 (7%) patients in groups A, B, C, and D respectively (p=0.037). Conclusions: Plerixafor + G-CSF provided the greatest benefit to risk ratio for PSBC collection in MM patients.
Management of chronic myeloid leukemia in chronic phase (CML-CP) by American Hematology-Oncology Physicians (AHOP's): Diagnostic and treatment preferences after first-line imatinib (2010-2012).
Authors: Foran James M. , Williams Michael E. , Willey Joanne , Green Mark R.
Published: March 2020

7046

Background: In CML-CP there is perceived complexity in risk stratification at diagnosis, and in testing for BCR-ABL kinase domain mutation (KD mut, including T315I) at relapse. We sought to understand AHOP practices in the context of NCCN and European LeukemiaNet guidelines. Methods: Between 2010 and 2012, we studied time dependent practice preferences of n=1,335 AHOP’s using a proprietary, live, case-based market research tool. A core case scenario and variations based on available diagnostic & treatment options were constructed. Preference data were acquired using blinded audience response technology. All responses for each scenario were obtained contemporaneously prior to any display of summary respondent selections. All sources of research support were double blinded. AHOP's were presented with a scenario of 59-year old CML-CP patient, then indicated preferred management from up to 9 relevant available/emerging diagnostic or therapeutic options following relapse after 1st-line imatinib. Results: The majority of AHOP’s in 2012 either did not calculate (52%), or were unfamiliar (21%) with Sokal or Hasford risk stratification score. Diagnostic preferences following relapse from 2010-12 are noted in Table (distribution over time, p<0.0001). If T315I was then detected in scenario, we noted marked differences in subsequent treatment preference in 2012 vs. 2011, respectively: decreased AlloBMT (16% vs. 32%); & increased 2nd-line dasatinib (26% vs. 14%) or bosutinib (12% vs. 8%) vs. nilotinib (8% vs. 20%) despite lack of efficacy for each in T315I. Preference increased slightly for ponatinib (16% vs. 14%), but not for omacetaxine (2% vs. 6%). Conclusions: Most AHOP’s do not apply risk stratification. Increasing preference for KD mut panel testing at relapse conforms to guidelines, although not all AHOP’s test. Heterogeneity in T315I treatment suggests uncertainty or unfamiliarity with newer agents, and evidence-based efforts are needed to improve awareness. [Table: see text]
Analysis of the cardiovascular risk profile of Ph+ leukemia patients treated with ponatinib.
Authors: Khoury Hanna Jean , Cortes Jorge E. , Kim Dong-Wook , Pinilla-Ibarz Javier , Le Coutre Philipp D. , Paquette Ronald , Chuah Charles , Nicolini Franck E. , Apperley Jane , Talpaz Moshe , DiPersio John F. , DeAngelo Daniel J. , Abruzzese Elisabetta , Rea Delphine , Baccarani Michele , Müller Martin C. , Gambacorti-Passerini Carlo , Lustgarten Stephanie , Yanase Kumiko , Kantarjian Hagop M.
Published: March 2020

7048

Background: Coronary artery disease (CAD), peripheral arterial occlusive disease and cerebrovascular disease have been observed in pts treated with BCR-ABL tyrosine kinase inhibitors (TKIs). While uncommon, these events can be serious complications of BCR-ABL TKI therapy. Methods: The cardiovascular (CV) profile of ponatinib (45 mg/day) was evaluated in 449 pts with chronic myeloid leukemia (CML) or Ph+ acute lymphoblastic leukemia (Ph+ ALL) resistant or intolerant to prior TKIs in the phase 2 PACE trial. At analysis (23 July 2012), median follow-up was 12 (0.1-21) mos. Myocardial ischemic events including myocardial infarction (MI), CAD, and angina were analyzed. Results: Myocardial ischemic serious adverse events (SAEs) (14 MI, 5 CAD, 2 angina) were reported in 21/449 pts (5%). 10 of these 21 pts had active cardiac disease at entry characterized by prior MI (4 pts), coronary revascularization (4 pts), or documented CAD; 5 had MI reported on study. 5/21 pts had other cardiac disease at entry (eg, valvular or pericardial disease); 5 had MI on study. Thus, 10/14 MIs occurred in 15 pts with known cardiac disease. 6/21 pts had no history of cardiac disease, but 5/6 had ≥1 CAD risk factor; 4 MIs occurred in these pts, all had risk factors. Of 21 pts with myocardial ischemic SAEs (13 CP-CML, 6 AP-CML, 2 BP-CML/Ph+ALL), mean age was 67 (42-87), and median duration since diagnosis was 12 (1-20) yrs. They were heavily pretreated (67% TKI use ≥5 yrs) with multiple CAD risk factors at entry (71% ischemia, 57% hypertension, 38% hypercholesterolemia, 33% diabetes [62% BMI >25]); 81% had ≥2 risk factors, 95% had ≥1. Median time to onset and duration of SAE was 160 (9E402) and 7 (1E98) days, respectively. At analysis, 18/21 pts had the SAE reported as resolved (managed by dose interruption [50%] or no dose change [33%]), and 13/21 pts remained on study. Response rates for the subset of 21 pts with cardiac SAEs were major cytogenetic response 77% in CP-CML; major hematologic response 67% in AP-CML. Conclusions: In this uncontrolled study in heavily pretreated pts, these CV SAEs occurred mostly in pts with preexisting cardiac disease, and were primarily managed with satisfactory outcomes. Pts with preexisting CV co-morbidities should be monitored. Clinical trial information: NCT01207440.
Effect of dose-optimized imatinib (IM) 800 mg on deep molecular responses (CMR 4.5) and prediction of survival: Results from the randomized CML-study IV.
Authors: Hehlmann Rüdiger , Lauseker Michael , Hanfstein Benjamin , Müller Martin C. , Schreiber Annette , Proetel Ulrike , Pfirrmann Markus , Schnittger Susanne , Dengler Jolanta , Falge Christiane , Neubauer Andreas , Stegelmann Frank , Pfreundschuh Michael , Waller Cornelius F. , Spiekermann Karsten , Baerlocher Gabriela M. , Krause Stefan W. , Hochhaus Andreas , Hasford Joerg , Saussele Susanne ,   SAKK and the German CML-Study Group
Published: March 2020

7051

Background: Since complete molecular remission (CMR 4.5) defines a subgroup of patients who may stay in remission even after discontinuation of treatment, we analysed whether CMR 4.5 is reached faster with dose optimized IM 800 mg and whether the achievement of CMR 4.5 at specified points in time results in better survival than the achievement of less deep remissions. Methods: Confirmed CMR 4 and CMR 4.5 are defined as ≤ 0.01% BCR-ABL IS or ≥ 4 log reduction and ≤ 0.0032% BCR-ABL IS or ≥ 4.5 log reduction, respectively, from standardized baseline as determined by real-time PCR in 2 independent analyses. Details on CML-Study IV have been published (Hehlmann et al., JCO 2011). Cumulative incidences were estimated under consideration of competing risks. Landmark analyses were performed to evaluate the prognostic impact of different remissions at 4 years on survival. Results: Of 1551 randomized patients with newly diagnosed chronic phase CML 1525 were evaluable. Median age was 52 years, 88% were EUTOS low risk, 12% high risk. 113 patients were transplanted (73 in first chronic phase), 246 received 2nd generation TKI. 152 patients have died. After a median observation time of 67.5 months, 6-year OS was 88.2%.CMR 4.5 was reached after a median of about 76.1 months with IM 800 and 107.3 months with IM 400. EUTOS low-risk patients reached all remissions faster than high-risk patients. Independent of treatment approach CMR 4.5 at 4 years predicted OS significantly better than complete cytogenetic remission (p=0.043), but not significantly better than major molecular remission (MMR) or CMR4. After a median observation of 3.9 years 1 of 626 patients with CMR 4 has progressed. Only six of the 394 patients with CMR 4.5 have died after a median observation time of 3.0 years, no patient has progressed. An additional finding was that achieving MMR at 3 and at 6 months predicts faster achievement of CMR 4.5. Conclusions: We conclude that dose optimized IM 800 induces CMR 4.5 faster than IM 400 and that CMR 4.5 at 4 years is associated with a survival advantage. Dose optimized IM 800 may provide an improved therapeutic basis for treatment discontinuation in patients with CML. Clinical trial information: NCT00055874.
Pharmacokinetics (PK) of ibrutinib in patients with chronic lymphocytic leukemia (CLL).
Authors: Sukbuntherng Juthamas , Jejurkar Purvi , Chan Stephen , Tran Anh L. , Moussa Davina , James Danelle Frances , Loury David
Published: March 2020

7056

Background: Ibrutinib is a first-in-class selective small molecular inhibitor of Bruton’s tyrosine kinase (BTK) under development for the treatment of B-cell malignancies. Because of covalent binding to cys-481 of BTK, ibrutinib has a sustained pharmacodynamic (PD) effect. The aim of this study was to determine the PK of ibrutinib in patients (pts) with CLL. Methods: A Phase 1b/2 study (PCYC-1102-CA) of an oral dosing of single agent ibrutinib was conducted in pts with treatment-naïve (TN) or relapsed/refractory (R/R) CLL. Pts were enrolled into one of the following groups: R/R pts at 420 mg/day (n=27), TN pts at 420 mg/day (n=26), R/R pts at 840 mg/day (n=34), R/R high-risk pts at 420 mg/day (n=24), TN pts at 840 mg/day (n=5), and R/R pts at 420 mg/day for food-effect evaluation (n=16). One cycle was 28 days. Blood samples for PK assessment were obtained during the first cycle. PK parameters were calculated using non-compartmental analyses. Results: A total of 132 pts (98 males and 34 females) with CLL were treated across the 6 groups. Median ages for Groups 1 through 6 were 64, 71, 64, 68, 71, and 62 years, respectively. Ibrutinib exhibited rapid absorption (median Tmax of 2 h) and a mean elimination plasma half-life of approximately 6-9 hours. The AUCtau increased approximately proportional to doses from 420 to 840 mg/day. No accumulation of ibrutinib was apparent on Day 8. Ibrutinib exposure in males and females was similar. At 420 mg/day, pts ≥ 65 years old had AUC values that were ~30% higher than those of pts < 65 years. In R/R pts, there were no substantive differences in systemic exposure to ibrutinib between the del 17p positive and del 17p negative pts. An increase in ibrutinib exposure (<2-fold) was observed when administration with high-fat breakfast was compared to administration following an overnight fast. In all cases, %CV of AUC ranged from 50 to 100%. Conclusions: Ibrutinib demonstrated rapid absorption and elimination and was well tolerated at doses of 420 and 840 mg/day. Lack of significant exposure differences with respect to age, gender, or 17p del status indicates that dose adjustment in these populations is not required. Because of a sustained PD effect ibrutinib can be dosed once daily despite a relatively rapid clearance. Clinical trial information: NCT01105247.
Final report of phase I/II study of PR104, a hypoxia-activated pro-drug, in relapsed/refractory acute leukemia.
Authors: Arana Yi Cecilia Ysabel , Borthakur Gautam , Thall Peter F. , Coveler Andrew L. , Ravandi Farhad , Jabbour Elias , Faderl Stefan , Thomas Deborah A. , Cortes Jorge E. , Kadia Tapan M. , Kornblau Steven Mitchell , Daver Naval Guastad , Pemmaraju Naveen , Nguyen Hoang Q. , Wilson William R. , Melink Teresa J. , Gutheil John , Kantarjian Hagop M. , Estey Elihu , Konopleva Marina
Published: March 2020

7074

Background: Hypoxia is prevalent in leukemia bone marrow (BM) microenvironment, suggesting its role as a therapeutic target. PR104 is a pro-drug activated by hypoxia-dependent reductases and by hypoxia-independent aldo-ketoreductase 1C3 (AKR1C3). Methods: Patients (pts) with relapsed/refractory AML (n=40) after 1 or 2 prior treatments; or ALL (n=10) after any number of prior treatments received PR104 as a 1-hr i.v. infusion q 2 weeks. Biomarkers for hypoxia and AKR1C3 were assessed. Results: Pts received PR104 at doses of 1.1 (n=6), 1.6 (n=1), 2.2 (n=1), 3 (n=20) and 4 gm/m2 (n=22) for a median of 1 cycle (range, 1 – 3 cycles). 17 pts had PR104 doses assigned using an adaptive method using toxicity-response trade-offs, patient age, and prior remission duration, and 33 pts were assigned doses by investigators for cohort expansion at 3 and 4gm/m2. Most common treatment-related grade 3/4 adverse events included myelosupression (anemia 44%, neutropenia 56%, thrombocytopenia 52%), febrile neutropenia (22%), infection (22%) and enterocolitis (14%). 3 (14%) PR104-related deaths occurred at the 4 gm/m2 dose level: hepatic failure (n=1), enterocolitis (n=1) and pneumonia (n=1). 49 of 50 pts were evaluable for response. No CRs were seen at doses < 3 gm/m2. 10 of 31 AML pts (32%, (0.19, 0.5)% CI) and 2 of 10 ALL pts (20%, (0.06,0.51)% CI) at 3 or 4 gm/m2 had responses (CR, n=1; CRp, n=5; morphologic leukemia-free state (MLFS), n=6). In AML pts with 1 prior treatment, responses were seen in 7 of 21 pts (CR, n=1; CRp, n=3; MLFS, n=3). Median overall survival of all pts treated at 3 and 4 gm/m2 was 72 days, and of pts who achieved CR/CRp/MLFS 143 days. 3 pts with AML (MLFS, n=2; CRp, n=1) and 1 with B-ALL (CRp, n=1) underwent allogeneic stem cell transplantation. Biomarker studies showed hypoxia in the BM; and levels of AKR1C3 in leukemic blasts did not correlate with responses (Benito et al., ASH 2012). Conclusions: PR104 administered at doses 3 to 4x the solid tumor MTD had moderate toxicity (most commonly myelosuppression and enterocolitis) in pts with relapsed/refractory AML and ALL. Evidence of activity supports continued evaluation of hypoxia-activated cytotoxins in acute leukemias. Clinical trial information: NCT01037556.
Hypomethylating agents as first-line therapy in acute myeloid leukemia (AML).
Authors: Bailey Samuel D , Gul Zartash , Slone Stacey A. , Van Meter Emily Marie , Lawson Amber , Raufi Ali , Hayslip John W. , Monohan Gregory , Howard Dianna S. , McDonagh Kevin T. , Alkadhimi Zaid
Published: March 2020

7084

Background: Hypomethylating agents are used in older AML patients (pts) who are not considered candidates for standard induction therapy. However, data regarding their efficacy remains unclear. Methods: We retrospectively evaluated a cohort of 24 consecutive AML pts who were placed on hypomethylation therapy at diagnosis between October 2010 and June 2012 at Markey Cancer Center. Results: Baseline characteristics of the patients are described in table 1. Response rate (CR+PR) was 45.8%. Median number of infections were 1 (8 pts), 2 (5 pts), 3 (4 pts).Median hospital admissions required were 1 (10 pts), 2 (4 pts), 3 (5 pts), 4 or greater (2 pts). Average length of hospital stay was 10.3 days (0-37 days). Median units of packed red cell and platelet transfusions were 10 and 11 units (Range=0-64 and 0-78) respectively. After a median follow up of 145.5 days, 13 pts had died. Cause of death was AML (6 pts), infection and end organ failure (7pts).Median overall survival (OS) was 9.7 months (95%CI: 3.2-16.5 months). On multivariate analysis, blast count less than 30% was borderline significantly associated with better OS (P=0.05). However after addition of average hospital stay in the model only age (HR=1.3, CI=1.06- 1.67), gender (HR=11.5, CI=1.2, 110.5), and average hospital stay were significantly associated with OS (HR=1.2, CI = 1.04- 1.32). Conclusions: In this cohort of pts the median OS was 9.7 months. Older pts and those with longer average hospital stay had a higher mortality. Better selection of pts in a larger cohort who are likely to gain more benefit from these agents may impact outcomes. [Table: see text]
Use of flow cytometry during induction chemotherapy to determine outcomes in acute myeloid leukemia.
Authors: Donnellan William Bruce , Ghosh Monalisa Ghosh , Rangarajan Sunil , Jackson Bradley , Borate Uma , Erba Harry P. , Foran James M.
Published: March 2020

7104

Background: The use of MRD to predict outcome in AML is controversial. We sought to determine concordance between FC and BM biopsy morphology on day 14 (D14BM) and CR bone marrow (CRBM) specimens and whether MRD detected by FC predicted for inferior outcomes. Methods: We performed a retrospective analysis of adult AML patients treated between 2005 and 2010 with standard induction chemotherapy. Based upon BM morphology and FC, patients were designated as BM+FC+, BM+FC-, BM-FC+, or BM-FC-. Outcomes assessed included induction failure, RFS and OS. Results were adjusted for age at diagnosis, NCCN risk classification, and secondary AML status. Results: Of 287 evaluable patients, 74 had D14 BM and FC results and 98 had CR BM and FC results. Using BM morphology as the gold standard, discordance rates for the presence and absence of disease for the D14 BM by FC were 29% and 23% respectively. Multivariate analysis revealed that patients categorized as BM-FC+ at D14 were more likely to experience induction failure (HR 8.62, CI 0.36-208) and had lower RFS and OS (HR 1.47, 1.95 CI 0.40-5.41, 0.52-7.36 respectively). Analysis of the CR BM samples showed similar results. Conclusions: In this retrospective study there was a high discordance rate between FC and BM morphology on D14 BM and CR BM. While there was a trend toward inferior patient outcomes when disease was detected by FC but not morphology, this was not statistically significant. Limitations of our study include the retrospective nature of the analysis, paucity of patient samples that had a FC evaluation, lack of data to see if positive FC at D14 or CR changed clinician therapy choices and interpretation bias by pathologists as a result of access to FC results during BM morphology interpretation. Larger prospective studies are needed to evaluate whether MRD detected by FC as early as D14 during AML therapy affects clinical outcomes.
Identification of pSTAT5 gene signature in hematologic malignancy.
Authors: Sonkin Dmitriy , Regnier Catherine , Rong Xianhui , Fanton Christie , Palmer Michael , Holash Jocelyn , Squires Matthew , Sirulnik L. Andres , Radimerski Thomas , Schlegel Robert , Morrissey Michael , Cao Z, Alexander
Published: March 2020

7111

Background: The JAK/STAT pathway is an important signaling pathway downstream of multiple cytokine and growth factor receptors. Receptor-associated JAKs are activated following receptor-ligand binding. Activated JAKs phosphorylate STAT proteins, which then dimerize and translocate to the nucleus where they modulate the expression of target genes. Dysregulated JAK/STAT signaling has been implicated in the pathogenesis of multiple human malignancies. Activating mutations in JAK2 and the associated activation of STAT5 in myeloproliferative neoplasia is one example of the involvement of this pathway in human cancer. Additionally, overactivated JAK/STAT signaling has been suggested as a survival mechanism in several human cancers. Given the importance of JAK/STAT dysregulation in human diseases, it is important to identify patients with an overactivated JAK/STAT pathway for possible treatment with JAK inhibitors. Thus, we developed a gene signature assay to detect overactivated JAK/STAT5 signaling. Methods: The cancer cell line encyclopedia (CCLE) and associated gene-expression data were used to correlate the activation status of STAT5 with the induction of a set of STAT5 target genes. First, we used 27 tumor cell lines of hematologic lineage, with predetermined phosphorylated STAT5 (pSTAT5) status, to derive STAT5 activation gene signatures. Next, the putative gene signatures were validated against a different set of 13 hematologic tumor cell lines. Results: With this approach, a collection of 7 target genes were identified (PIM1, CISH, SOCS2, ID1, LCN2, EPOR, and EGR1) whose expression significantly correlated with pSTAT5 status in the 40 hematologic tumor cell lines (P < .0001), either together or in specific subsets of 4 and 6 genes (Table). Conclusions: These 4-, 6-, and 7-gene signatures can be used to stratify or select for a patient population with activated JAK/STAT5 signaling that could potentially benefit from treatments targeting the JAK/STAT5 signaling pathway. [Table: see text]
Characterization of Philadelphia-negative myeloproliferative neoplasm patients with chromosome 12 abnormalities.
Authors: Benton Christopher Brent , Tanaka Maria Florencia , Pierce Sherry , Zhou Lingsha , Cortes Jorge E. , Kantarjian Hagop M. , Verstovsek Srdan
Published: March 2020

7112

Background: Chromosome 12 (Chr 12) abnormalities have been reported as infrequent events in myelofibrosis (MF). Structural abnormalities at 12q13-15 and 12q24 have been reported in primary MF (PMF), and understanding genes at these loci, such as Hmga2 and Lnk may help in the treatment of Philadelphia-negative (Ph-neg) myeloproliferative neoplasms (MPN). We sought to better characterize Ph-neg MPN patients (pts) with Chr 12 aberrations. Methods: We queried a database of pts with any Ph-neg MPN who were referred to MD Anderson Cancer Center from 1985 to 2012. We identified pts with Chr 12 abnormalities and reviewed available clinical information. We compared characteristics and outcomes of pts who had Chr 12 abnormalities with pts who had no Chr 12 abnormality. Results: Of 1,787 pts with Ph-neg MPN, 36 pts (2%) were found to have a Chr 12 abnormality. Of these, 31 (86%) had MF, 1 (3%) had polycythemia vera (PV), 3 (8%) had hypereosinophilic syndrome, and 1 (3%) had unspecified MPN. Fourteen pts (39%) had successive biopsies demonstrating evolving cytogenetic abnormalities. The percentage of pts with MF was significantly higher among patients with Chr 12 abnormalities (86% vs. 54%, p-value < 0.001). A larger fraction of MF pts with Chr 12 abnormalities had post-PV MF (PPMF) (31% vs. 14%, p-value < 0.001). Age, JAK2 status, and incidence and rate of leukemic transformation from MF were not significantly different between the two groups. Of the 31 Chr 12 pts with MF, 12 (39%) had an abnormality at 12q13, 8 (26%) at 12q24, 6 (19%) had trisomy 12, 5 (16%) at 12q15, and 6 (19%) had another Chr 12 abnormality. Four pts (13%) had a structural abnormality at >1 site along the long arm of Chr 12. Survival of Chr 12 MF pts as a whole or subdivided by chromosomal abnormality was not significantly different than MF pts without Chr 12 abnormalities. Conclusions: Our investigation into pts with Ph-neg MPN harboring Chr 12 abnormalities is the largest of its kind, and shows 3% of MF pts possessed some type of Chr 12 abnormality, most frequently at 12q13. We found that Chr 12 Ph-neg MPN pts were more likely to have MF and PPMF. Further investigation into the functional significance of these structural abnormalities is warranted.