bluuebunny/crossref_metadata_2025 huggingface dataset:
CT-guided percutaneous radiofrequency ablation in the treatment of stage I thymoma.
Authors: Dong Jun , Geng Xiaojing , Li Wang , Zhang Bei , Xia Liangping , Hu Pili , Peng Roujun , Wu Peihong
Published: September 2018

e18287

Background: Thymoma is an uncommon tumor originating from the epithelial cells of the thymic epithelium. It is commonly associated with myasthenia gravis. Though surgical resection might provide the hope of curing thymoma, potential risks of invasive trauma and post operation complications still exists. Video-assisted thoracoscopic surgery (VATS) has many advantages over traditional surgery including minor trauma. However, surgeons operating the equipment to perform VATS need to be highly specifically trained. Although CT-guided percutaneous radiofrequency ablation (RFA) has emerged as a minimally invasive and curative treatment in other tumors, it has never been used in the treatment of stage I thymoma. Methods: The current study enrolled 13 patients with stage I thymomas whom refused open surgery or VATS. As a result, all patients received first-line CT-guided percutaneous RFA as treatment. The procedure was clearly described and displayed for clinical promoting. Results: The feasibility and treatment effectiveness were also recorded. The median time of ablation was 15 mins (range, 10 - 20 mins). Minimum blood loss was associated with the puncture. All lesions were completely ablated (13/13, 100%). Only one patient out of thirteen had thymoma recurrence at 35.5 months after initial ablation treatment (1/13, 7.7%) at follow-up period (median 80.5 months, range, 64.6-116.9 months). There was no procedure-related death after RFA treatment. Myasthenia gravis was cured in most patients (10/13,76.9%), alleviated in 3 patients (23.1%). The most common complications recorded were fever (13/13, 100%), incisional pain (13/13, 100%), nausea (38.5%), pleural effusion (69.2%), pneumothorax (69.2%) and hemoptysis (84.6%). Conclusions: It is clinically applicable for CT-guided percutaneous RFA to be considered as a safe and effective treatment in stage I thymoma.
Comparison of IHC testing for HER-2 in breast cancer specimens before and after adoption of new 2013 ASCO/CAP guidelines in a single institution: Impact on outcome and cost.
Authors: Sharma Anurag , Hegde Poornima , Vadehra Deepak , Kaiser Talal , Tannenbaum Susan
Published: September 2018

e18294

Background: Revised guidelines for HER-2 testing in Breast Cancer Specimens occurred in 2007 and again in 2013 with an intention to capture more patients who could benefit from HER-2 directed therapy. Methods: The purpose of this study was to compare the HER 2 + cases outright and the equivocal cases that resulted in a reflex FISH test that was ultimately positive utilizing both guidelines. The number of equivocal tests results and those that ultimately were positive, negative or remained equivocal were quantitated. A retrospective analysis on specimens from 2003-2008 and 2013-2016 was performed. Results: see table. Conclusions: An expansion of 8.8% is seen in the equivocal category after adoption of the 2013 guidelines. Despite an increased number of reflex FISH testing there was no significant increase in the number of FISH positive patients. The end result was a greater delay in time to treat patients appropriately for send-out FISH tests and significant increase in costs for testing that did not result in management change. If the additional costs are multiplied by the number of patients with breast cancer each year and resultant equivocal results calculated for the almost 9% increase, that extra cost is close to 12 million dollars. Based on our small institution study, reconsideration of guideline criteria is important in this era of value-based medicine. [Table: see text]
Measuring cost in the value equation using time-driven activity-based costing (TDABC) at The University of Texas MD Anderson Cancer Center, Division of Radiation Oncology.
Authors: Olivieri Nicholas D. , Frank Benjamin D. , Calhoun John D. , Guzman Alexis B. , Onwenu Justin N. , De La Cerda Isela , Sharma Mallika , Loggenberg Aidan , Shaitelman Simona Flora , Minsky Bruce D. , Jeter Melenda , Ghafar Robert , Feeley Thomas W. , Hahn Stephen M.
Published: September 2018

e18305

Background: The cost of a full cycle of radiation therapy at MD Anderson Cancer Center has not been determined using a bottom-up measurement approach. Due to the complexity and variation in clinical processes, typical costing strategies do not provide the level of detail necessary to evaluate the value equation, defined as outcomes over cost. To address this limitation, we designed and implemented a practice-wide Time-Driven Activity-Based Costing (TDABC) strategy to capture our total direct cost of care for all treatment modalities within each of 9 disease site-specific services. Methods: Process maps were created for each of the 9 disease site-specific services. Care delivery times were captured by treatment modality for each service as determined by multidisciplinary teams routinely performing each step of the process. The data were entered into a standardized tool, which calculated step costs based upon capacity cost rates for each human resource. The costing tool also calculated total direct labor costs for specific treatment plans based on modality, complexity, and fractionation. Results: The analysis took six months to complete and required the use of approximately 1,000 administrative hours, 250 physician hours, 250 clinical staff hours and 100 medical physics hours. Approximately 17 process maps were created for each of the 9 services with each process map receiving further analysis based upon radiation treatment modality. As a result of observed variation in costs between disease-site services, best practices were identified and 15 standardization opportunities were discovered. Additionally, the cost-benefit analysis between high profile modalities within each disease-site service, such as Proton Therapy and Intensity Modulated Radiation Therapy (IMRT) on the Head and Neck service, were easier to complete. Conclusions: Time-Driven Activity-Based Costing is a valid method for calculating direct costs in a large academic radiation oncology practice. Standardized clinical outcome data can be used to complete the value equation and ultimately provide insight for better clinical and administrative decision making.
Patients’ willingness to pay for blood-based EGFR T790M testing: Results from a Canadian validation study of circulating DNA T790M testing.
Authors: Barnes Tristan Alexandra , Laskin Janessa J. , Cheema Parneet Kaur , Liu Geoffrey , Iqbal Mussawar , Rothenstein Jeffrey , Burkes Ronald L. , Owen Scott Peter , Laurence David , Carvalhana Ilda , Markin Leslie , Wong Linda , Perera-Low Nicole , Sawczak Magdalena , Tsao Ming-Sound , Leighl Natasha B.
Published: September 2018

e18329

Background: Detection of EGFRmutations in circulating tumor DNA (ctDNA) in peripheral blood has been shown to have high concordance with definitive tumor biopsy samples. Patients’ perceived value and willingness to pay for novel technology can help inform policy and funding decisions in the public healthcare system. Methods: Canadian patients undergoing screening for the ASTRIS clinical trial (NCT02474355) were invited to participate in a national Canadian validation study of blood-based ctDNA T790M testing. All participants had metastatic EGFRmutant lung cancer with acquired resistance to EGFR kinase inhibitors. In addition to collection of blood samples and demographic data, patients completed a structured interview measuring their perceived value of blood-based ctDNA testing as an alternative to tumor biopsy and willingness to pay for testing using both open-ended and iterative bidding approaches. The study was supported by a grant from AstraZeneca. Results: 55 patients have been accrued of a planned 60. As of 01/31/2017, demographic data for 55 and willingness to pay data for 52 patients were available, the rest are pending. The median age of the cohort is 64 years (range 31-87), 68% are Asian (36/53), 56% female (31/55). Patients received a median of 1 prior line of treatment (range 1-7); all received prior EGFR kinase inhibitor therapy (66% gefitinib), and 34% also received prior cytotoxic chemotherapy (18/53). All but one patient preferred to have the blood test over repeat tumor biopsy. Patients were personally willing to pay a median of $400 CAD for the test (IQR $600, range 0-$10000). Patients estimated that a reasonable price for the test was a median of $150 (IQR $300, range 0-$2500). Conclusions: Lung cancer patients value ctDNA testing highly and prefer it to tumor biopsy. Despite the expectation that services like molecular testing should be covered through the Canadian public healthcare system, patients expressed willingness to pay out of pocket for ctDNA blood testing, reflecting perceived major value of this technology.
Cost effectiveness of treating endemic Burkitt lymphoma in Uganda.
Authors: Denburg Avram
Published: September 2018

e18339

Background: Despite high cure rates achieved in high-income countries, outcomes for children with Burkitt lymphoma (BL) in most low- and middle-income countries (LMICs) remain suboptimal. Perceptions of high cost and resource intensity remain political barriers to the prioritization of BL and other childhood cancer treatment programs in many LMIC health systems. Little to no knowledge exists of the actual cost and cost-effectiveness of treating paediatric cancers in LMICs. To improve outcomes for children with BL, the Uganda Cancer Institute implemented a comprehensive BL treatment program in 2012. Drawing on centralized patient-level data, we undertook an economic evaluation of the program to ascertain the cost-effectiveness of BL therapy in a specific LIC setting. Methods: We compared the treatment of BL (local standard) to usual care (no care), in a cohort of 215 patients treated between 2012 and 2015. Costs included direct, indirect healthcare, and indirect patient costs. Our primary measure of effectivenesswas overall survival (OS). Patient outcomes were determined through electronic chart abstraction. The cost per DALY averted was calculated using WHO-CHOICE methodology and compared to standard definitions of cost-effectiveness. Results: The 2-year OS with treatment was 53% (95% CI, 43% to 62%). Nine percent of patients abandoned therapy. The cost per DALY averted in the treatment group was US$78. Cumulative estimate of national DALYs averted through treatment was 11,046 years, and the total national cost of treatment was US$755,216. The ratio of cost per DALY averted to per capita gross domestic product (GDP) was 0.12, reflecting a very cost-effective intervention. Conclusions: This study demonstrates that treating BL with locally tailored protocols is very cost-effective relative to per capita GDP in Uganda. Studies of this kind will furnish crucial evidence to assist policymakers prioritize the allocation of LMIC health system resources among NCDs, including childhood cancer.
Treatment, healthcare resource utilization, and costs associated with non-metastatic and metastatic castration-resistant prostate cancer: A claims analysis.
Authors: Valderrama Adriana , Tangirala Krishna , Babajanyan Svetlana , Appukkuttan Sreevalsa , Wen Lonnie Kent , Malacan Jean , Shore Neal D.
Published: September 2018

e18341

Background: Limited evidence exists about economic burden in non-metastatic castrate resistant prostate cancer (nmCRPC). The aim of this study was to describe the real-world treatments in this setting and to quantify both the costs and healthcare resource utilization (HCRU) during the year before and after metastasis for this patient population. Methods: A retrospective cohort of metastatic castrate resistant prostate cancer (mCRPC) patients was identified from Truven Health MarketScan database from January 2009 to March 2015 with metastasis diagnosis as index date. mCRPC algorithm was based on ICD-9 codes for both prostate cancer and secondary metastatic disease, and a subsequent claim for a FDA approved treatment for mCRPC. Patients were also required to have evidence of surgical or medical castration in the baseline period to define nmCRPC. Costs and HCRU were compared in the 1 year pre- and post-index time periods. Results: Among 341 mCRPC patients identified, mean age was 71.9 years (72.4% ≥65 years old), 72.7% were Medicare Advantage patients and 19.4% had Klabunde comorbidity > 1. Most common treatments in the pre index period were bicalutamide (90%), leuprolide (83.6%), docetaxel (27.6%), abiraterone (22.9%) and ketoconazole (21.4%). Mean per patient per year (PPPY) all cause HCRU and costs were significantly higher (all P < 0.05) in the mCRPC patients compared to nmCRPC patients (Table). Conclusions: Average yearly costs more than doubled following mCRPC diagnosis, which indicates the need for appropriate management strategies for nmCRPC patients in order to optimize the potential delay of disease progression. [Table: see text]
Real-world prescribing patterns in acute myeloid leukemia in the United States.
Authors: Medeiros Bruno C. , Pandya Bhavik J. , Hadfield Anna , Wilson Samuel , Mueller Cynthia , Bailey Tom , Flanders Scott , Horvath Laura E. , Rider Alex
Published: September 2018

e18524

Background: The effective treatment of patients with acute myeloid leukemia (AML) remains a challenge in clinical practice. This analysis describes the patient characteristics and real-world use of AML treatments in the United States for patients on high- and low-intensity treatment. Methods: Data from the Adelphi AML Disease-Specific Programme, a real-world, cross-sectional survey conducted between February–May 2015, were analysed. A total of 61 hematologist/hem-oncologists, across academic, non-academic and office-based practice locations, provided data on 457 AML patients. Patient characteristics were derived from physician-completed patient record forms where each physician was asked to provide treatment details, including the treatment intensity, for each line of therapy. Results: A total of 91% (n = 415) of patients included in this analysis were previously untreated for AML. Patients had a mean age of 60 years and been diagnosed with AML for a median of 5.0 months. At first-line induction therapy, over half (53%; n = 241) of the patients were initiated on a high-intensity treatment, the most common regimen being cytarabine plus anthracycline (61%; n = 147). The remaining 47% (n = 216) of patients received a low-intensity induction therapy such as low dose cytarabine monotherapy (28%, n = 61), azacitidine monotherapy (25%, n = 54), or decitabine monotherapy (21%, n = 45). Over half (55%, n = 62) of patients suited to high intensity treatment went on to receive cytarabine monotherapy during the consolidation phase of their first-line treatment. Conclusions: According to treating physicians, the large majority of patients receive traditional, well-established therapies at first-line induction for AML. Whilst cytarabine combinations dominate the high-intensity treatment setting, the hypomethylating agents, azacitidine and decitabine, are frequently used for those more suited to low-intensity treatment.
Determinants of quality of life in patients with acute myeloid leukemia.
Authors: Buckley Sarah A. , Jimenez-Sahagun Diana , Othus Megan , Walter Roland B. , Lee Stephanie
Published: September 2018

e18528

Background: There is growing interest in quantifying quality of life (QOL) effects of acute myeloid leukemia (AML) therapy. As there are no AML-specific QOL instruments available, we conducted a cross-sectional study to elicit concepts for the development of such an instrument, the AML-QOL. Methods: Adults with AML at various time points during the course of participated in an open-ended interview and completed the FACT-G, -LEU, -BMT and the PROMIS-29 questionnaires in order to elicit concepts impacting QOL. In addition, patients were asked to quantify the degree to which each impacted their QOL on a 3-point scale (little, some, large impact). Positive concepts (i.e., sources of support) were included in the AML-QOL based on prevalence; negative concepts were included based on both prevalence and the percent of cases in which the concept had high impact on QOL. Results: Among 82 patients, commonly described positive concepts were family support (85%), maintaining a positive attitude (63%), friends or community (52%), and trust in the medical team (52%). Negative concepts with the highest prevalence and impact product are shown in the Table. After completing FACT and PROMIS, 22% of patients reported confusion with items querying functional status because of ambiguity between temporary functional restrictions (e.g., inability because of an inpatient stay) and functional limitations (e.g., inability due to weakness). Conclusions: Our interviews identified concepts most important to patients during AML therapy and allowed development of a 40-item survey that is now undergoing validation. [Table: see text]
Neutropenic fever prophylaxis during induction therapy for acute myeloid leukemia.
Authors: Nabbout Nassim H.
Published: September 2018

e18531

Neutropenic Fever Prophylaxis During Induction Therapy for Acute Myeloid Leukemia Nassim Nabbout, MD, Salam Kadhem, MD, Rawaa Ebrahem, MD, Rossa Khalaf, MD, Baharat Malhotra, MD, K. James Kallail, PhD Background: Neutropenic fever is an oncological emergency [1] that occurs at a high rate in patients with acute myeloid leukemia (AML) undergoing induction chemotherapy. Oral antibiotics have been considered standard of care for prophylaxis for these patients once they develop neutropenia [2]. To determine the efficacy of this approach, we conducted a retrospective review of newly diagnosed AML patients. Methods: All adult patients who underwent induction treatment for newly diagnosed AML at one Wichita, Kansas medical center between January 1, 2011 and December 31, 2013 were identified. The medical records were reviewed and pre-specified variables were collected. Results: Thirty-eight patients were included and their charts were reviewed. Nineteen (50%) were males. Thirty-six patients (95%) were white. The average white blood count on day 1 of treatment was 34000 cell/mm3 and the range was 1300 - 305,000 cell/mm3. The average ANC was 3700 cell/mm3 with the range of 10 - 28288 cell/mm3. All patients received prophylactic oral antibiotics once they became neutropenic. In all, but one patient, this regimen consisted of combination of levofloxacin, acyclovir, and fluconazole. Thirty-four patients (89%) developed neutropenic fever while they were on oral prophylactic antibiotics. Two patients (5%) developed septic shock. Four patients (11%) died during the first 21 days of induction, all due to infections, and three (8%) went to hospice. Causative organisms were identified in 11 patients (29%). All patients were switched to intravenous vancomycin and cefepime once they became febrile. Conclusions: Eighty-nine percent of patients developed neutropenic fever despite prophylaxis with oral antibiotics. These dismal results suggest that the current standard of care for neutropenic fever prophylaxis is ineffective and highlight the need for a different approach. Future studies should consider changing the regimens of antibiotics and/or the route of administration toward more aggressive prophylactic strategies.
Intensive sequential chemoterapy with etoposide, mitoxantrone and cytarabine (EMA) as salvage in patients with AML relapsing after hematopoietic stem cell transplantation.
Authors: Gokmen Ayla , Soydan Ender , Gokgoz Zafer , Ozkumur Kerem ozan , Arslan Onder , Ilhan Osman , Ozcan Muhit
Published: September 2018

e18537

Background: Relapse after allogeneic hematopoietic stem cell transplantation ( HSCT) for AML is the main cause of treatment failure.The optimal treatment strategy for patients with AML relapsing after HSCT remains controversial. We evaluated the efficacy of intensive sequential chemotherapy with etoposide,mitoxantrone and cytarabine as salvage therapy in patients with AML relapsing after alloHSCT. Methods: Fifteen AML patients relapsing after HSCT who were treated with EMA regimen between January 2015 and December 2016 were analysed retrospectively. EMA regimen consisted of mitoxantrone 12 mg/m² on days 1-3, etoposide 200 mg/m² on days 8-10 and cytarabine 500 mg/m² on days 1-3 and 8-10. Results: Median age was 49 ( range 22-64) years. At transplantation , 12 patients were in CR ( 10 CR1 and 2 CR2) , 3 patients had active disease. 9 donors were matched related, 3 were matched unrelated and 3 were haploidentical. Median time from transplantation to relapse was 163 ( 62-576) days. Complete response ( CR) was achieved in 7 of 15 patients ( 46.6 %). Five patients died during treatment before assessment of response to treatment with a median day of 32 due to infection. Three patients did not respond to treatment. All patients suffered grade 4 neutropenia and thrombocytopenia. Neutropenic fever was obseved in all patients. Grade 2-3 a GVHD was observed in 10 patients (66%) during EMA chemotherapy at a median day of 15. Further treatment was given in 6 patients who achieved CR with EMA : 2 patients underwent second allogeneic HSCT, 1 patient underwent second haploidentical HSCT, 2 patients were treated with DLI, 1 patient was treated with azacytidine-DLI combination. Median OS was 100 d ( range 24-402). Median duration of OS in responding patients were 248 d ( 67-402). At last folllow-up 3 patients are still alive and disease free. Conclusions: Intensive sequential chemotherapy with EMA is an efficacious option as salvage therapy in patients with AML relapsing after HSCT. However further treatment strategies such as second transplantation, DLI after chemoterapy or maintanence with targeted drugs are required to obtain long term remission.
Magnesium alterations of graft immune cells (MAGIC).
Authors: Sedhom Ramy , Zloza Andrew , Kohlhapp Frederick Joseph , Medina Daniel , Strair Roger
Published: September 2018

e18541

Background: Magnesium plays important roles in cellular processes. Allogeneic hematopoietic stem cell transplantation provides potentially curative therapy to patients with a variety of hematologic malignancies. A common abnormality post transplant is hypomagnesaemia. Recent studies identified magnesium transporter 1 deficiency in association with XMEN syndrome. These patients exhibit low intracellular [Mg++] and low T cell and NK cell NKG2D expression. Therefore, we investigated this potential functional link between magnesium deficiency and immune function in patients post transplant. Methods: A pilot study investigated whether detectable changes in T and NK cells were associated with IV magnesium repletion post hematopoietic transplant. Blood was obtained before and after magnesium transfusions. Immunophenotypic analysis of T and NK cell NKG2D levels using commercially available monoclonal antibodies (CD3, CD16, CD56, CD4, CD8, CD314 [NKG2D]) was performed. Samples from patients demonstrating an increase in NKG2D expression were subsequently analyzed for ex vivo NK activity. Here, NK activity and cytotoxicity of Jurkat cells were assayed using standard laboratory techniques and changes > 2 fold were considered significant. A total of 7 patients were enrolled. Results: NKG2D expression on T and NK cell subsets were determined by flow cytometry using commercially available monoclonal antibodies. NK reactivity and killing of K562 were undertaken using standard cytotoxicity assays. Our findings indicate a significant response in five of the seven enrolled patients. NKG2D expression on CD8+ T cells increased by up to 31%. Conclusions: Our results suggest that magnesium infusions post allogeneic transplant are associated with augmented NKG2D expression on immune cells. Additional studies are needed to clarify the mechanisms by which therapeutic magnesium repletion restores the cytotoxicity of NK cells and T lymphocytes. Although the clinical utility of magnesium supplementation remains to be validated, our data indicate that NKG2D is regulated by magnesium post transplant and magnesium may play a key role in immune regulation.
Bortezomib, rituximab, and risk of graft-versus-host disease (GVHD) after BEAM conditioning for allogeneic stem cell transplantation (alloSCT).
Authors: Chamoun Kamal , Gulbis Alison M , Milton Denai , Jabbour Elias , Turturro Francesco , Khouri Issa F.
Published: September 2018

e18543

Background: GVHD remains the main limitation of alloSCT and is exacerbated by the intensity of the conditioning regimen. In a recent study, the risk of acute grade II-IV GVHD and extensive chronic GVHD (cGVHD) after a nonmyelobaltive (NMA) regimen was 11%, and 26%, respectively (Khouri I. Blood 2014 124:2306). Higher rates were previously observed (32% and 54%, respectively) with the BEAM regimen. Based on clinical data showing a reduction in GVHD with the use of rituximab or bortezomib, we conducted a phase I/II study evaluating the addition of bortezomib to rituximab+BEAM in patients (pts.) who were not eligible for NMA alloSCT. Methods: Bortezomib was administered at 1.3 mg/m2 IV on days -13, -6, -1 and +2. The dose was later reduced to 1 mg/m2 after the occurrence of C. Difficile colitis in the first 3 pts. leading to 2 deaths. Rituximab was given on day -13 at a dose of 375 mg/m2, then at 1000 mg/m2 on days -6, +1, and +8 of alloSCT. BEAM was administered between days -6 and -1. All pts. received our standard GVHD prophylaxis with tacrolimus and methotrexate. In addition, thymoglobulin 1 mg/kg IV was given on days -2, and -1 in patients receiving matched unrelated donor (MUD) or mismatched (MM) transplants. Results: Thirty-nine pts. were studied. Median age was 54 yrs. Thirteen (33%) and 26 (67%) pts. had indolent or aggressive lymphoma histologies, respectively. Sixteen (41%) pts. were refractory. Twenty-two (56%) received alloSCT from HLA-compatible siblings, 16 (41%) from MUDs and 1 (3%) from mm donors. Peripheral blood was the source of stem cells in 97% of pts. ABO and CMV-mismatch rates were 56% had 50%, respectively. Median follow up surviving patients was 65 mos. Five-year OS and PFS rates were 35% and 28%, respectively. The CI of acute grade II-IV, III-IV, and cGVHD were 55%, 34%, and 41%, respectively. No predictor for acute GVHD was identified. Instead, we found that sex-mismatched transplants were predictive of a higher risk of cGVHD ( P= 0.01). Conclusions: The current trial is the first one evaluating the safety and efficacy of bortezomib plus rituximab as a part of the BEAM regimen for alloSCT. A better prophylaxis regimen is needed to lessen the risk of GVHD in this setting. Clinical trial information: NCT00439556.
Musculoskeletal symptoms in chronic myeloid leukemia patients after stopping tyrosine kinase inhibitors.
Authors: Diab Maria , Jeyakumar Ghayathri , Schiffer Charles Alan
Published: September 2018

e18547

Background: TKIs have revolutionized outcomes for CML patients (pts) but are not without cost or side effects. For pts with a prolonged response to treatment, discontinuing (d/c) treatment is appealing and has been investigated in a number of trials. In pts in whom treatment was stopped, musculoskeletal (MSK) symptoms were reported that were shown in some cases to resolve with resuming TKIs. Methods: Records of pts with chronic phase CML who stopped TKIs were reviewed. Results: We report 8 pts with chronic phase CML whose TKI was stopped following a prolonged molecular remission. 5 pts were receiving imatinib and 3 dasatinib. 5 pts were experiencing intolerable side effects of TKIs and agreed to a trial of d/c; 2 pts requested d/c; a third pt was planning for pregnancy. The median duration of therapy with TKI before d/c was 10 years. 6/8 pts developed MSK complaints with arthralgias and joint stiffness after cessation. Involved joints included the cervical spine, shoulders, elbows, small joints of the hand, hips and knees. Arthralgia was Grade 1 in 3 pts, and Grades 2 and 3 in 1 and 2 pts, respectively. Joints were not swollen, erythematous or tender to touch. The median time from cessation of TKIs to the onset of symptoms was 2.25 mos (range: < 1-6 months). 3 pts with symptoms underwent rheumatologic work up that was nonrevealing. 5/8 pts remain in molecular remission. Of the 3 with molecular relapse, 2 had arthralgias that improved with resuming TKIs; the third remained asymptomatic. Of those who did not relapse, 1 remains symptom-free and 2 had resolution of their MSK symptoms. 1 had little benefit with corticosteroid therapy and imatinib was resumed. However, this retreatment was d/c due to side effects and she continues to experience mild arthralgias. 1 pt did not benefit from resuming TKIs, which was therefore d/c. Conclusions: The etiology of the so-called TKI “withdrawal syndrome” remains unclear. The incidence of this syndrome has not been fully elucidated, and it seems to be underappreciated and perhaps under-reported by patients. Although most symptoms are relatively mild and self-limited, this should be discussed with patients considering stopping TKIs.
Generic imatinib therapy among Jordanians: An observational assessment of safety and efficacy in routine clinical practice.
Authors: Awidi Abdallah , Abbasi Salah Y. , Al-Rabi Kamal Hosni , Kheirallah Khalid
Published: September 2018

e18548

Background: Generic imatinib therapy is being globally considered due to cost considerations. Evidence about its efficacy and safety in developing country settings, however, is scarce. Methods: The efficacy and safety of generic imatinib among Jordanian patients diagnosed with chronic myeloid leukemia (CML) was assessed utilizing an observational, multicenter, prospective study design. All patients (N = 91) were adults with CML treated with generic imatinib, mainly 400 mg/day, who either received generic imatinib (n = 33) as first-line therapy “first-line patients “or switched from patented imatinib to generic imatinib “switched patients” (n = 58). The primary objective was to measure proportions (95% Confidence Interval (CI)) of optimal response for first-line and switched patients at 12 months of treatment with generic imatinib, as defined in the 2009 ELN guidelines (CCyR [no Ph+ metaphases], or MMR [a ratio of BCR-ABL1 to ABL1 ≤0.1% on the International Scale]) and assessed by complete blood counts, fluorescence in situ hybridization and real-time quantitative PCR. Results: A total of 84.8% (n = 28/33) of the first-line patients achieved complete hematologic response (CHR) within 3 months of starting generic imatinib therapy (100% after 6 months). Out of the 23 evaluable first-line patients, [(87%, 95% CI = 73% - 100%), (n = 20)] in the per-protocol population (60.6 %, 95% CI = 51% - 86%) of the 33 patients in the intention-to-treat (ITT) population) achieved an optimal response at 12 months. All 58 switched patients had CHR at enrollment. Out of the 55 evaluable switched patients, [(96.4%, 95% CI = 91%-100%), (n = 53)] in the PP population (91.4%, 95% CI = 83%-98%) of the 58 patients in the ITT population) gained or maintained an optimal response at 12 months after switching to generic imatinib therapy. Most (84.7%, n = 144 out of 170) adverse events (AEs) were mild. Frequencies of drug-related AEs were similar to patented imatinib. Conclusions: Efficacy and safety of generic imatinib among middle eastern population in routine clinical practice is comparable to that of patented imatinib, and to that of the global population. Clinical trial information: NCT02977312.
Correlation of patient prognosis with PU.1 and JDP2 to provide potential novel prognostic/diagnostic markers in MDS.
Authors: Simpson Rachael , Goddard Alan , Lally James , Simmonds Matthew , Rinaldi Ciro Roberto
Published: September 2018

e18558

Background: PU.1 is a key transcription factor in haematopoiesis that plays important roles in various haematological malignancies. Previously, significant down-regulation of PU.1 has been reported in high risk myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) patients. Methods: To clarify PU.1 molecular function we investigated the gene expression of PU.1 and JDP2 (c-Jun dimerization protein-2), a member of the activating protein-1 family located downstream of PU.1, in bone marrow from 12 MDS patients stratified according to IPSS-R score (6-low, 3-intermediate, 3-high risk), 1 AML patient and 10 normal controls. Samples were enriched for the mononuclear fraction by Ficoll separation. Total RNA was extracted and analysed by Real Time PCR for PU.1 and JDP2 expression relative to the housekeeping gene GAPDHusing the 2-ΔΔCT method. Results: We revealed both PU.1 and JDP2 are down regulated in MDS. In addition, our data suggests that PU.1 and JDP2 expression inversely correlates with disease, with expression of these genes consistently reducing according to IPSS-R groups. Furthermore, a positive correlation of PU.1 and JDP2expression < R = O.9333, s = 0.0004 > , provides additional evidence that suppression of JDP2 by PU.1 could contribute to the pathogenesis of AML. Notably, PU.1 and JDP2 do not correlate to the same extent in normal HSCs, indicating that cofactors are required for PU.1 to exert its JDP2-regulating function and that such cofactors are not present under normal conditions. To confirm that JDP2 suppression is a direct result of reduced PU.1 we performed PU.1-knockdown in K562 cells stably expressing PU.1 short interfering RNAs versus control cells. These analyses reveal only a partial reduction in JDP2 expression when analysed by RT-PCR and Western blot, suggesting a more complex regulatory mechanism. Additionally, both PU.1 and JDP2 expression was recovered by treatment with azacitidine, which is routinely used to treat MDS, suggesting an involvement in treatment response. Conclusions: PU.1 and JDP2 expression correlates with patients prognosis highlighting a potential role as new diagnostic and prognostic markers in MDS.
Interaction between ring sideroblasts and treatment with hypomethylating agents (HMA) in patients with refractory anemia with ring sideroblasts.
Authors: Nanah Rama , Zblewski Darci , He Rong , Nguyen Phuong L. , Gangat Naseema , Begna Kebede , Elliott Michelle A. , Hogan William J. , Patnaik Mrinal , Litzow Mark Robert , Al-Kali Aref
Published: September 2018

e18559

Background: Myelodysplastic syndromes (MDS) are a group of myeloid neoplasms defined by ineffective hematopoiesis, dysplastic morphologic features, and variable risks of progression to acute myeloid leukemia (AML). Refractory anemia with ring sideroblasts (RARS) is a subtype of MDS defined by < 5% basts and > 15% ring sideroblasts (per 2008 WHO). Because RARS is a lower risk disease which does not frequently require HMA therapy, very little is known about the effects of HMA on RARS. Methods: A total of 1325 MDS patients’ data from 1993-2016 at Mayo Clinic were reviewed after appropriate IRB approval was obtained. All cases had their bone marrow slides reviewed at our center. Patients were considered for our study if they received HMA for their RARS. Response was identified based on MDS IWG 2006 criteria. Prognostic factors were analyzed by univariate and multivariate analyses. Survival estimates were calculated using Kaplan-Meier curves. Results: 168 of the initial 1325 patient were RARS (14%); only 14 (8%) were treated with HMA. Median age was 72 years (range, 51-85); half were males, with median overall survival of 91.3 months. The median number of ring sideroblasts (RS) at diagnosis was 40% (range 10-85%). Of the 14 patients, 11 (79%) received azacitidine (AZA), 2 (14%) decitabine (DAC) and one received both (7%). The median number of cycles for AZA was 6.5 (range, 2-28) vs 6 cycles for DAC (range, 1-24). Of the 14 patients receiving HMA, only 3 responded (21%) achieving hematologic improvement. All 3 responders received AZA. 6 of the 14 RARS patients (43%) had their bone marrow biopsy repeated after HMA therapy, 3 of whom were among the responders to AZA therapy and 3 were non-responders. In 5 patients, ring sideroblasts decreased after HMA therapy by a median of 15% (range 0-80); they remained the same in 1 patient; one patient who had developed AML had a decrease in RS from 85% to 5%. Conclusions: RARS is a low-risk subtype of MDS that is infrequently treated with HMA (8% in our study). Response rate to HMA (21%) was inferior to known rates in MDS. HMA therapy seems to decrease the number of ring sideroblasts irrespective of response. RARS patients should be treated on clinical trials if available.
Response to induction or hypomethylating agent therapy among patients with myeloproliferative neoplasms progressing to accelerated or leukemic phase.
Authors: Hobbs Gabriela , Lombardi Story Jennifer , Blaney Maura A. , Amrein Philip C. , Fathi Amir Tahmasb , Brunner Andrew Mark
Published: September 2018

e18561

Background: Post-myeloproliferative neoplasm (MPN) acute myeloid leukemia (AML) and accelerated phase disease (AP) are associated with poor outcomes; the optimal management of these patients at transformation is uncertain in the era of widely available molecular testing. Methods: We performed a retrospective analysis of adult patients with MPN that had transformed into AML (greater than 20% blasts) or AP (10-19% blasts and dysplastic features) from 2006-2016. Patients were 18 or older at AML/AP diagnosis. Outcomes were described by Kaplan and Meier and the Log rank test. Results: We identified 30 patients, with transformed MPN into AML (n = 23) or AP (n = 7), including one patient in AP at presentation. Most were male (73%). Disease evolved from polycythemia vera (n = 6), essential thrombocythemia (n = 11), primary myelofibrosis (n = 9) and other MPN diagnoses (MPN/MDS overlap, n = 3; MPN NOS, n = 1). The median age at MPN diagnosis was 67.5 yrs, and at transformation 72 yrs. The median time from MPN diagnosis to transformation was 5.6 yrs (range 0.3-36.0). 12 patients had JAK2 V617F testing both at MPN diagnosis and AML diagnosis; 6 had JAK2 mutations at both time points and 2 lost JAK2 at transformation. At AML/AP transformation, 11 patients had NGS mutation testing; the most common somatic mutations were NRAS (5/11), RUNX1 (2/11), and SRSF2 (2/11). 20 patients received treatment outside of supportive care. Of these, 8 achieved a CR or CRi (40%; 7/10 with induction and 1/8 with HMA). The only HMA response was on a trial of HMA+SGN33a. The median survival from AML/AP transformation was 5.8 mo. Of treated patients, median survival was 7.4 mo; 37% of treated patients were alive at 1 yr. Nine patients (31%; 7 with AML and 2 with AP) underwent allogeneic transplantation; 2 relapsed during follow-up. 74% of patients treated with allo-HCT were alive at 1 yr after AML/AP transformation. Conclusions: AML or accelerated phase disease arising out of MPN carries a dismal prognosis. HMA monotherapy had little efficacy in this group (0/7 achieved remission). Allogeneic transplantation offered the best chance of survival at one year, but fewer than a third of patients were able to proceed to transplant.
The emotional journey among caregivers of patients with leukemia: The caregivers’ perspective using social media listening.
Authors: Gabriel Susan , Phillips Kerri , Slater Mary Ann , Zhou Jifang , Pathak Ashutosh K. , Lee Lulu K.
Published: September 2018

e18568

Background: The burden of cancer has largely focused on the patient. However, caregivers also experience considerable burden. The study's aim was to use social media posts to better understand the emotional journey of caregivers who provide care for patients with leukemia from their own perspective. Methods: Publicly available social media posts (in English) mentioning chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), and acute promyelocytic leukemia (APL) from blogs, discussion boards, and Facebook were collected and linguistically analyzed. Results: A total of 145 social media posts by CML caregivers, 149 posts by CLL caregivers, and 65 posts by APL caregivers were analyzed. Common themes emerged among CML, CLL, and APL caregivers as they journeyed from pre-diagnosis, to diagnosis, and to survivorship alongside their loved ones. At the pre-diagnosis phase, caregivers expressed uneasiness or worry about the symptoms their loved ones were experiencing. Additionally, caregivers were often frustrated with doctors because they felt that their loved ones’ symptoms were ignored, which led to a delay in diagnosis. Once the diagnosis was confirmed, caregivers were shocked and scared. Further, caregivers were desperate for information on the disease and what the future would hold. During the survivorship phase of the journey, an amalgam of complex positive and negative emotions emerged among caregivers. Caregivers can become obsessed with finding ways to treat their loved ones, including use of alternative medicine. Caregivers experienced both positive (a more “enriched relationship”) and negative (felt alone or pushed away) relationship changes. Many caregivers were proud of their loved ones’ remission and felt triumphant. Caregivers felt a sense of gratitude toward doctors, friends, family, and social media sites for their support. Conclusions: Caregivers of CML, CLL, and APL patients experience a gamut of emotions at every stage of the disease. Additionally, the relationship between caregivers and loved ones can be negatively affected. Findings suggest that relationship counseling and social support groups could potentially relieve some caregiver burden.
Differences in outcomes between patients whose relapse was diagnosed radiologically versus clinically after autologous transplantation for relapsed/refractory diffuse large B-cell lymphoma.
Authors: Mohyuddin Ghulam Rehman , Clark Ashley Elizabeth , Shune Leyla Osman , Lin Tara L. , Abhyankar Sunil H. , Dias Ajoy , Dunavin Neil , McGuirk Joseph , Ganguly Siddhartha , Singh Anurag Kumar
Published: September 2018

e19001

Background: Surveillance scans performed after autologous stem cell transplant (AutoSCT) for patients with relapsed/refractory (RR) diffuse large B Cell lymphoma (DLBCL) have no proven survival benefit. We studied survival differences among patients with RR DLBCL post AutoSCT whose recurrences were detected on clinical history and exam, versus those detected on routine surveillance scan. Methods: We retrospectively identified 139 patients from our institutional database with DLBCL who underwent AutoSCT from 2000 to 2014. All patients had surveillance scans performed at days 100, 180 and at 1-year post AutoSCT. Results: Among the 139 patients with RR DLBCL that underwent AutoSCT, 37 relapsed, of which 21 were clinical and 16 radiological. There were no statistically significant differences in patient characteristics, although more patients in the clinical cohort had extra-nodal and bulky disease (Table 1). The median time to progression was 167 days for the clinical cohort and 565 days for the radiological cohort (p= 0.03). Median follow-up was 587 days for the clinical cohort and 1503 days for the radiological cohort (p=0.002). Median overall survival (OS) was 587 days for the clinical cohort, and was not reached for the radiological cohort (p=0.006). Conclusions: In our review, most patients with relapsed DLBCL after AutoSCT were diagnosed clinically. Patients whose relapse was diagnosed clinically were likely to be detected earlier and have a shorter OS. Our data indicates that patients with aggressive disease may be detected when clinically relevant, regardless of scanning. Given the known risks of excess radiation exposure, our data suggests that routine scanning may not be necessary in the majority of patients with DLBCL following AutoSCT. [Table: see text]
Dimethyl sulfoxide (DMSO) cryopreserved stem cell infusion-related seizures: A single institution experience.
Authors: Attarian Shirin , Janakiram Murali , Ezzati Ali , Gucalp Rasim A.
Published: September 2018

e19002

Background: An essential step in hematopoietic stem cell transplantation (HSCT) is the cryopreservation of stem cells in DMSO. Neurologic complications related to DMSO are well known and include strokes, seizures, encephalopathy and coma, but risk factors have not been identified. We focused on seizures as a DMSO-related neurologic adverse event. Methods: From 1/2006 to 4/2016, 982 cases of HSCT were reviewed. We identified neurologic adverse events within 24h of stem cell infusion (SCI). Results: 16 cases of neurologic adverse events occurred, including transient paresthesias (2), altered mental status (5), syncope (3), stroke (1), and 5 seizures. The mean age of the patients (pt) was 64.2 years (range 52-79), with 2 females and 3 males. All 5 pts developed seizures during SCI. 4 pts had conditioning: 2 Melphalan, 1 BEAM and 1 Bu/Cy. One pt received SCI without conditioning as a last resort to treat severe neutropenia and overwhelming sepsis. Of these 5 cases, one had a prior history of seizures in the setting of primary CNS lymphoma and 1 had a prior history of stroke, and 1 pt had an acute stroke during SCI. These 3 cases had abnormal EEG with a potential focus for seizure. Conclusions: Understanding the predisposing factors for developing seizures with SCI will improve patient safety and outcomes. History of structural brain lesions or seizure may be a risk factor for development of seizures. Applying prophylactic strategies, such as DMSO removal or prophylactic antiepileptic medications prior to SCI may decrease the risk of seizures. [Table: see text]
Additional value of quantitative expression of ZAP-70 and CD38 for prognostic factors in chronic lymphocytic leukemia.
Authors: Klabusay Martin , Hrabcakova Viera , Coupek Petr , Trbusek Martin , Pevna Michaela
Published: September 2018

e19006

Background: Chronic lymphocytic leukemia (CLL) has heterogeneous clinical course. Identification of prognostic markers is important for proper management of disease. Cytogenetics, IgVH mutation status, TP53 functional status, CD38, ZAP-70 and CD49d expression are accepted prognostic factors in CLL. ζ-chain-associated protein kinase 70 (ZAP-70) is associated with disease progression. However, measurement of ZAP-70 and CD38 expression relies on qualitative flow cytometry. Authors tested hypothesis whether quantitative analysis of markers can improve information about prognosis of CLL. Methods: 217 CLL patients were included; diagnosis was made from peripheral blood by morphology and immunophenotyping by flow cytometry with common antibodies. Expressions of intracellular ZAP-70 and surface CD38 were measured using quantitative fluorescence cytometry. Standardized fluorescent microparticles were used to quantify molecules of equivalent soluble fluorochrome (MESF units). Analysis of rearrangement of the IgVH gene was performed according to the European recommendation. Deletions at 11q22-q23 ( ATM), 17p13 ( TP53), 13q34 ( RB1) loci and trisomy of chromosome 12 were detected by I-FISH. Results: Patients’ ages ranged from 33 to 86 years and included all Rai stages. Expression of ZAP-70 ranged from 546 to 5,955 MESF, CD38 from 1,886 to 31,619 MESF. 48% patients embodied mutated and 52% unmutated IgVH status. In cytogenetics, del(13q) was detected in 59%, trisomy 12 in 13%, del(11q) in 21%, and del(p53) in 8% of patients. IgVH (in %) was plotted against ZAP-70 (in MESF) and patients were divided into high (HR) and low risk (LR) groups by cluster analysis based on Kaplan-Meier overall survival curves. Patients in HR group had significantly poorer prognoses (p = 0.0001) than those in LR group. When patients from HR group were clustered according to CD38 expression, very high risk (VHR) group with high CD38 and significantly worse prognosis (p = 0.035) was identified. Conclusions: We have demonstrated that quantitative ZAP-70 and CD38 expressions cannot replace IgVH analysis, but, contrary to that, addition of quantitative data can further specify prognoses of patients with CLL.