Assessment of individual molecular response in chronic myeloid leukemia patients with atypical BCR-ABL1 fusion transcripts: recommendations by the EUTOS cooperative network.

PURPOSE: Approximately 1-2% of chronic myeloid leukemia (CML) patients harbor atypical BCR-ABL1 transcripts that cannot be monitored by real-time quantitative PCR (RT-qPCR) using standard methodologies. Within the European Treatment and Outcome Study (EUTOS) for CML we established and validated robust RT-qPCR methods for these patients. METHODS: BCR-ABL1 transcripts were amplified and sequenced to characterize the underlying fusion. Residual disease monitoring was carried out by RT-qPCR with specific primers and probes using serial dilutions of appropriate BCR-ABL1 and GUSB plasmid DNA calibrators. Results were expressed as log reduction of the BCR-ABL1/GUSB ratio relative to the patient-specific baseline value and evaluated as an individual molecular response (IMR). RESULTS: In total, 330 blood samples (2-34 per patient, median 8) from 33 CML patients (19 male, median age 62 years) were analyzed. Patients expressed seven different atypical BCR-ABL1 transcripts (e1a2, n = 6; e6a2, n = 1; e8a2, n = 2; e13a3, n = 4; e14a3, n = 6; e13a3/e14a3, n = 2; e19a2, n = 12). Most patients (61%) responded well to TKI therapy and achieved an IMR of at least one log reduction 3 months after diagnosis. Four patients relapsed with a significant increase of BCR-ABL1/GUSB ratios. CONCLUSIONS: Characterization of atypical BCR-ABL1 transcripts is essential for adequate patient monitoring and to avoid false-negative results. The results cannot be expressed on the International Scale (IS) and thus the common molecular milestones and guidelines for treatment are difficult to apply. We, therefore, suggest reporting IMR levels in these cases as a time-dependent log reduction of BCR-ABL1 transcript levels compared to baseline prior to therapy.

Clinical, social, and psycho-oncological needs of adolescents and young adults (AYA) versus older patients following hematopoietic stem cell transplantation.

PURPOSE: To analyze demand for information and advice as well as medical, psychological, and social needs of adolescents and young adults (AYAs) and older patients (non-AYA) after hematopoietic stem cell transplantation (HSCT). METHODS: A questionnaire was sent to 100 HSCT recipients comprising n = 50 AYAs (aged 19-39 years) and n = 50 non-AYAs (> 39 years). The questionnaire covered the categories: (a) patient characteristics; (b) need for advice, on medical, psychological, and social care topics; (c) medical, psychological, and social needs, and (d) preferred forms and channels of information. RESULTS: The return rate was 65%. 62.5% of patients indicated medical needs; 41.1% psychological needs, and 64.9% had needs concerning social issues. Among medical aspects, aftercare was important to both groups. Nutrition was of highest interest for AYA, while non-AYAs identified fatigue and vaccination as their most pressing concerns. Body shape/sexuality and relaxation techniques were the most common psychological issues for AYA, while coping strategies were important for both cohorts. Family, relationship and friends were of less interest in both groups. Rehabilitation and premature retirement were of highest interest for both cohorts. The preferred mode of communicating advice was one-to-one conversation in a quiet environment as opposed to informational sessions. CONCLUSION: Despite well-established aftercare programs following HSCT, many patients describe unmet needs regarding medical, psychological, and social policy issues. AYA and non-AYA differ in informational needs after HSCT, and, therefore, age-appropriate informational materials are necessary. Particularly AYA may profit from information covering body-shape/sexuality and nutrition, while both cohorts require information covering coping strategies and aftercare.

Laying the foundation for genomically-based risk assessment in chronic myeloid leukemia.

Outcomes for patients with chronic myeloid leukemia (CML) have substantially improved due to advances in drug development and rational treatment intervention strategies. Despite these significant advances there are still unanswered questions on patient management regarding how to more reliably predict treatment failure at the time of diagnosis and how to select frontline tyrosine kinase inhibitor (TKI) therapy for optimal outcome. The BCR-ABL1 transcript level at diagnosis has no established prognostic impact and cannot guide frontline TKI selection. BCR-ABL1 mutations are detected in ~50% of TKI resistant patients but are rarely responsible for primary resistance. Other resistance mechanisms are largely uncharacterized and there are no other routine molecular testing strategies to facilitate the evaluation and further stratification of TKI resistance. Advances in next-generation sequencing technology has aided the management of a growing number of other malignancies, enabling the incorporation of somatic mutation profiles in diagnosis, classification, and prognostication. A largely unexplored area in CML research is whether expanded genomic analysis at diagnosis, resistance, and disease transformation can enhance patient management decisions, as has occurred for other cancers. The aim of this article is to review publications that reported mutated cancer-associated genes in CML patients at various disease phases. We discuss the frequency and type of such variants at initial diagnosis and at the time of treatment failure and transformation. Current limitations in the evaluation of mutants and recommendations for future reporting are outlined. The collective evaluation of mutational studies over more than a decade suggests a limited set of cancer-associated genes are indeed recurrently mutated in CML and some at a relatively high frequency. Genomic studies have the potential to lay the foundation for improved diagnostic risk classification according to clinical and genomic risk, and to enable more precise early identification of TKI resistance.

Results of the European survey on the assessment of deep molecular response in chronic phase CML patients during tyrosine kinase inhibitor therapy (EUREKA registry).

PURPOSE: The advent of tyrosine kinase inhibitor (TKI) therapies has revolutionized the treatment of chronic myeloid leukemia (CML). The European LeukemiaNet (ELN) recommends quantification of BCR-ABL1 transcripts by real-time quantitative PCR every 3 months during TKI treatment. Since a proportion of patients in deep molecular response (DMR: MR4, MR4.5, MR5) maintain remission after treatment stop, assessment of DMR is crucial. However, systematically collected molecular data, monitored with sensitive standardized assays, are not available outside clinical trials. METHODS: Data were collected on the standardized assessment of molecular response in the context of real-life practice. BCR-ABL1 transcript levels after > 2 years of TKI therapy were evaluated for DMR by local laboratories as well as standardized EUTOS laboratories. Since standardized molecular monitoring is a prerequisite for treatment discontinuation, central surveillance of the performance of the participating laboratories was carried out. RESULTS: Between 2014 and 2017, 3377 peripheral blood samples from 1117 CML patients were shipped to 11 standardized reference laboratories in six European countries. BCR-ABL1 transcript types were b3a2 (41.63%), b2a2 (29.99%), b2a2/b3a2 (3.58%) and atypical (0.54%). For 23.72% of the patients, the initial transcript type had not been reported. Response levels (EUTOS laboratory) were: no MMR, n = 197 (6.51%); MMR, n = 496 (16.40%); MR4, n = 685 (22.64%); MR4.5, n = 937 (30.98%); MR5, n = 710 (23.47%). With a Cohen's kappa coefficient of 0.708, a substantial agreement between EUTOS-certified and local laboratories was shown. CONCLUSIONS: Multicenter DMR assessment is feasible in the context of real-life clinical practice in Europe. Information on the BCR-ABL1 transcript type at diagnosis is crucial to accurately monitor patients' molecular response during or after TKI therapy.

Information needs and usage of complementary and alternative medicine in members of a German self-help group for gastrointestinal stroma tumours, sarcoma, and renal cancer.

OBJECTIVE: 40-50% of German cancer patients use some method of complementary and alternative medicine (CAM) and both patients and doctors often feel insufficiently informed. We examined the information-seeking behaviour and satisfaction with information on patients' interest in CAM and the therapy decision. DESIGN AND SETTING: An anonymous, voluntary online survey was conducted among the members of "Das Lebenshaus e.V." (House of Life), a decentralized support group for patients with gastrointestinal stroma tumours (GIST), sarcoma, and renal cancer. Data was collected from March 2015 until January 2016 using closed questions with multiple choice if appropriate and in case of ranking, a 5-point Likert scale. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Correlations between CAM interest, usage, information needs, sources of information and therapy decision were calculated using chi square tests for univariate analyses. RESULTS: Overall, 431 patients took part in our survey, thus return rate was 19.6%. 43.9% (n = 189) of the participants were female, 37.1% (n = 160) were male, 19.0% (n = 82) did not respond. Mean age was 59.8 years. The most common tumours were GIST (346%, n = 149), renal cancer (22.3%, n = 96) and sarcoma (20.0%, n = 86). 55.2% (n = 138) of the respondents were patients undergoing treatment, 19.7% (n = 85) were after treatment, 2.6% (n = 11) were relatives and 4.4% (n = 19) others while 18.1% (n = 78) did not respond. A total of 81.8% (n = 337) of the participants were interested in CAM, but only 44.7% (n = 152) used one of the methods. Women were more commonly interested in CAM (87.2%, n = 163) and used it more often: 53.0% (n = 97) vs. 36.2% (n = 55). Information about CAM was considered important by 85.5% (n = 360) and the Internet was the most commonly used source for information about CAM (77.9%, n = 205). However, 61.4% (n = 233) were not satisfied with the information received about CAM, especially from doctors and hospitals. Patients unsatisfied with the information they had formally received about the course of their disease significantly more often used CAM (p = 0.029). Users would also make the therapy decision by themselves more often (p = 0.036). Nearly a fifth did not disclose their use to a doctor. CONCLUSIONS: Dissatisfaction with received information reveals a strong need for scientific information to be available to both patients and doctors. Physicians should get special training about CAM. As the Internet is an important source, high-quality and scientific information should be portrayed on webpages easily accessible to patients.

Modelling cost effectiveness of horse antithymocyte globulin for treating severe aplastic anaemia in Germany.

Acquired severe aplastic anaemia (AA) is a serious condition caused by immune-triggered bone marrow failure. For patients not eligible for bone marrow transplantation, treatment of choice is immunosuppression by a combined treatment with antithymocyte globulin (ATG) and cyclosporine. The debate on treatment optimization in AA is focused on conflicting data regarding ATG preparations from horse (h-ATG) versus rabbit (r-ATG), recently favouring h-ATG. H-ATG has been withdrawn from the European market in 2007. Reimbursement for imported preparations from outside Europe is frequently denied in negotiations with statutory health insurance companies. This raises the question of whether h-ATG is cost effective and a sensible investment with regard to healthcare budgets as well as patient health. We modelled the cost effectiveness of r-ATG versus h-ATG based on a recent randomized trial and cost data provided by the hospital pharmacy of Jena University Hospital. We calculated the amount of life years gained and the average incremental costs per life year gained when comparing h-ATG and r-ATG. Our calculations revealed average incremental costs per life year gained of 11,033.80 for the examined patient population treated with h-ATG when compared to r-ATG. Assuming a cost effectiveness threshold of 25,000-35,000 per life year gained, our calculations demonstrate cost effectiveness of h-ATG as compared to r-ATG.

Educational session: managing chronic myeloid leukemia as a chronic disease.

Elucidation of the pathogenesis of chronic myeloid leukemia (CML) and the introduction of tyrosine kinase inhibitors (TKIs) has transformed this disease from being invariably fatal to being the type of leukemia with the best prognosis. Median survival associated with CML is estimated at > 20 years. Nevertheless, blast crisis occurs at an incidence of 1%-2% per year, and once this has occurred, treatment options are limited and survival is short. Due to the overall therapeutic success, the prevalence of CML is gradually increasing. The optimal management of this disease includes access to modern therapies and standardized surveillance methods for all patients, which will certainly create challenges. Furthermore, all available TKIs show mild but frequent side effects that may require symptomatic therapy. Adherence to therapy is the key prerequisite for efficacy of the drugs and for long-term success. Comprehensive information on the nature of the disease and the need for the continuous treatment using the appropriate dosages and timely information on efficacy data are key factors for optimal compliance. Standardized laboratory methods are required to provide optimal surveillance according to current recommendations. CML occurs in all age groups. Despite a median age of 55-60 years, particular challenges are the management of the disease in children, young women with the wish to get pregnant, and older patients. The main challenges in the long-term management of CML patients are discussed in this review.

Results of comprehensive geriatric assessment effect survival in patients with malignant lymphoma.

PURPOSE: The prevalence of elderly and comorbid patients (pts) with malignant lymphoma (ML) will steadily increase in future. Elderly patients comprise a heterogeneous population. Comprehensive geriatric assessment (CGA) is an established diagnostic tool in geriatric medicine. However, the prognostic value in patients with ML is unclear. We sought to establish a relationship between results of CGA and survival time in patients with ML. METHODS: Newly diagnosed patients with ML and indication for chemotherapeutical treatment were prospectively recruited in an observational trial. In addition to usual diagnostic work up, a CGA including activities of daily living (ADL), instrumental activities of daily living (IADL) and comorbidities was performed. Association of patients' characteristics and results of CGA with survival were analysed according to Kaplan-Meier method and in a multivariate Cox-regression analysis. RESULTS: About 143 patients were included, median age was 63 years, 63 patients were women. Median follow-up of surviving patients was 62 months. Sixty-six patients died within this time. Advanced age, poor Karnofsky performance status, dependence in ADL and IADL and presence of severe comorbidity were significantly associated with shorter survival time. In a Cox-regression analysis, IADL (HR 2.1; 95% CI 1.1-3.9) and comorbidity (HR 1.9; 95% CI 0.9-3.9) were independent and strongest associated with survival time. CONCLUSION: Results of CGA, such as IADL and comorbidities, are prognostic variables for survival of patients with ML. Results should be validated in homogeneous clinical groups and if confirmed included in diagnostic and therapeutic algorithm.

Phospho-CRKL monitoring for the assessment of BCR-ABL activity in imatinib-resistant chronic myeloid leukemia or Ph+ acute lymphoblastic leukemia patients treated with nilotinib.

Actual BCR-ABL kinase inhibition in vivo as determined by phospho-CRKL (pCRKL) monitoring has been recognized as a prognostic parameter in patients with chronic myelogenous leukemia treated with imatinib. We report a biomarker sub-study of the international phase I clinical trial of nilotinib (AMN107) using the established pCRKL assay in imatinib-resistant chronic myeloid leukemia or Ph+ acute lymphoblastic leukemia. A minimum dose (200 mg) required for effective BCR-ABL inhibition in imatinib resistant/intolerant leukemia was determined. The pre-clinical activity profile of nilotinib against mutant BCR-ABL was largely confirmed. Substantial differences between peripheral blood baseline pCRKL/CRKL ratios were observed when comparing chronic myeloid leukemia with Ph+ acute lymphoblastic leukemia. Finally, rapid BCR-ABL-reactivation shortly after starting nilotinib treatment was seen in acute lymphoblastic leukemia patients with progressive disease carrying the P-loop mutations Y253H, E255K, or mutation T315I. Monitoring the actual BCR-ABL inhibition in nilotinib treated patients using pCRKL as a surrogate is a means to establish effective dosing and to characterize resistance mechanisms against nilotinib.