Pretreatment Vitamin D Deficiency Is Associated With Impaired Progression-Free and Overall Survival in Hodgkin Lymphoma.

PURPOSE: Vitamin D deficiency is described as a modifiable risk factor for the incidence of and mortality in many common cancers; however, data in Hodgkin lymphoma (HL) are lacking. PATIENTS AND METHODS: We thus performed a study measuring pretreatment vitamin D levels in prospectively treated patients with HL and correlated this with clinical outcomes. A total of 351 patients from the German Hodgkin Study Group clinical trials (HD7, HD8, and HD9) were included. RESULTS: Fifty percent of patients were vitamin D deficient (< 30 nmol/L) before planned chemotherapy. Pretreatment vitamin D deficiency was more common in relapsed/refractory patients than matched relapse-free controls (median baseline vitamin D, 21.4 nmol/L v 35.5 nmol/L; proportion with vitamin D deficiency, 68% v 41%; P < .001). Vitamin D-deficient patients had impaired progression-free survival (10-year difference, 17.6%; 95% CI, 6.9% to 28.4%; hazard ratio, 2.13; 95% CI, 1.84 to 2.48; P < .001) and overall survival (10-year difference, 11.1%; 95% CI, 2.1% to 20.2%; hazard ratio, 1.82; 95% CI, 1.53 to 2.15; P < .001), consistent across trials and treatment groups. We demonstrated that vitamin D status is an independent predictor of outcome and hypothesized that vitamin D status might be important for the chemosensitivity of HL. We subsequently performed experiments supplementing physiologic doses of vitamin D (calcitriol) to cultured HL cell lines and demonstrated increased antiproliferative effects in combination with chemotherapy. In an HL-xenograft animal model, we showed that supplemental vitamin D (dietary supplement, cholecalciferol) improves the chemosensitivity of tumors by reducing the rate of tumor growth compared with vitamin D or chemotherapy alone. CONCLUSION: On the basis of our clinical and preclinical findings, we encourage that vitamin D screening and replacement be incorporated into future randomized clinical trials to properly clarify the role of vitamin D replacement therapy in HL.

Phase I study of domatinostat (4SC-202), a class I histone deacetylase inhibitor in patients with advanced hematological malignancies.

OBJECTIVES: Domatinostat (4SC-202) is a selective class I histone deacetylase inhibitor (HDACi). This phase I study investigated safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and antitumor activity in patients with advanced hematological malignancies. METHODS: Domatinostat was administered orally once (QD) or twice daily (BID) on days 1-14 with 7 days off or continuously days 1-21 in a 3 + 3 design at 7 dose levels from 25 to 400 mg total daily dose (TDD). Twenty-four patients were treated with domatinostat. RESULTS: No formal maximum tolerated dose (MTD) was determined. One dose-limiting toxicity (DLT, grade 4 hypercalcemia) occurred during 200 mg BID continuous treatment. Six patients were reported with ≥ grade 3 treatment-related adverse events (TRAE; grade 3 hematological in three patients, grade 3 and grade 4 liver enzyme increase in 2 patients, grade 4 pulmonary embolism, and grade 4 hypercalcemia in one patient each). Higher grade hepatic TRAE occurred in the 200 mg BID continuous treatment cohort. Out of 24 patients, 1 achieved a complete response, 1 achieved a partial response, and 18 had stable disease as best response. CONCLUSION: Administration of domatinostat was safe, well tolerated with signs of antitumor activity. Four hundred milligram TDD in a 200 mg BID schedule (14 + 7) is the recommended phase II dose for monotherapy.

Aerobic physical exercise for adult patients with haematological malignancies.

BACKGROUND: Although people with haematological malignancies have to endure long phases of therapy and immobility which is known to diminish their physical performance level, the advice to rest and avoid intensive exercises is still common practice. This recommendation is partly due to the severe anaemia and thrombocytopenia from which many patients suffer. The inability to perform activities of daily living restricts them, diminishes their quality of life and can influence medical therapy. OBJECTIVES: To evaluate the efficacy, safety and feasibility of aerobic physical exercise for adults suffering from haematological malignancies. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2014, Issue 1) and MEDLINE (1950 to January 2014) as well as conference proceedings for randomised controlled trials (RCTs). SELECTION CRITERIA: We included RCTs comparing an aerobic physical exercise intervention, intending to improve the oxygen system, in addition to standard care with standard care only for adults suffering from haematological malignancies. We also included studies that evaluated aerobic exercise in addition to strength training. We excluded studies that investigated the effect of training programmes that were composed of yoga, tai chi chuan, qigong or similar types of exercise. We also excluded studies exploring the influence of strength training without additive aerobic exercise. Additionally, we excluded studies assessing outcomes without any clinical impact. DATA COLLECTION AND ANALYSIS: Two review authors independently screened search results, extracted data and assessed the quality of trials. We used risk ratios (RRs) for adverse events and 100-day survival, standardised mean differences for quality of life (QoL), fatigue, and physical performance, and mean differences for anthropometric measurements. MAIN RESULTS: Our search strategies identified 1518 potentially relevant references. Of these, we included nine RCTs involving 818 participants. The potential risk of bias in these trials is unclear, due to poor reporting.The majority of participants suffered from acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML), malignant lymphoma and multiple myeloma, and six trials randomised people receiving stem cell transplantation. Mostly, the exercise intervention consisted of various walking intervention programmes with different duration and intensity levels.Our primary endpoint of overall survival (OS) was not analysed in any of the included trials, but three trials reported deceased participants during the course of the study or during the first 100 days. There is no evidence for a difference between participants exercising and those in the control group (RR 0.93; 95% CI 0.59 to 1.47; P = 0.75; 3 trials, 269 participants, moderate quality of evidence).Four trials analysed the influence of exercise intervention on quality of life (QoL). Excluding one trial with serious baseline imbalances, physical exercise improves QoL (SMD 0.26; 95% CI 0.03 to 0.49; P = 0.03; 3 trials, 291 participants, low quality of evidence). This positive effect of exercise was also found in the subscales physical functioning (SMD 0.33; 95% CI 0.13 to 0.52; P = 0.0009; 4 trials, 422 participants, moderate quality of evidence) and depression (SMD 0.25; 95% CI -0.00 to 0.50; P = 0.05; 3 trials, 249 participants, low quality of evidence). However, there is no evidence for a difference between additional exercise and standard treatment for the subscale anxiety (SMD -0.18; 95% CI -0.64 to 0.28; P = 0.45; 3 trials, 249 participants, low quality of evidence). Seven trials (692 participants) evaluated fatigue. There is moderate quality of evidence that exercise improves fatigue (SMD 0.24; 95% CI 0.08 to 0.40; P = 0.003).Eight studies evaluated various aspects of physical performance (e.g. aerobic capacity, cardiovascular fitness), but none of them could be pooled in a meta-analysis. In seven trials there is a tendency or statistically significant effect favouring the exercise group (very low quality of evidence).Three trials (266 participants) investigated serious adverse events (SAEs) (e.g. bleeding, fever, pneumonia, deep vein thrombosis, and infection), and one trial (122 participants) assessed adverse events (AEs). There is no evidence for a difference between arms in terms of SAEs (RR 1.44; 95% CI 0.96 to 2.18; P = 0.06) or AEs (RR 7.23; 95% CI 0.38 to 137.05; P = 0.19); both findings are based on low quality of evidence. AUTHORS' CONCLUSIONS: There is no evidence for differences in mortality between the exercise and control groups. Physical exercise added to standard care can improve quality of life, especially physical functioning, depression and fatigue. Currently, there is inconclusive evidence regarding anxiety, physical performance, serious adverse events and adverse events.We need further trials with more participants and longer follow-up periods to evaluate the effects of exercise intervention for people suffering from haematological malignancies. Furthermore, we need trials with overall survival as the primary outcome to determine whether the suggested benefits will translate into a survival advantage. To enhance comparability of study data, development and implementation of core sets of measuring devices would be helpful.

Yoga in addition to standard care for patients with haematological malignancies.

BACKGROUND: Haematological malignancies are malignant neoplasms of the myeloid or lymphatic cell lines including leukaemia, lymphoma and myeloma. In order to manage physical and psychological aspects of the disease and its treatment, complementary therapies like yoga are coming increasingly into focus. However, the effectiveness of yoga practice for people suffering from haematological malignancies remains unclear. OBJECTIVES: To assess the effects of yoga practice in addition to standard cancer treatment for people with haematological malignancies. SEARCH METHODS: Our search strategy included the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1950 to 4th February 2014), databases of ongoing trials (controlled-trials.com; clinicaltrials.gov), conference proceedings of the American Society of Clinical Oncology, the American Society of Hematology, the European Haematology Association, the European Congress for Integrative Medicine, and Global Advances in Health and Medicine. We handsearched references of these studies from identified trials and relevant review articles. Two review authors independently screened the search results. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of yoga in addition to standard care for haematological malignancies compared with standard care only. We did not restrict this to any specific style of yoga. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data for eligible studies and assessed the risk of bias according to predefined criteria. We evaluated distress, fatigue, anxiety, depression and quality of sleep. Further outcomes we planned to assess were health-related quality of life (HRQoL), overall survival (OS) and adverse events (AE), but data on these were not available. MAIN RESULTS: Our search strategies led to 149 potentially relevant references, but only a single small study met our inclusion criteria. The included study was published as a full text article and investigated the feasibility and effect of Tibetan Yoga additional to standard care (N = 20; 1 person dropped out before attending any classes and no data were collected) compared to standard care only (N = 19). The study included people with all stages of Hodgkin and non-Hodgkin's lymphoma, with and without current cancer treatment. The mean age was 51 years.We judged the overall risk of bias as high as we found a high risk for performance, detection and attrition bias. Additionally, potential outcome reporting bias could not be completely ruled out. Following the recommendations of GRADE, we judged the overall quality of the body of evidence for all predefined outcomes as 'very low', due to the methodical limitations and the very small sample size.The influence of yoga on HRQoL and OS was not reported. There is no evidence that yoga in addition to standard care compared with standard care only can improve distress in people with haematological malignancies (mean difference (MD) -0.30, 95% confidence interval (CI) -5.55 to 4.95; P = 0.91). Similarly, there is no evidence of a difference between either group for fatigue (MD 0.00, 95% CI -0.94 to 0.94; P = 1.00), anxiety (MD 0.30, 95% CI -5.01 to 5.61; P = 0.91) or depression (MD -0.70, 95% CI -3.21 to 1.81; P = 0.58).There is very low quality evidence that yoga improves the overall quality of sleep (MD -2.30, 95% CI -3.78 to -0.82; P = 0.002). The yoga groups' total score for the Pittsburgh Sleep Quality Index (PSQI) was 5.8 (± 2.3 SD) and better than the total score (8.1 (± 2.4 SD)) of the control group. A PSQI total score of 0 to 5 indicates good sleep whereas PSQI total score 6 to 21 points towards significant sleep disturbances. The occurrence of AEs was not reported. AUTHORS' CONCLUSIONS: The currently available data provide little information about the effectiveness of yoga interventions for people suffering from haematological malignancies. The finding that yoga may be beneficial for the patients' quality of sleep is based on a very small body of evidence. Therefore, the role of yoga as an additional therapy for haematological malignancies remains unclear. Further high-quality randomised controlled trials with larger numbers of participants are needed to make a definitive statement.

Heat shock protein 90 inhibitor BIIB021 (CNF2024) depletes NF-kappaB and sensitizes Hodgkin's lymphoma cells for natural killer cell-mediated cytotoxicity.

PURPOSE: In Hodgkin's lymphoma, constitutive activation of NF-kappaB promotes tumor cell survival and proliferation. The molecular chaperone heat shock protein 90 (HSP90) has immune regulatory activity and supports the activation of NF-kappaB in Hodgkin's lymphoma cells. EXPERIMENTAL DESIGN: We analyzed the effect of HSP90 inhibition on viability and NF-kappaB activity in Hodgkin's lymphoma cells and the consequences for their recognition and killing through natural killer (NK) cells. RESULTS: The novel orally administrable HSP90 inhibitor BIIB021 (CNF2024) inhibited Hodgkin's lymphoma cell viability at low nanomolar concentrations in synergy with doxorubicin and gemcitabine. Annexin V/7-aminoactinomycin D binding assay revealed that BIIB021 selectively induced cell death in Hodgkin's lymphoma cells but not in lymphocytes from healthy individuals. We observed that BIIB021 inhibited the constitutive activity of NF-kappaB and this was independent of IkappaB mutations. Furthermore, we analyzed the effect of HSP90 inhibition on NK cell-mediated cytotoxicity. BIIB021 induced the expression of ligands for the activating NK cell receptor NKG2D on Hodgkin's lymphoma cells resulting in an increased susceptibility to NK cell-mediated killing. In a xenograft model of Hodgkin's lymphoma, HSP90 inhibition significantly delayed tumor growth. CONCLUSIONS: HSP90 inhibition has direct antitumor activity in Hodgkin's lymphoma in vitro and in vivo. Moreover, HSP90 inhibition may sensitize Hodgkin's lymphoma cells for NK cell-mediated killing via up-regulation of ligands engaging activating NK cell receptors.

Fludarabine in chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in the Western world. Historically, CLL patients have received prednisone- or chlorambucil-containing regimens, resulting in modest responses and a slim chance of long-term survival. The addition of purine nucleoside analogues, specifically fludarabine, to the armamentarium has significantly improved efficacy in treatment-naive or heavily pretreated CLL patients. Since the 1980s, fludarabine monotherapy has demonstrated an improvement in response over historical chemotherapeutic agents. Single-agent fludarabine therapy has expanded into a combination regimen containing cyclophosphamide and has further evolved to incorporate monoclonal antibodies. A review of the fludarabine literature shows that these advancements in fludarabine-containing therapy have enhanced the overall patient response with a potential increase in survival time, thus representing progress towards a superior treatment for CLL.