Barbara Deschler

Acute Myeloid Leukemia: Epidemiology and Etiology

Acute myeloid leukemias (AMLs) are infrequent, yet highly malignant neoplasms responsible for a large number of cancer‐related deaths. The incidence has been near stable over the last years. It continuously shows 2 peaks in occurrence in early childhood and later adulthood. With an incidence of 3.7 per 100,000 persons and an age‐dependent mortality of 2.7 to nearly 18 per 100,000 persons, there is a rising awareness in the Western world of AMLs special attributes resulting from an ever‐aging population. To objectively describe epidemiologic data on this patient population, recent publications were evaluated to make transparent the current trends and facts. A review of the literature is presented, reflecting highlights of current research with respect to AML etiology. To estimate outcome and discuss informed treatment decisions with AML patients of different age groups and different biologic risk categories, it is mandatory to consider that the outcome results reported in clinical trials were until now heavily biased toward younger patients, whereas the overall dismal prognosis documented in population‐based studies most likely reflects the exclusion of older patients from aggressive treatment. The etiology for most cases of AML is unclear, but a growing knowledge concerning leukemogenenic agents within chemotherapy regimens for other malignancies is already available. This includes specific associations of the most frequent balanced translocations in AML, including the “good‐risk” abnormalities comprised by the core binding factor leukemias (i.e., AML with the translocation (8;21) and inversion of chromosome 16, and acute promyelocytic leukemia with the translocation (15;17)). In contrast to these genetic alterations, epigenetic lesions, e.g., promoter silencing by hypermethylation of the p15/INK4b and other genes, are increasingly recognized as important in the pathogenesis of AML. Cancer 2006.

Parameters detected by geriatric and quality of life assessment in 195 older patients with myelodysplastic syndromes and acute myeloid leukemia are highly predictive for outcome

Myelodysplastic syndromes and acute myeloid leukemia exemplify the complexity of treatment allocation in older patients as options range from best supportive care, non-intensive treatment (e.g. hypomethylating agents) to intensive chemotherapy/hematopoietic cell transplantation. Novel metrics for non-disease variables are urgently needed to help define the best treatment for each older patient. We investigated the feasibility and prognostic value of geriatric/quality of life assessments aside from established disease-specific variables in 195 patients aged 60 years or over with myelodysplastic syndromes/acute myeloid leukemia. These patients were grouped according to treatment intensity and assessed. Assessment consisted of eight instruments evaluating activities of daily living, depression, mental functioning, mobility, comorbidities, Karnofsky Index and quality of life. Patients with a median age of 71 years (range 60-87 years) with myelodysplastic syndromes (n=63) or acute myeloid leukemia (n=132) were treated either with best supportive care (n=47), hypomethylating agents (n=73) or intensive chemotherapy/hematopoietic cell transplantation (n=75). After selection of variables, pathological activities of daily living and quality of life/fatigue remained highly predictive for overall survival in the entire patient group beyond disease-related risk factors adverse cytogenetics and blast count of 20% or over. In 107 patients treated non-intensively activities of daily living of less than 100 (hazard ratio, HR 2.94), Karnofsky Index below 80 (HR 2.34) and quality of life/’fatigue’ of 50 or over (HR 1.77) were significant prognosticators. Summation of adverse features revealed a high risk of death (HR 9.36). In-depth evaluation of older patients prior to individual treatment allocation is feasible and provides additional information to standard assessment. Patients aged 60 years or over with newly diagnosed myelodysplastic syndromes/acute myeloid leukemia and impairments in activities of daily living, Karnofsky Index below 80%, quality of life/’fatigue’ of 50 or over, are likely to have poor outcomes.

Extramedullary vs medullary relapse after autologous or allogeneic hematopoietic stem cell transplantation (HSCT) in multiple myeloma (MM) and its correlation to clinical outcome.

Summary:Risk-adapted treatment of multiple myeloma (MM) includes autologous (auto-) and allogeneic (allo-) hematopoietic stem cell transplantation (HSCT). Case reports on extramedullary (EM) compared to bone marrow (BM) relapse after HSCT suggest a dismal prognosis. We compared the outcome of 78 MM patients relapsing after auto- (group A: n=53) or allo- (group B: n=25) HSCT, stratified into BM (64 patients) vs EM (14 patients) relapse. The relapse-specific groups were also compared with respect to risk factors, including age, β2-microglobulin, pretreatment, cytogenetics and stage. EM relapse sites were lungs (5), soft tissue (4), pericardium (2), bone (1), skin (1) and CNS (1). As of May 2004, the overall (OS) and progression-free (PFS) survival after HSCT in patients relapsing from EM sites was not significantly different from BM relapse patients, both after auto- and allo-HSCT. Although MM patients relapsing from EM sites after allo-HSCT used to be regarded as having few therapeutic options, we observed encouraging responses to donor lymphocyte infusions (DLI). Treatment responses to DLIs were observed in 5/9 (56%) BM relapse patients, and in 3/4 (75%) EM relapse patients. These observations suggest that EM relapse after HSCT is common and needs an individualized diagnostic and therapeutic approach in MM during clinical follow-up after HSCT.

Detection of renal impairment as one specific comorbidity factor in multiple myeloma: multicenter study in 198 consecutive patients

Objectives:  Comorbidity factors have been reported in cancer patients to predict progression free survival (PFS) and overall survival (OS). Renal impairment (RI) is postulated as one negative prognostic factor in multiple myeloma (MM). The study aim was to detect the best way to define RI and the impact of different RI stages on MM outcome.

Valuation of transfusion-free living in MDS: results of health utility interviews with patients

BackgroundThis study measured how myelodysplastic syndrome (MDS) patients value transfusion independence (TI), reduced transfusions (RT) and transfusion-dependence (TD) using health utility assessment methodology.Methods47 MDS patients were interviewed, US (n = 8), France (n = 9), Germany (n = 9) and the UK (n = 21), to elicit the utility value of TI, RT and TD. Health states were developed based on literature; patient forum discussions; and were validated by a hematologist. Face-to-face interviews used the feeling thermometer Visual Analogue Scale (VAS) and the Time Trade-Off (TTO) method to value the health states on a 0 (dead) to 1 (perfect health) scale. Socio-demographic, clinical, and quality-of-life (EQ-5D) characteristics were surveyed to describe the patient sample.Results and DiscussionThe mean age was 67 years (range: 29-83); 45% male, 70% retired; 40% had secondary/high school education, or higher (32%), and 79% lived with family, a partner or spouse, or friends. The mean time from MDS diagnosis was 5 years (range:1-23). Most patients (87%) received previous transfusions and 49% had received a transfusion in the last 3 months. Mean EQ-5D index score was 0.78; patients reported at least some problem with mobility (45%), usual activities (40%), pain/discomfort (47%), and anxiety/depression (34%). Few patients had difficulty understanding the VAS (n = 3) and TTO (n = 4) exercises. Utility scores for TI were higher than for RT (0.84 vs. 0.77; p < 0.001) or TD (0.84 vs. 0.60; p < 0.001). Three patients rated TD worse than dead. Corresponding VAS scale scores were 78 vs. 56; (p < 0.001), and 78 vs. 31 (p < 0.001), respectively.ConclusionPatients value TI, suggesting an important role for new treatments aiming to achieve greater TI in MDS. These results can be used in preference-based health economic evaluation of new MDS treatments, such as in future cost-utility studies.

Geriatric assessment and quality of life in older patients considered for allogeneic hematopoietic cell transplantation: a prospective risk factor and serial assessment analysis

Allogeneic hematopoietic cell transplantation (alloHCT) in older patients requires the weighing of risks and benefits for this potentially curative treatment while facing age-related limitations. Comprehensive geriatric and quality of life (EORTC QLQ C-30) assessements (CGA/QOL) in addition to disease-specific data were obtained in 108 consecutive patients (≥60 years) pre-HCT, at day +30, +100, and +180. Median follow-up of 106 patients alive at alloHCT was 43.5 months, median age 66 years (range 60–78). Eighty-six (81.2%) had advanced disease risk at HCT and 99 (91.7%) patients received reduced intensity conditioning (RIC). Median PFS was 13.4 months with 38.3% (95% CI: 28.6–47.4) alive and in remission at 2 years; median OS was 15.6 months with 43.9% (95% CI: 34.3–53.4) alive at 2 years. Prognostic factors for PFS were: age: HR 1.084 (95% CI: 1.032–1.137, p = 0.0011); HCT-CI: HR 1.13 (95% CI: 1.001–1.274, p = 0.048); for OS: age: HR 1.08 (95% CI: 1.031–1.139, p = 0.0017), Karnofsky Index: HR 0.97 (95% CI: 0.954–0.996, p = 0.02); EORTC QLQ C–30 fatigue: HR 1.09 (95% CI: 1.004–1.185, p = 0.039); Up-and-Go: HR 3.26 (95% CI: 1.001–10.6, p = 0.049). Follow-up assessments as time-dependent covariates were highly prognostic for OS and PFS. CGA/QOL confer additional prognostic utility in older alloHCT recipients.

Striking complete remission after interferon-α for secondary recurrent non-Hodgkin’s lymphoma but rare interferon-induced side effects

Interferon (IFN) treatment is a therapeutic option in the treatment of non-Hodgkin’s lymphoma (NHL). Although randomized trials have failed to show significant differences in progression-free and overall survival (OS) with IFN compared to placebo after peripheral blood stem cell transplantation (PBSCT) as well as standard therapy for NHL, anecdotal case reports have documented impressive results in selected patients. With this case report, we demonstrate an astounding success of IFN therapy given in the treatment of a young man with second relapse after two consecutive autologous PBSCTs and abdominal irradiation. With occurrence of multiple lymph node enlargements despite this intensive treatment, he received IFN and obtained a well-documented complete remission (CR). Yet, treatment with IFN always has to be considered in the context of its significant side effect profile, which can have considerable impact on the patient’s quality of life as illustrated in this case report.

Patients Reported Outcome/Quality of Life

Measures of patient-reported outcomes and quality of life in people with hematological malignancies resemble the subjective and thus highly personal aspects of what impacts life most when facing a malignant disease. They are of importance to both, the patients as well as their treating physicians. Despite this obvious relevance, we have a relatively poor knowledge and understanding of how these outcomes are affected in elderly patients with hematological malignancies.