Yousef Ezaydi

Living with advanced but stable multiple myeloma: a study of the symptom burden and cumulative effects of disease and intensive (hematopoietic stem cell transplant-based) treatment on health-related quality of life.

CONTEXT The cumulative impact of disease and treatment-related factors on health-related quality of life (HRQoL) in long-term survivors of multiple myeloma is poorly characterized. OBJECTIVES To characterize HRQoL and symptom burden in advanced, intensively treated myeloma. METHODS We performed detailed assessments in patients who had undergone hematopoietic stem cell transplantation and subsequent treatment for at least one episode of progressive disease. To exclude the impact of active disease and acute toxicity of treatment, patients were in a stable plateau phase. Patients were assessed for HRQoL (Short Form-12, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30, and Multiple Myeloma Module), pain (Brief Pain Inventory-Short Form), peripheral neuropathy (self-report Leeds Assessment of Neuropathic Symptoms and Signs), and concerns (adapted from Profile of Concerns). Serum interleukin-6 and tumor necrosis factor-alpha were measured. RESULTS A total of 32 patients were enrolled, with a median age of 55 years at diagnosis and 60 years at assessment. After a median 5.5 years from diagnosis and three lines of treatment, physical functioning was significantly compromised (P<0.001) and associated with progressive work disability and concerns regarding loss of independence. Fatigue and pain were the predominant symptoms, impacting negatively on physical functioning (P<0.001). Pain was predominantly neuropathic in half the patients. Serum interleukin-6 levels positively correlated with pain (P=0.03), pain interference (P=0.003), insomnia (P=0.02), and appetite loss (P=0.02), and inversely correlated with physical functioning (P=0.03). CONCLUSION Despite disease control and supportive care, intensively treated long-term myeloma survivors have significantly compromised HRQoL related to symptom burden. Systematic assessment is routinely indicated in advanced phase myeloma, even when disease activity is stable. Further studies should investigate the utility of interventional strategies and the relationship of cytokines with symptoms.

Health-related quality of life in patients with newly diagnosed multiple myeloma in the FIRST trial: lenalidomide plus low-dose dexamethasone versus melphalan, prednisone, thalidomide

We compared the health-related quality-of-life of patients with newly diagnosed multiple myeloma aged over 65 years or transplant-ineligible in the pivotal, phase III FIRST trial. Patients received: i) continuous lenalidomide and low-dose dexamethasone until disease progression; ii) fixed cycles of lenalidomide and low-dose dexamethasone for 18 months; or iii) fixed cycles of melphalan, prednisone, thalidomide for 18 months. Data were collected using the validated questionnaires (QLQ-MY20, QLQ-C30, and EQ-5D). The analysis focused on the EQ-5D utility value and six domains pre-selected for their perceived clinical relevance. Lenalidomide and low-dose dexamethasone, and melphalan, prednisone, thalidomide improved patients’ health-related quality-of-life from baseline over the duration of the study across all pre-selected domains of the QLQ-C30 and EQ-5D. In the QLQ-MY20, lenalidomide and low-dose dexamethasone demonstrated a significantly greater reduction in the Disease Symptoms domain compared with melphalan, prednisone, thalidomide at Month 3, and significantly lower scores for QLQ-MY20 Side Effects of Treatment at all post-baseline assessments except Month 18. Linear mixed-model repeated-measures analyses confirmed the results observed in the cross-sectional analysis. Continuous lenalidomide and low-dose dexamethasone delays disease progression versus melphalan, prednisone, thalidomide and has been associated with a clinically meaningful improvement in health-related quality-of-life. These results further establish continuous lenalidomide and low-dose dexamethasone as a new standard of care for initial therapy of myeloma by demonstrating superior health-related quality-of-life during treatment, compared with melphalan, prednisone, thalidomide.

Central Pain Processing in Chronic Chemotherapy-Induced Peripheral Neuropathy: A Functional Magnetic Resonance Imaging Study

Life expectancy in multiple myeloma has significantly increased. However, a high incidence of chemotherapy induced peripheral neuropathy (CIPN) can negatively influence quality of life during this period. This study applied functional magnetic resonance imaging (fMRI) to compare areas associated with central pain processing in patients with multiple myeloma who had chemotherapy induced peripheral neuropathy (MM-CIPN) with those from healthy volunteers (HV). Twenty-four participants (n = 12 MM-CIPN, n = 12 HV) underwent Blood Oxygen Level-Dependent (BOLD) fMRI at 3T whilst noxious heat-pain stimuli were applied to the foot and then thigh. Patients with MM-CIPN demonstrated greater activation during painful stimulation in the precuneus compared to HV (p = 0.014, FWE-corrected). Patients with MM-CIPN exhibited hypo-activation of the right superior frontal gyrus compared to HV (p = 0.031, FWE-corrected). Significant positive correlation existed between the total neuropathy score (reduced version) and activation in the frontal operculum (close to insular cortex) during foot stimulation in patients with MM-CIPN (p = 0.03, FWE-corrected; adjusted R2 = 0.87). Painful stimuli delivered to MM-CIPN patients evoke differential activation of distinct cortical regions, reflecting a unique pattern of central pain processing compared with healthy volunteers. This characteristic activation pattern associated with pain furthers the understanding of the pathophysiology of painful chemotherapy induced peripheral neuropathy. Functional MRI provides a tool for monitoring cerebral changes during anti-cancer and analgesic treatment.

Endocrine, metabolic, nutritional and body composition abnormalities are common in advanced intensively-treated (transplanted) multiple myeloma

Modern treatment strategies have increased life expectancy in multiple myeloma, but little is known about the endocrine, metabolic and nutritional status of long-term survivors. We performed endocrine, metabolic, bone, body composition and nutritional evaluations in 32 patients with intensively-treated, advanced but stable, myeloma a median duration of 6 years from diagnosis and three lines of intensive treatment, including at least one haematopoietic SCT procedure. All patients were off active treatment. There was a high prevalence of endocrine dysfunction: hypothyroidism (9%), hypogonadism (65% males) and elevated prolactin (19%). Adrenocortical function was preserved despite large cumulative corticosteroid pretreatment. Biochemical markers were consistent with postmenopausal status in all females and infertility in males. Nutritionally, 59% were vitamin D insufficient/deficient, reduced serum folate in 25% and vitamin B12 in 6%. Total body DEXA scanning confirmed ‘sarcopenic-obesity’ in 65%, but reduced bone density was seen in a minority. We conclude that potentially correctable endocrine, metabolic and nutritional abnormalities are prevalent in heavily-treated patients with stable multiple myeloma. Preservation of bone supports the efficacy of bisphosphonate treatment from diagnosis, but sarcopenic-obesity may contribute to frailty. Ultimately, multi-system screening and appropriate interventions may optimise quality of long-term survival and further studies are warranted.

High prevalence of cardiovascular and respiratory abnormalities in advanced, intensively treated (transplanted) myeloma: The case for ‘late effects’ screening and preventive strategies

Objectives: Modern management of myeloma has significantly improved survival, with increasing numbers of patients living beyond a decade. However, little is known about the long-term cardiovascular and respiratory status of intensively treated and multiply relapsed survivors. Methods: We performed detailed cardiovascular and respiratory evaluations in patients with intensively treated, advanced but stable myeloma. All patients had received at least two lines of treatment, including at least one haematopoietic stem cell transplantation procedure, but had stable, controlled disease and were off active treatment at the time of evaluation. Results: Thirty-two patients with a median duration of 6 years (range 2–12) from original diagnosis of myeloma and three lines (range 2–6) of treatment were evaluated. Despite normal physical examination in the majority, there was a high prevalence of sub-clinical cardiac and respiratory dysfunction, reflected by abnormalities of electrocardiography (45%), echocardiography (50%), serum N-terminal pro-B-type natriuretic peptide level (NT-pro-BNP, 50%), and pulmonary function testing (45%). NT-pro-BNP level correlated negatively with quality of life (P = 0.012) and positively with serum ferritin (P = 0.027). Dyspnoea score correlated with BMI (P = 0.001). Risk factors for cardiovascular disease (obesity, hypertension, hyperlipidaemia, and hyperinsulinaemia) were common. Discussion: Even in the absence of overt clinical features, the majority of intensively treated long-term survivors of myeloma have established cardiovascular and/or respiratory dysfunction, above levels expected in the general population of a similar age. Conclusion: This study supports routine screening and lifestyle modification combined with primary and secondary preventive strategies to reduce cardiovascular and respiratory disease and to preserve quality of life in transplanted myeloma patients.

Myelofibrosis as the initial presentation of donor-derived myelodysplastic syndrome/AML: failure of a lasting response to a second allogeneic transplant from the original donor

Myelofibrosis as the initial presentation of donor-derived myelodysplastic syndrome/AML: failure of a lasting response to a second allogeneic transplant from the original donor

Treatment of relapsed myelodysplastic syndrome following double umbilical cord blood transplantation with interferon alpha and 5-azacytidine

Downing, J.R. & Shannon, K.M. (2002) Acute leukemia: a pediatric perspective. Cancer Cell, 2, 437–445. Faderl, S., O’Brien, S., Pui, C.H., Stock, W., Wetzler, M., Hoelzer, D. & Kantarjian, H.M. (2010) Adult acute lymphoblastic leukemia: concepts and strategies. Cancer, 116, 1165–1176. Huguet, F., Leguay, T., Raffoux, E., Thomas, X., Beldjord, K., Delabesse, E., Chevallier, P., Buzyn, A., Delannoy, A., Chalandon, Y., Vernant, J.P., Lafage-Pochitaloff, M., Chassevent, A., Lheritier, V., Macintyre, E., Bene, M.C., Ifrah, N. & Dombret, H. (2009) Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. Journal of Clinical Oncology, 27, 911–918. Papaemmanuil, E., Hosking, F.J., Vijayakrishnan, J., Price, A., Olver, B., Sheridan, E., Kinsey, S.E., Lightfoot, T., Roman, E., Irving, J.A., Allan, J. M., Tomlinson, I.P., Taylor, M., Greaves, M. & Houlston, R.S. (2009) Loci on 7p12.2, 10q21.2 and 14q11.2 are associated with risk of childhood acute lymphoblastic leukemia. Nature Genetics, 41, 1006–1010. Prasad, R.B., Hosking, F.J., Vijayakrishnan, J., Papaemmanuil, E., Koehler, R., Greaves, M., Sheridan, E., Gast, A., Kinsey, S.E., Lightfoot, T., Roman, E., Taylor, M., Pritchard-Jones, K., Stanulla, M., Schrappe, M., Bartram, C.R., Houlston, R.S., Kumar, R. & Hemminki, K. (2010) Verification of the susceptibility loci on 7p12.2, 10q21.2, and 14q11.2 in precursor B-cell acute lymphoblastic leukaemia of childhood. Blood, 115, 1765–1767. Pui, C.H., Robison, L.L. & Look, A.T. (2008) Acute lymphoblastic leukaemia. Lancet, 371, 1030–1043. Sherborne, A.L., Hosking, F.J., Prasad, R.B., Kumar, R., Koehler, R., Vijayakrishnan, J., Papaemmanuil, E., Bartram, C.R., Stanulla, M., Schrappe, M., Gast, A., Dobbins, S.E., Ma, Y., Sheridan, E., Taylor, M., Kinsey, S.E., Lightfoot, T., Roman, E., Irving, J.A., Allan, J.M., Moorman, A.V., Harrison, C.J., Tomlinson, I.P., Richards, S., Zimmermann, M., Szalai, C., Semsei, A.F., Erdelyi, D.J., Krajinovic, M., Sinnett, D., Healy, J., Gonzalez, N.A., Kawamata, N., Ogawa, S., Koeffler, H.P., Hemminki, K., Greaves, M. & Houlston, R.S. (2010) Variation in CDKN2A at 9p21.3 influences childhood acute lymphoblastic leukemia risk. Nature Genetics, 42, 492–494. Trevino, L.R., Yang, W., French, D., Hunger, S.P., Carroll, W.L., Devidas, M., Willman, C., Neale, G., Downing, J., Raimondi, S.C., Pui, C.H., Evans, W.E. & Relling, M.V. (2009) Germline genomic variants associated with childhood acute lymphoblastic leukemia. Nature Genetics, 41, 1001–1005. Xu, H., Cheng, C., Devidas, M., Pei, D., Fan, Y., Yang, W., Neale, G., Scheet, P., Burchard, E.G., Torgerson, D.G., Eng, C., Dean, M., Antillon, F., Winick, N.J., Martin, P.L., Willman, C.L., Camitta, B.M., Reaman, G.H., Carroll, W.L., Loh, M., Evans, W.E., Pui, C.H., Hunger, S.P., Relling, M.V. & Yang, J.J. (2012) ARID5B genetic polymorphisms contribute to racial disparities in the incidence and treatment outcome of childhood acute lymphoblastic leukemia. Journal of Clinical Oncology, 30, 751–757. Yang, W., Trevino, L.R., Yang, J.J., Scheet, P., Pui, C.H., Evans, W.E. & Relling, M.V. (2010) ARID5B SNP rs10821936 is associated with risk of childhood acute lymphoblastic leukemia in blacks and contributes to racial differences in leukemia incidence. Leukemia, 24, 894–896.

Histopathological Response of Transitional Cell Carcinoma to Arsenic Trioxide during the Treatment of Concurrently Diagnosed Acute Promyelocytic Leukaemia

Sir d We enjoyed the recent review of the naturally occurring double-stranded RNA oncolytic reovirus by Comins et al. [1]. In addition to discussing the direct anticancer activity of reovirus, the authors mentioned the induction of an anti-viral humoral immune response as a limiting factor in virotherapy: high titres of neutralising antibody are rapidly generated in response to the systemic delivery of reovirus [2]. Considerable efforts are being made with a variety of oncolytic viruses to design methods of protecting viral particles from neutralisation within the circulation, including lipid encapsulation, polymer coating and cellular carriage; the success of these approaches may be critical to the future of oncolytic virotherapy. We wish to highlight the possibility that, in contrast to the antibody response, the cellular immune system may play a central role in mediating anti-tumour activity. In addition to direct oncolysis, oncolytic viruses may generate anti-tumour immunity or anti-viral cellular immune responses eliminating virally infected tumour cells. Reovirus infection of melanoma cells has been shown to result in the secretion of a range of pro-inflammatory cytokines and chemokines, including interleukin-8, RANTES, MIP-1a and MIP-1b [3]. These soluble mediators will act to recruit other cells of the immune system to the tumour microenvironment. Reovirus additionally directly activates dendritic cells [4], the professional antigen presenting cells of the immune system. The presence of ‘danger’ signals are required for the generation of an effective anti-tumour immune response [5]. Tumour infection by an oncolytic virus can powerfully provide such signals. In the case of reovirus, ‘danger’ signals may be provided by alterations in the tumour microenvironment, including cytokine secretion and innate immune cell infiltration, or the recognition of double-stranded RNA via the double-stranded RNA-dependent protein kinase or tolllike receptor 3 present within dendritic cells. Consistent with this concept is the finding that reovirus infection of both human and murine melanoma cell lines can generate adaptive anti-tumour immune responses [6]. Oncolytic virotherapy trials should be designed with specific assessment of both anti-viral and anti-tumour immune responses. An understanding of, and the ability to harness, the immunotherapeutic potential of these novel agents may be required for these novel agents to fulfil their maximum potential. In this regard, the outcome of planned studies combining reovirus with immunomodulation using cyclophosphamide will be intriguing.

Lessons from a Jehovah’s Witness with 5q‐ syndrome: role of systemic immunosuppression and kinetics of recovery with lenalidomide from a life threatening anaemia

who have failed fludarabine: results of a large international study. Blood, 99, 3554–3561. Vivas, S., Ruiz de Morales, J.M., Ramos, F. & Suárez-Vilela, D. (2006) Alemtuzumab for refractory celiac disease in a patient at risk for enteropathy-associated T-cell lymphoma. New England Journal of Medicine, 354, 2514–2515.