bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of non-compliance with imatinib (IM) therapy on health care costs
Authors: Henk H. J. , Thomas S. K. , Feng W. , Jean-Francois B. , Goldberg G. A. , Hatfield A.
Published: March 2020

6083

Background: While compliance to drug therapy is vital to receive optimal patient benefits, the costs of delivering adequate medical care for cancer patients remain an important consideration for society and payers. This study examined the relationship between compliance with IM therapy and health care costs for patients with CML and GIST. Methods: Claims data from 6/1/01–3/31/04 from a US health plan were used to identify non-Medicare IM-treated patients with a CML or GIST diagnosis who had continuous pharmacy and medical benefits in the 3 months prior and 12 months following initiation of IM therapy. Compliance was defined by medication possession ratio (MPR=total days IM supply in the first year ÷365) and patients were stratified into three segments by MPR (<50%, 50–90%, 90–100%). Total health care costs include hospital, laboratory testing, office, ER, and pharmacy charges. Disease-related health care costs were also analyzed. Multivariate analyses were used to examine the relationship between MPR and first-year health care costs, controlling for age, sex, number of medications, initial starting dose, diagnosis (CML or GIST), year of initial IM fill, and complications due to underlying disease. Results: Total 878 IM-treated patients were identified of whom 413 had at least 15 months of continuous eligibility. Of these, 307 were non-Medicare CML or GIST patients. Total health care costs per patient in the first year of therapy in MPR < 50%, 50–90%, and 90–100% groups were $163,828, $53,924, and $40,924 respectively (p < 0.001). The corresponding numbers for disease-related health care costs were $103,118, $36,436, and $34,086 (p<0.001). Controlling for the variables listed above, a 10% increase in MPR is associated with a 5% decrease in total health care costs (p=0.021). Similar association was found between MPR and disease-related health care costs. Conclusions: Improved compliance with imatinib therapy is associated with decreased total health care costs and disease-related health care costs. Improving compliance to imatinib therapy may not only optimize clinical outcomes but may also reduce the overall societal burden of health care costs associated with cancer.

[Table: see text]
A comparison of patient and physician attributes that promote patient involvement in treatment decision making in the oncology consultation
Authors: Ellis P. M. , Dimitry S. J. , O’Brien M. A. , Charles C. A. , Whelan T. J.
Published: March 2020

6098

Background: Cancer patients have indicted a desire to be more involved in treatment decision making (TDM). However, little is known about the attributes of patients, physicians and their interaction that promotes patient involvement in TDM in the oncology consultation. This study compared attributes generated by patients and physicians that make it easier for patients to be involved in TDM. Methods: Semi-structured interviews were undertaken with 19 patients with cancer (lung, breast, prostate, GI) and 21 medical and radiation oncologists at a regional cancer centre. Participants were asked to identify attributes of physicians, patients and their interaction that promotes patient involvement in TDM. Interview transcripts were independently coded by 2 analysts using decision rules to identify specific attributes. Attributes identified by each analyst were compared and a high level of agreement was found. The analysts then independently compared the physician and patient generated lists and identified common vs unique items. There was a high level of agreement on which attributes were common to both lists versus unique. Results: Oncologists identified 173 physician, 59 patient and 9 interaction items. Patients identified 50 physician, 42 patient and 11 interaction items. Patients and physicians identified 17 common physician items, 29 common patients items and 1 common interaction item. Physicians identified 138 more attributes than patients, most of which were physician related. Common patient attributes centred on information seeking (eg prepare for the consultation by reading, be aware of all treatment options and question the options). Common physician attributes focused on specific communication behaviors (eg, make eye contact, tailor information to patient needs, be direct with patients, ensure patient understands information). The common interaction item was to keep the discussion informal. Conclusions: Patients and physicians appear to have different ideas about what is important to promote patient involvement in TDM. Many of the attributes identified can be easily incorporated into current practice. There is a need to develop and evaluate communication skills training to promote patient involvement in TDM.

No significant financial relationships to disclose.
Health promotion and cancer screening services for African refugee women
Authors: Carroll J. K. , Epstein R. , Fiscella K. , Volpe E. , Jean-Pierre P. , Morrow G.
Published: March 2020

6101

Background: Previous work has shown that refugee women do not receive adequate preventive healthcare services, especially cancer screening. To identify factors that could affect the provision of cancer screening services to African Somali refugee women living in Rochester, NY, we assessed beliefs these women have about health promotion, access to care and use of preventive healthcare services. Methods: Individual in-depth interviews were conducted on a community-based sample of 34 resettled Somali-born women who were older than 18 years. Interviews were audiotaped and transcribed verbatim. A professional interpreter listened to all audiotaped interviews to check accuracy of transcription and translation. Content was analyzed by a multidisciplinary team using a grounded theory approach. Results: Median age of the women was 27 years. Length of residence in US was two months to nine years. For these women, health maintenance for acute survival took precedence over long-term prevention of disease. All women were familiar with basic health promotion practices, immunizations and routine medical examinations, and participants used both US-based and traditional techniques to prevent illness. Most women (71%, n=24), recognized the importance of maintaining good hygiene (59%, n=20) understood the need to have an adequate source of safe food and water, (74%, n=25) saw the need for access to a regular source of healthcare and (65%, n=22) acknowledged the need to function well at home. Few women understood cancer prevention services. Only three (9%) women recognized that the purpose of the Papanicalaou test was to screen for cervical cancer. Only six women (18%) recognized mammography (either the term or the procedure) and all of them were English-speaking, had lived in the US five years or longer, and had worked in the healthcare field. Conclusions: While traditional beliefs about health promotion did not appear to impede delivery of most preventive services, and participants understood prevention of infectious disease, their familiarity with cancer and cancer screening services was poor. Future health promotion programs need to increase refugee women’s knowledge about these services while building on other positive health-promoting beliefs. Supported by AHRQ 5R03HS014105 and NCI 1R25CA102618

No significant financial relationships to disclose.
Economic analysis of prophylactic granulocyte colony-stimulating factor (G-CSF) use based on a risk model for neutropenic complications in breast cancer patients receiving adjuvant chemotherapy
Authors: Dale D. C. , Cosler L. E. , Wolff D. A. , Culakova E. , Poniewierski M. S. , Crawford J. , Lyman G. H.
Published: March 2020

6107

Background: Although recent economic analyses of prophylactic G-CSF provide cost saving febrile neutropenia (FN) risk estimates of approximately 20%, many regimens have reported rates <20%. A prospective nationwide cohort study was undertaken to develop risk models for neutropenic complications (NC) including severe and febrile neutropenia in patients receiving cancer chemotherapy (Lyman ASCO 2005). A cost-effectiveness model is presented to evaluate the economic impact of G-CSF prophylaxis based on the model. Methods: Data on 974 consecutive breast cancer patients receiving adjuvant chemotherapy at 115 randomly selected practice sites were analyzed. The clinical and cost impact of G-CSF prophylaxis in high-risk patients based on the model was compared with: 1) no G-CSF; 2) primary prophylaxis; and 3) secondary prophylaxis. Pegfilgrastim costs were based on Medicare pricing while hospitalization costs and mortality on national hospitalization data. Results: Independent predictors of first cycle NC included: type and schedule of chemotherapy, diabetes, elevated bilirubin, planned RDI >85%, low glomerular filtration rate and low neutrophil count. Prophylactic G-CSF was associated with a decreased risk. Model R2=0.327 and c-statistic=0.80 [95% CI: 0.78–0.83; P<.001]. At a baseline FN risk of 8.4% per cycle, the expected costs over four cycles of chemotherapy were: no pegfilgrastim: $1,285; primary prophylaxis: $2,573; secondary prophylaxis: $2,040 and model-targeted G-CSF: $1,527. Expected cost varied with FN risk and model performance. Primary prophylaxis was associated with lower cost than no prophylaxis at FN risk >18%, while the model outperformed both strategies at an FN risk >10%. At a baseline cycle risk of FN of 8.4%, model-guided G-CSF was associated with an expected cost of $44,980 per life saved. Cost savings increased as model discrimination increased. The model was consistently associated with lower cost compared to secondary prophylaxis. Conclusions: A risk model for NC has been developed in breast cancer patients receiving adjuvant chemotherapy. Use of the model to guide G-CSF support appears to be cost-effective at an overall FN risk of 10%.

[Table: see text]
How much missing data is too much? A single study exploration
Authors: Dueck A. , Atherton P. , Tan A. , Sloan J.
Published: March 2020

6116

Background: Analyses of patient-reported outcomes rely on the dependability of patients to complete and submit assessments in a timely manner – not all data is obtained. In recent work focusing on quality of life (QOL) data and imputation, it has been found that most methods do not alter study results. But how much data can be missing before study results are affected? Methods: Missing data was investigated using a 2-arm study (109 patients) who completed Linear Analogue Self Assessments at 4 intervals. Patients (11%) had missing data at the second interval. Existing data was analysed for differences in scores between arms, then cases were randomly deleted to create increasing percentages (12%-20%) of missing data. Ten simulations were conducted per percent. Imputation methods applied were carrying forward the last value (LVCF), average value (AVCF), and maximum value (MVCF). Student’s t-tests were performed between arms for each simulation. Results: Imputation did not alter results of our study data which was statistically significant (SS) between arms for overall QOL (p=0.036) and spiritual well-being (SWB) (p=0.006), and not statistically significant (NS) for mental well-being (MWB) (p=0.174). After data deletion and t-test calculations, AVCF did not impact results. For overall QOL, data deletion changed the p-value to NS in 1 of 10 simulations starting at 12% missing data and 5 of 10 simulations starting at 16% missing data. No matter what percentage of missing data, imputation produced a SS p-value over 80% of the time. Data deletion and subsequent imputation did not affect the study decision for SWB. For MWB, all differences between arms were NS prior to imputation. After imputation, there was at most a 7% disagreement in conclusions. LVCF and MVCF performed equally in all simulations. Conclusions: For this particular study, when p-values are close to the study-defined alpha, the increase in missing data can change the study results and imputation methods are more likely to determine SS differences. The further the p-values are from the study alpha, there is little effect from increasing missing data or applying imputation. These results are for one particular study and further research is needed.

No significant financial relationships to disclose.
Survival and cost-effectiveness of docetaxel (D) and paclitaxel (P) in patients with metastatic breast cancer (MBC): A population-based evaluation
Authors: Vu T. T. , Ellard S. , Olivotto I. , Taylor S. C. , De Lemos M. L. , Speers C. , Kuik K. , Hu F.
Published: March 2020

6117

Background: A randomized comparison between P and D for MBC reported that overall survival (OS) was significantly superior for D (Ravdin, et al). We report a population-based comparison of P (3-hour infusion) to D (1-hour infusion) in MBC patients with prior exposure to anthracycline in terms of OS and cost-effectiveness (CE). Methods: Data on MBC patients treated with single-agent P or D (January 1999 - December 2002) were retrospectively reviewed. OS, defined as time from initiation of taxane to death from any cause, was compared using a 2-tailed log-rank test and expressed as Kaplan-Meier plots. A CE analysis, including cost of drug (list price $CDN), labour and supplies, was performed using median cost/patient and median OS (MOS). Incremental CE ratios (ICERs) were compared in a sensitivity analysis varying MOS to the extremes of the 95% confidence interval (95% CI). Results: 435 patients met eligibility criteria. MBC prognostic factors were balanced between D and P groups ( table ). MOS was significantly longer for D vs. P. (10.9 vs. 8.3 months; HR 0.76; 95% CI, 0.62 to 0.92; P = 0.006). The median number of cycles administered were 4 (D) and 3 (P). The respective cost/month of MOS is $805 (D) and $303 (P). The ICER of D vs. P was $2,434/month MOS gained. The range of ICERs in the sensitivity analysis was $1,121 to 7,361/month MOS gained. These results were robust except that P dominates when the low end of the 95%CI of MOS for D is compared to the high end for P. Conclusion: This population-based study corroborates the randomized trial’s conclusion that for patients with metastatic breast cancer, D provided superior survival compared to P. Each additional month of survival had an incremental cost of $2,434.

[Table: see text]

[Table: see text]
Patient characteristics influencing quality of life in gynecologic cancer
Authors: Gil K. , Frasure H. , Jenison E. , Hopkins M. , Von Gruenigen V.
Published: March 2020

6132

Background: The Functional Assessment of Cancer Therapy general (FACT) questionnaire was developed to assess disease and treatment specific issues affecting patients’ quality of life (QoL). Factors other than cancer and its treatment, such as age, general physical and emotional health, and socio-economic status, may have significant effects on QoL and patients’ response to treatments. This study examined the effect of these variables on the domains of the FACT in gynecologic oncology patients undergoing surgery for pelvic mass suspected to be malignant or endometrial cancer. Methods: Demographic information and patient characteristics were obtained pre-operatively. Patients also completed the FACT and the SF-36, a general health questionnaire that measures physical and mental well-being but is not designed to be sensitive to the detection of small treatment effects. Correlation and multiple regression analysis were used to assess the effect of diagnosis, age, body mass index (BMI), educational level, marital status, smoking status, physical (PCS) and mental (MCS) summary scores of the SF-36 on FACT domain scores. Results: Data were collected on 157 women at their pre-operative visit (endometrial cancer, n=45; benign masses, n=79; ovarian cancer, n=33). PCS, MCS and age were positively correlated with scores on the FACT, while BMI and smoking were negatively correlated ( Table ). Educational level was negatively correlated with scores on the social domain but positively correlated with physical scores on the FACT. PCS and MCS accounted for a significant amount of the variance (R2) in regression models for each of the FACT domains ( Table ). Conclusion: Patients’ QoL, as measured by a questionnaire that is sensitive to their disease and treatment, is affected by their baseline characteristics. As treatment options become more complex, these variables are likely to be of increasing importance in evaluating QoL.

[Table: see text]

No significant financial relationships to disclose.
Circulating tumor cells (CTCs) in metastatic breast cancer: Biological value beyond tumor burden
Authors: Cristofanilli M. , Guarneri V. , Valero V. , Fritsche H. A. , Broglio K. R. , Reuben J. M. , Lara J. , Krishnamurthy S. , Hortobagyi G. N.
Published: March 2020

615

Background: The detection of circulating tumor cells (CTCs) can predict progression-free (PFS) and overall survival (OS) in patients with metastatic breast cancer (MBC). We evaluated the prognostic significance of baseline CTCs in relation to standard measures of tumor burden. Furthermore, we assessed if the prognostic value of CTCs was related to any particular molecular phenotype. Patients and Methods: One hundred twenty-three consecutive MBC patients (pts) evaluated prospectively between 12/2000 and 5/2005 were included in this analysis. CTCs from 7.5 mL of whole blood were isolated and enumerated using CellSearch system. Prognostic value was determined by analyzing the following factors, baseline level of CTCs (negative: <5 CTCs/7.5 mL; positive: ≥ 5 CTCs/7.5 mL), age (50 yrs/=50 yrs), hormonal receptor (HR), Her-2/neu status, metastatic site (visceral vs. non-visceral), Swenerton score, CA27.29 levels, and previous chemotherapy for MBC (none vs. pre-treated), Results: Median age was 52 years (range 24–88) and the median follow-up was 7.7 months (range 0–53.4 months). The median OS for the alive pts was 17.5 months. Fifty-two pts (42%) had positive CTCs and abnormal CA27.29 was detected in 80 pts (66%). The median OS for patients with negative vs. positive CTCs were 28.3 months (range 1.28 - 31.24) and 12.8 months (range 1.71 to 36.83) respectively (p=0.0001). In the multivariable model, HR status, CTCs, and CA27.29 level were the only factors significantly related to OS. CTCs demonstrated the strongest predictor for OS and were associated with 2.53 times the risk of death (p = 0.003). The prognostic value of CTCs was independent of line of treatment, site of recurrence and phenotype of the disease. Conclusions: CTCs demonstrated prognostic value independent of standard measures of tumor burden and phenotypic characteristics of the disease. CTCs are an important marker of tumor biology in metastatic breast cancer.

No significant financial relationships to disclose.
Safety analysis from PACS 04—A phase III trial comparing 6 cycles of FEC100 with 6 cycles of ET75 for node-positive early breast cancer patients, followed by sequential trastuzumab in HER2+ patients: Preliminary results
Authors: Spielmann M. , Roché H. , Delozier T. , Romieu G. , Bourgeois H. , Serin D. , Canon J. , Asselain B. , Roca L. , Genève J.
Published: March 2020

632

Background: Following the BCIRG 001, PACS 01 and HERA trials, this randomised, multicentre, open-label, Phase III trial was designed to demonstrate the benefit of concomitant docetaxel and epirubicin versus anthracyclines, and evaluate the use of sequential trastuzumab. Methods: Patients (pts) with localised, resectable, unilateral breast cancer who met the following criteria were eligible: age <65 years, ≥1 positive node, M0, adequate heart and organ functions. Pts were randomised to receive either 6 cycles of 5-fluorouracil-epirubicin-cyclophosphamide (FEC100: F and C, 500 mg/m2, E 100 mg/m2) (Arm A) or epirubicin-docetaxel (ET75: E 75 mg/m2, T 75 mg/m2) (Arm B). Primary prophylaxis with G-CSF was not planned. Radiotherapy was mandatory after conservative surgery and tamoxifen was required in pts with hormone receptor-positive tumours. Pts with HER2-positive disease were then further randomised to observation only or to 1 year of trastuzumab monotherapy (6 mg/kg iv every 3 weeks). In HER2-positive pts receiving trastuzumab, left ventricular ejection fraction (LVEF) was determined at Cycles 2, 4, 8, 13, 18 and after 2 years. Otherwise, LVEF was determined at baseline and at 1 year post-surgery. Results: Of the 3010 pts recruited (2622 evaluable for safety to date), 1518 received FEC100 and 1492 received ET75 after the first randomisation. Haematologic toxicity was the most frequent toxicity in both arms. Grade 3–4 toxicities were similar for Arms A and B, except febrile neutropenia (10.3% and 31.4%, respectively) and nausea/vomiting (13.2% and 7.5%, respectively). Grade 2 clinical cardiac toxicity (decreased LVEF) was observed in 4 pts in Arm A and 5 in Arm B, with median LVEF scores of 63% in both arms at the end of chemotherapy. HER2-positive pts (n=500) were then randomised to either receive trastuzumab (n=259) or observation only (n=241). Conclusions: These preliminary safety data indicate that FEC100 and ET75 were both well tolerated, with acceptable cardiac safety values. The trial is ongoing and further analysis regarding the use of trastuzumab in this setting will be presented.

[Table: see text]
PIK3CA mutations in breast cancer: A potential predictive marker
Authors: Santarpia M. , Altavilla G. , Margeli M. , Mesiti M. , Cavallari V. , Cirauqui B. , Reguart N. , Barnadas A. , Taron M. , Rosell R.
Published: March 2020

639

Background: Somatic mutations in phosphoinositide-3-kinase catalytic alpha (PIK3CA) activates Akt, attenuates apoptosis and promotes tumor invasion. The common mutations E545K and H1047R confer resistance to paclitaxel in immortalized breast cancer cell lines. We screened primary breast cancers for PIK3CA mutations in the helical and catalytic domains. Methods: Tumor samples from 61 stage I-III breast cancer patients treated with adjuvant chemo- and/or hormone therapy were examined for PIK3CA mutations E542K, E545K and H1047R by the 5-nuclease assay (TaqMan) using the ABI Prism 7900HT Sequence Detection System. Results: Mutations were found in 17 patients (27.9%): 6 E542K; 5 E545K; 6 H1047R. PIK3CA mutations were not associated with expression of estrogen or progesterone receptors, lymph node metastases, or ERBB2 overexpression. (See table ) Conclusions: PIK3CA mutations occur frequently in breast cancer and could be a novel predictive marker of chemoresistance and an appealing target for therapeutic inhibition, independent of hormone receptors and ERBB2 status.

[Table: see text]

No significant financial relationships to disclose.
Treatment outcome after induction chemotherapy before allogeneic hematopoietic SCT in patients with advanced MDS
Authors: Ramos C. A. , Jakubowski A. A. , Boulad F. , Papadopoulos E. B. , Young J. W. , Kernan N. A. , Perales M. A. , Small T. N. , Berman E. , O’Reilly R. J. , Castro-Malaspina H. R.
Published: March 2020

6502

Background: The need for induction chemotherapy (IC) before allogeneic hematopoietic stem cell transplant (alloSCT) in advanced myelodysplatic syndrome (MDS) remains controversial. Methods: This is a retrospective analysis of the remission rate in 99 patients with advanced MDS (≥5% marrow blasts) and acute myeloid leukemia (AML, ≥ 20% blasts) evolving from MDS, who were treated with IC before receiving cytoreduction for SCT. These patients were referred to MSKCC for alloSCT from 6/1980 to 10/2004, and subsequently underwent an unmodified or T cell-depleted (TCD) SCT from a matched or mismatched related or unrelated donor after myeloablative cytoreduction in the majority. Results: All patients had MDS at diagnosis: 33% had high risk (HR), 22% intermediate risk (IR) and 42% good risk (GR) cytogenetics; 38% had HR, 32% IR-2 and 25% IR-1 IPSS. The median age was 43 (range 2–66). 76% had primary and 24% had secondary MDS (chemotherapy or radiation). At the time of IC, 64% had frank AML, 33% RAEB-1 and 2, and 3% CMML-2. A combination of an anthracycline (Ac) and standard dose (SD) cytarabine (AraC) was administered to 53% of the patients. Other regimens included Ac with high dose (HD) AraC (15%), Ac with SD AraC and etoposide (15%), HD AraC alone (8%), and HD AraC with etoposide (4%). 26% of patients required a second line regimen and 4% went on to a third. None of the patients died of complications due to IC. CR was achieved in 60% of patients overall (64% in those receiving Ac + SD AraC ± etoposide and 52% for HD AraC ± Ac ± etoposide). The CR rate was 65% in primary and 42% in secondary MDS, and was similar in adults (60%) and children (56%). CR rates were 44% in HR, 68% in IR, and 65% in GR cytogenetics; 58% in HR, 59% in IR-2, and 60% in IR-1 IPSS. According to disease status at IC, the CR rate was 60% for RAEB-1 and 2 and 59% for AML. 12% of complete responders relapsed prior to cytoreduction for SCT. 49% of all patients underwent a TCD SCT from an HLA identical sibling. There are no long term survivors after SCT in patients who did not achieve CR after IC, in contrast to 47% overall survival at 10 years for responders. Conclusions: IC in advanced MDS is associated with a high rate of CR. IC before cytoreduction for SCT is an effective approach to reduce the burden of disease particularly prior to TCD SCT.

No significant financial relationships to disclose.
Dasatinib in patients with chronic phase chronic myeloid leukemia (CP-CML) who are resistant or intolerant to imatinib: Results of the CA180013 ’START-C’ Study
Authors: Hochhaus A. , Kantarjian H. , Baccarani M. , Cervantes F. , Facon T. , Goldberg S. , Erben P. , Countouriotis A. , Ezzedine R. , Druker B. J.
Published: March 2020

6508

Background: Dasatinib (BMS-354825) is a novel, oral, multi-targeted kinase inhibitor of BCR-ABL and SRC kinases with proven preclinical and clinical activity against imatinib resistant BCR-ABL mutations. Methods: CA180013 is an open-label Phase II study of dasatinib in imatinib-resistant (IM-R) or -intolerant (IM-I) patients (pts) with CP-CML. Between February-August 2005, 424 pts were recruited from 75 centers worldwide. Dasatinib was given at 70 mg twice daily (BID) with dose escalation to 90 mg BID in pts lacking response, and dose reductions to 50 and 40 mg BID for toxicity. Evaluations were weekly blood counts for the first 12 weeks; bone marrow cytology and cytogenetics every 3 months. The primary endpoint was rate of major cytogenetic response (MCyR; ≤35% Philadelphia pos. metaphases) in IM-R pts. Results: Data are currently available from the first 186 pts (127 IM-R, 59 IM-I) accrued prior to May 12, 2005. Median age was 59 yrs (range 24–79); 46% were male. Median time from diagnosis of CML was 64 months. Of the IM-R pts, 72% received IM >3 yrs, and 72% had >600 mg/day of IM. Overall, 70% had received prior interferon alpha. 62 (33%) pts achieved a prior MCyR to IM. With ≥6 months of follow up, 168 (90%) pts had a complete hematologic response (CHR). MCyR were achieved in 83 (45%) pts including 40 (31%) of IM-R pts, and 43 (73%) of IM-I pts. Mutations in the BCR-ABL domain were found in 65/176 (37%) pts; 57 (88%) achieved CHR, and 24 (37%) MCyR. Molecular response analysis is ongoing. 160 (86%) pts remain on study without progression. Grade 3/4 neutropenia or thrombocytopenia was reported in 83 (45%) pts and 85 (46%) pts with onset after 4–8 weeks of therapy in most pts. Temporary dose interruptions occurred in 146 (78%), and dose reductions in 96 (52%) pts with a median daily of 108 (range 19–169) mg. Non-hematologic toxicity consisted mainly of Grade 1/2 diarrhea, headache, superficial edema, and pleural effusion, with ≤2% Grade 3/4. There was no cross-intolerance between dasatinib and IM. Conclusions: Dasatinib demonstrated substantial hematologic and cytogenetic activity in IM-R and IM-I pts with CP-CML. An updated analysis of 424 pts with ≥6 months of follow up will be presented.

[Table: see text]
Phase II study of lenalidomide (CC-5013) for patients with myelofibrosis
Authors: Verstovsek S. , Cortes J. , Thomas D. , Beran M. , Koller C. , Giles F. , Kantarjian H.
Published: March 2020

6510

Background: Lenalidomide (CC-5013, Revlimid), analogue of thalidomide, a new drug in a group known as ImiDs, with broad cytokine modulatory activity. Lenalidomide is less toxic than thalidomide without teratogenicity, sedation, or neurotoxicity, and is 50,000-fold more potent in inhibiting, tumor necrosis factor-α, that is involved in the pathophysiology of myelofibrosis (MF). Patients (pts) with MF currently have no approved standard effective therapy. Methods: Phase II study of lenalidomide for MF pts with plts >30×109, performance status ≥3, total bilirubin and creatinine of <3mg/dL, accrued 41 pts. Pts with prior hypersensitivity to thalidomide excluded. Pts received lenalidomide 10mg orally daily (5mg if platelets <100x109). Median age 65 (range, 42–83). 36 pts (88%) had received prior therapy for MF, including thalidomide 13 (32%), hydroxyurea 13 (32%), interferon 11 (27%), anagrelide 10 (24%), and erythropoietin 6 (15%). Baseline hemoglobin was <10g/dl in 19 (46%) (13 or 32% were transfusion dependent), platelets <100x109 in 12 (29%), absolute neutrophils <1.5x109 in 2 (5%), 20/34 (59%) had splenomegaly (median 10cm BCM, range 1–30; 7 with prior splenectomy), and 17 (42%) had cytogenetic abnormality. Results: Median follow is 5 months (range 1–14). Therapy has been well tolerated. Most common toxicities of any grade were rash 6(39%) and pruritus 9 (22%). Grade ≥3 toxicities were neutropenia 13 (32%), thrombocytopenia 11 (27%), fatigue 3 (7%) and rash 2 (5%). 8 (20%) pts required dose reduction; 4 discontinued therapy due to toxicity. Responses have been observed in 19 (46%) pts. These include CR 3(7%; normalization of hemoglobin and WBC), PR 5 (12%; improvement in platelets and hemoglobin ± spleen), and hematologic improvement 11 (27%) pts (improvement in platelets - 4, spleen - 2, WBC - 4, BM blasts - 1). 5 of 13 transfusion-dependent pts have become transfusion-independent. 6 of 12 (50%) pts with platelets <100x109 improved the count by >50%. Median time to response was 6 wks (range 1–22). Responses have been sustained for a median of 31+ wks (range 1+-40+). Conclusions: Lenalidomide has clinical activity in a subset of pts with MF with an acceptable toxicity profile. Studies using lenalidomide in combination with other agents are planned.

No significant financial relationships to disclose.
Infusions of HSV-TK genetically modified donor lymphocytes enable a wider use of partially mismatched allogeneic transplantation by reducing infection related mortality and improving survival in high risk acute leukemia
Authors: Ciceri F. , Bonini C. , Lupo Stanghellini M. , Santoro A. , Slavin S. , Apperley J. , Bruzzi P. , Toma S. , Gallo Stampino C. , Bregni M. , Bordignon C.
Published: March 2020

6519

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

[Table: see text]
Bcr-Abl mutations in imatinib-resistant CML and Ph+ALL patients (pts) enrolled in a phase I study of AMN107
Authors: Ottmann O. , Bhalla K. , Kantarjian H. , Hochhaus A. , Jones D. , Dawson K. , Rose K. , Alland L. , Dugan M. , Lilleburg S. , Giles F.
Published: March 2020

6527

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

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Natural killer (NK) cells are associated with reduced relapse without increased graft-versus-host disease (GVHD) after allogeneic hematopoetic stem-cell transplantation (HSCT)
Authors: Reddy V. , Levine J. B. , Mahmood S. S. , Schold J. D. , Meier-Kriesche H. , Dunbar E. M.
Published: March 2020

6542

Background: Natural killer cells have potential for anti-leukemia activity after haplo-identical HSCT. However, the role of reconstituted NK cells in relapse and survival after matched HLA-identical HSCT is unknown. We investigated the correlation between NK reconstitution and death, relapse, and GVHD after HSCT. Methods: We prospectively studied NK reconstitution in 123 patients with predominantly high-risk hematologic malignancies. Peripheral blood absolute NK cell count (ANK) was determined by flow cytometry analysis of lymphocytes co-expressing bright staining CD56+ and CD16+. Cluster analysis distinguished patients at engraftment with high ANK (>12.2/mm3) (n=80) and low ANK (n=43), and at 60 days with high ANK (>20/mm3) (n=64) and low ANK (n=26). Primary study endpoints were death, relapse and acute grade II-IV GVHD with median follow up of 360 days (28–1967). A cox proportional hazard model was adjusted for important covariates, including age, transplant conditioning (myeloablative vs. non-myeloablative), graft source (peripheral blood vs. bone marrow), and donor-type (HLA-matched related vs. unrelated), dendritic cell level and absolute neutrophil count. Results: A low ANK at engraftment was significantly associated with death (p=0.03) after non-myeloablative HSCT. Using a selection model, only NK remained in the model, and a low ANK was associated with a 2.5 hazard ratio for subsequent death (p=0.04). Additionally, for the overall cohort, ANK at 60 days was strongly associated with time to death (92% in high vs 65% in low group; LR p=0.0007), at 310 days after HSCT. ANK level at 60 days was strongly associated with time to relapse (n=82, (LR p=0.0001). In a multivariate model, low ANK at 60 days was associated with a 4.2 fold relative risk (RR) of death (1.9, 9.1) and 8.6 RR for time to relapse (3.1, 24.3). Conclusions: High NK cell reconstitution is associated with reduced relapse and death without increased incidence of GVHD after HLA-identical HSCT. Our study suggests that NK may have both a potential anti-tumor effect, as well as be tolerogenic. Measuring NK after HSCT may have novel prognostic and therapeutic implications.

No significant financial relationships to disclose.
Long-term outcomes of survivors of autologous hematopoietic-cell transplantation for refractory and relapsed Hodgkin’s Disease
Authors: Goodman K. A. , Serrano V. , Riedel E. R. , Gulati S. , Moskowitz C. H. , Yahalom J.
Published: March 2020

6554

Background: With improvements in survival among refractory/relapsed Hodgkin’s Lymphoma (HL) patients after high-dose chemo-radiotherapy and autologous hematopoietic-cell transplant (AHCT), it is important to evaluate risk of late complications in this heavily treated population. Methods: From 1985–1998, 218 refractory/relapsed HL patients were treated on high dose chemo-radiotherapy and AHCT salvage protocols. 153 (70%) surviving ≥2 years after AHCT were analyzed. All received either radiotherapy with initial therapy or total lymphoid irradiation and involved field boost with the conditioning regimen (43%). Information from surviving patients was obtained through a self-administered questionnaire. The NDI was queried to determine vital status and cause of death. Primary endpoint was non-HL mortality, defined as mortality due to cardiac causes, infection or second malignancy (SM). Competing risk methods were used to calculate cause-specific mortality rates and examine its predictors. All events were calculated from 2 years post-AHCT to date of death/last follow-up. Results: Median follow-up time was 11 years. There have been 51 deaths, 32 due to HL and 19 due to other causes. Eleven deaths were due to SM: AML (3), MDS (2), NHL (2), NSCLC (2), gastric and colon cancer. There were 8 non-SM deaths: cardiac toxicity (4), infection, aplastic anemia, suicide, unknown causes (1 each). The 10 and 15-year overall survival (OS) rates are 64% and 57%, respectively. The 10-year cumulative incidence of death from HL and from non-HL causes were 22% and 13.5% ( table ). By univariate analysis, increased risk of death due to SM was associated only with higher age at AHCT (p=0.02). Conclusions: While HL initially accounts for the majority of deaths among patients surviving high-dose therapy, the HL mortality rate plateaus and risk of death from non-HL mortality increases after 5 years. Yet, even at 15-years, SM risk does not exceed that observed in patients treated with standard regimens.

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No significant financial relationships to disclose.
Erythroid response (ER) rates in myelodysplastic syndromes (MDS) patients treated with epoetin alfa (EPO): A meta-analysis using the International Working Group criteria (IWGc) for MDS response
Authors: Moyo V. , Lefebvre P. , Duh M. S. , Bourezak A. , Yektashenas B. , Woodman R. C. , Mundle S.
Published: March 2020

6572

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

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Transfusion independence in patients with myelodysplastic syndromes treated with azacitidine
Authors: Silverman L. R. , Peterson B. L. , Holland J. F. , Stone R. M. , Powell B. L. , Larson R. A.
Published: March 2020

6576

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

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Clinical and hematological improvement in patients receiving liposome doxorubicin (Myocet) therapy for myelofibrosis with myeloid metaplasia (MMM)
Authors: Iuliano F. , Molica S. , Serra A. , Sterpone P. , Russo A. , Cilloni D. , Peta A.
Published: March 2020

6593

Background: MMM is a chronic myeloproliferative disorder with bone marrow fibrosis, hepato-splenomegaly, extramedullary hematopoiesis,increase angiogenesis both in bone marrow and spleen. Myocet is a proprietary liposomal formulation of doxorubicin designed to enhance delivery of the drug to tumor cells and reduce side effects while maintaining equivalent anti-tumor efficacy. Liposomes are avidly removed from circulation by the macrophages of the RES or MPS and are taken up in the spleen, liver and bone marrow were show both a cytotoxic and antiangiogenic activity. Methods: We thus designed a phase II study for pts with MMM. The treatment program consisted of 25 mg total dose of Myocet given I.V. every two weeks for six months. Eligibility criteria included a histologically confirmed diagnosis, platelets ≥ 100 × 109/L, neutrophils ≥ 1 × 109/L, PS ≤ 2, LVEF > 45%, normal liver and renal function. Eight patients (median age, 66 years; range, 60–73) were enrolled to the trial. Median duration of disease prior to protocol treatment was 45 months (range, 24–144). All pts had received prior therapy for MMM, including thalidomide (37%) hydroxyurea (100%), interferon (25%), anagrelide (25%), erythropoietin (100%). 3 pts were RBC transfusion-dependent and 1 had severe constitutional symptoms. Baseline median (range) values for palpable spleen size, leukocyte count, platelet count, CD34 cell count, and serum lactate dehydrogenase (LDH) were: 10cm BCM (median, range 6 to 30), 8.5 × 109/L (3–36.2), 250 × 109/L (160–950), 151.1 × 106/L (1.9–3568), and 680 U/L (316–868), respectively. 8/8 pts had JAK2 V617F mutation. Results: 7/8 pts are evaluable (i.e., received six months of therapy), 1 pt discontinued for progression. Clinico-hematologic responses have been observed in 7/7 (100%) pts and were evaluated according to European Myelofibrosis Network criteria. These include CR in 1 pt, major response in 5/7 pts, minor response in one. The median time to response was 12 weeks (range, 4 to 18). Therapy has been well tolerated. Only a Grade 3 thrombocytopenia was seen. Conclusions: We conclude that Myocet has clinical activity in a subset of patients with myelofibrosis with an acceptable toxicity profile.

No significant financial relationships to disclose.