An MDS-specific frailty index based on cumulative deficits adds independent prognostic information to clinical prognostic scoring.

The frailty index (FI) is based on the principle that the more deficits an individual has, the greater their risk of adverse outcomes. It is expressed as a ratio of the number of deficits present to the total number of deficits considered. We developed an MDS-specific FI using a prospective MDS registry and assessed its ability to add prognostic power to conventional prognostic scores in MDS. The 42 deficits included in this FI included measurements of physical performance, comorbidities, laboratory values, instrumental activities of daily living, quality of life and performance status. Of 644 patients, 440 were eligible for FI calculation. The median FI score was 0.25 (range 0.05-0.67), correlated with age and IPSS/IPSS-R risk scores and discriminated overall survival. With a follow-up of 20 months, survival was 27 months (95% CI 24-30.4). By multivariate analysis, age >70, FI, transfusion dependence, and IPSS were significant covariates associated with OS. The incremental discrimination improvement of the frailty index was 37%. We derived a prognostic score with five risk groups and distinct survivals ranging from 7.4 months to not yet reached. If externally validated, the MDS-FI could be used as a tool to refine the risk stratification of current clinical prognostication models.

Long-term recovery of quality of life and physical function over three years in adult survivors of acute myeloid leukemia after intensive chemotherapy.

We previously described impairments in quality of life (QOL) and physical function among acute myeloid leukemia (AML) survivors between diagnosis and 1 year. The aim of the current study is to describe and compare to normative data QOL and physical function recovery over 3 years from diagnosis and treatment with intensive chemotherapy (IC). At assessments done at baseline (pre-IC) and at 11 time points over 3 years, QOL, fatigue, and 3 physical performance measures (PPMs; grip strength, 6-min walk test (6MWT), and timed chair stands) were collected. Long-term recovery was defined by reaching scores within the minimum clinically important difference of normative data. Global QOL recovery was seen in 79% at 1 year, 75% at 2 years, and 86% at 3 years. At 3 years, the QLQ-C30 subscales with the greatest recovery were physical and emotional functioning. For FACT-fatigue, recovery was seen in 68% at 1 year and 77% at 3 years. Recovery on PPMs was poorer on average, with only 17% on the 6MWT and 42% in grip strength returning to normal at 3 years. The vast majority of AML survivors after IC achieve recovery in QOL and fatigue by three years. However, recovery in physical performance remained blunted.

Overexpression of Arginase 1 is linked to DNMT3A and TET2 mutations in lower-grade myelodysplastic syndromes and chronic myelomonocytic leukemia.

Immune dysregulation is a common feature of myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML), particularly in early stages. However, the genetic basis remains poorly understood. We recently reported that macrophages from mice deficient in tet methylcytosine dioxygenase 2 (Tet2), a model of MDS/CMML, are hyperinflammatory and have increased expression of arginase 1 (Arg1). In macrophages and myeloid derived suppressor cells (MDSCs) expression of Arg1 contributes to T-cell suppression and immune evasion by L-arginine depletion, in the setting of chronic inflammation and cancer. Since human MDS and CMML are driven by TET2 mutations and associated with chronic inflammation, we hypothesized that arginase enzymatic activity and ARG1 expression would be increased in human MDS/CMML bone marrow. Elevated arginase activity was observed in bone marrow mononuclear cells of MDS and CMML patients with lower-grade features. Immunohistochemical studies confirmed that myelomonocytic cells overexpress ARG1. Additionally, mutations in the epigenetic regulators TET2 and DNMT3A corresponded to high ARG1 expression and activity. These findings suggest ARG1 is a biomarker of immune dysregulation in early MDS and CMML. Recent murine findings have implicated Tet2 and Dnmt3a in regulation of innate immunity. Our study suggests similar changes may be driven by human TET2 and DNMT3A mutations.

Prophylactic RhCE and Kell antigen matching: impact on alloimmunization in transfusion-dependent patients with myelodysplastic syndromes.

BACKGROUND AND OBJECTIVES: Thirty to 80 per cent of patients with myelodysplastic syndromes (MDS) become transfusion-dependent and are at risk for red blood cell (RBC) alloimmunization. This study compared alloimmunization rates in transfusion-dependent patients with MDS at an institution with a policy of prophylactic antigen matching for RhCE and K (PAM) with those transfused at institutions without such a policy (non-PAM). MATERIALS AND METHODS: Transfusion records were retrospectively reviewed to determine total number of RBC transfusions received, whether RBC phenotyping was performed, the type and date of first alloantibody development and receipt of prophylactic antigen matching for RhCE and K. RESULTS: In 176 transfusion-dependent patients with MDS, the overall rate of new alloimmunization was 17%; the majority of patients (87%) developed at least one alloantibody to Rh or Kell antigens. The alloimmunization rate at the institution with a PAM policy was 11% compared with 23% at non-PAM institutions (P = 0·06). The rate of Rh/K alloimmunization was 7 vs. 22%, respectively (P = 0·008). No patient who received PAM developed a Rh/K alloantibody. CONCLUSION: The rate of alloimmunization was 11% at an institution with a PAM policy which was non-significantly lower than 23% at institutions without a PAM policy. However, rates of Rh/K alloimmunization were significantly lower. Such a policy should be considered in transfusion-dependent patients with MDS, although further studies on cost-effectiveness and careful consideration of resource availability in the local context are required.

Granulocyte colony-stimulating factor in secondary prophylaxis for advanced-stage Hodgkin lymphoma treated with ABVD chemotherapy: a cost-effectiveness analysis.

Granulocyte colony-stimulating factor (G-CSF) is commonly administered to patients with Hodgkin lymphoma (HL) with neutropenia. We constructed a decision-analytic model to compare the cost-effectiveness of secondary prophylaxis with G-CSF to a strategy of 'no G-CSF' in response to severe neutropenia for adults with advanced-stage HL treated with ABVD. A Canadian public health payer's perspective was considered and costs were presented in 2013 Canadian dollars. The quality-adjusted life years (QALYs) attained with the G-CSF and 'no G-CSF' strategies were 1.403 and 1.416, respectively. Costs for the strategies with and without G-CSF were $38,971 and $33,982, respectively. In the base case analysis, the 'no G-CSF' strategy was associated with cost savings and improved QALYs; therefore, 'no G-CSF' was the dominant approach. For patients with severe neutropenia during ABVD chemotherapy for advanced-stage HL, a strategy without G-CSF support is associated with improved quality-adjusted outcomes, cost savings, and is the preferred approach.

Monthly blood transfusions decrease after four months of azacitidine.

BACKGROUND AND OBJECTIVES: Azacitidine (AZA) improves overall survival and transfusion independence in patients with myelodysplastic syndrome (MDS). We aimed to quantify the reduction in red blood cell (RBC) transfusions and to determine when this reduction occurs, in MDS patients treated with AZA. MATERIALS AND METHODS: We performed a retrospective audit of changes in RBC transfusion burden in 51 patients with predominantly higher risk MDS (26.5% high risk, 51.0% intermediate-2) who received AZA. Transfusion requirements were audited 6 months prior to and up to 18 months after therapy initiation, and data were analysed using a generalized linear mixed model. RESULTS: At baseline, 30 patients (58.8%) were transfusion dependent (TD). Seventeen patients (56.7%) achieved transfusion independence (TI) by 18 months, and 8 of these patients (47.1%) achieved this response by 4 months on therapy. Achievement of TI was not consistently durable in these 17 patients, as 11 patients reverted to TD while on therapy. Meanwhile, 6 of 21 patients who were TI at baseline became TD on therapy. The monthly average of RBC units transfused decreased significantly beginning at 4 months, with a reduction from 2.50 units per month at baseline to 1.00 units per month at month 4. This 60% reduction was significant (P = 0.002) and sustained beyond 12 months. CONCLUSION: These results bolster the notion that AZA significantly reduces transfusion burden and resource utilization and illustrate the limitations of the current WHO erythroid response criteria which do not account for differing durability and fluctuations of response.

Prolonged clinical remissions in patients with relapsed or refractory follicular lymphoma treated with autologous stem cell transplantation incorporating rituximab.

Three sequential phase II trials were conducted with different immunotherapy approaches to enhance the outcome of autologous transplant (high-dose therapy and autologous stem cell transplantation (HDT/ASCT)) for recurrent follicular lymphoma. Seventy-three patients were enrolled from 1996 to 2009. Patients received HDT/ASCT combined with (1) interferon-α 3 MU/m(2) subcutaneously (SC) three times per week (TIW) for 2 years post-ASCT, (2) rituximab (R) 375 mg/m(2) for in vivo purging 3-5 days pre-stem cell collection and 2 × 4 weekly R at 2 and 6 months post-ASCT, respectively, or (3) three infusions of R pre-stem cell collection followed by 6× R weekly and interferon-α 3 MU/m(2) SC TIW. Although not statistically significant, progression-free survival (PFS) for patients who received rituximab was 56.4 and 49.1% at 5 and 10 years compared to 36 and 21% in those who did not receive rituximab. Molecular relapse post-HDT/ASCT was the strongest predictor of PFS in a multivariate analysis. Molecular relapse was coincident with or preceded clinical relapses in 84% of patients who relapsed­median of 12 months (range 0-129 months). Adverse events included secondary malignancy, transformation to diffuse large B cell lymphoma, prolonged mostly asymptomatic hypogammaglobulinemia, and pulmonary fibrosis. The long-term toxicity profile must be considered when selecting patients for this treatment.

Do quality of life or physical function at diagnosis predict short-term outcomes during intensive chemotherapy in AML?

BACKGROUND: Intensive chemotherapy (IC) used to treat acute myeloid leukemia (AML) is associated with toxicity, particularly in older adults. Emerging data suggest that baseline quality of life (QOL) and physical function may predict outcomes in oncology, although data in AML are limited. We investigated the association between baseline QOL and physical function with short-term treatment outcomes in adults and elderly AML patients. MATERIALS AND METHODS: We conducted a prospective, longitudinal study of adults (age 18+) AML patients undergoing IC. Before starting IC, patients completed the European Organisation for the Research and Treatment of Cancer (EORTC) 30-item questionnaire (QLQ-C30) and Functional Assessment of Cancer Therapy Fatigue subscale (FACT-Fatigue) in addition to physical function tests (grip strength, timed chair stands, 2-min walk test). Outcomes included 60-day mortality, intensive care unit (ICU) admission and achievement of complete remission (CR). Logistic regression was carried out to evaluate each outcome. RESULTS: Of the 239 patients (median age 57.5 years), 56.7% were male and median Charlson comorbidity score was 0. Sixty-day mortality, ICU admission and CR occurred in 9 (3.7%), 15 (6.3%) and 167 (69.9%) patients, respectively. Using univariate regression, neither QOL nor physical function at presentation was predictive of 60-day mortality (all P > 0.05), whereas ICU admission (P < 0.001) and remission status at 30 days (P = 0.007) were. Fatigue (P = 0.004) and role functioning (P = 0.003) were predictors of ICU admission; QOL and physical function were not. A higher Charlson score predicted ICU admission (P = 0.01) and remission status (P = 0.002). The cytogenetic risk group was associated with achievement of CR (P = 0.02); QOL and physical function were not (all P > 0.05). Findings were similar when patients age 60+ were examined. Relationships between fatigue and role functioning with ICU admission deserve further exploration. CONCLUSIONS: Baseline QOL and physical function tests in this prospective study were not associated with short-term mortality, ICU admission or achievement of CR after the first cycle of chemotherapy.

Cost-effectiveness in Canada of azacitidine for the treatment of higher-risk myelodysplastic syndromes.

OBJECTIVE: Our goal was to determine the economic value of azacitidine in Canada compared with conventional care regimens (ccrs), including best supportive care (bsc) and low- or standard-dose chemotherapy plus bsc in the treatment of higher-risk myelodysplastic syndromes (mdss) and acute myeloid leukemia (aml) with 20%-30% blasts. METHODS: The cost-utility model is a lifetime probabilistic Markov model with a 35-day cycle length consisting of 3 health states: mds; transformation to aml with more than 30% blasts; and death. A third-party public payer perspective was adopted. Overall survival was extrapolated beyond the time horizon of the aza-001 trial comparing azacitidine with ccr. Resource use was determined through a questionnaire completed by Canadian hematologists. Utility values were obtained from two studies in which EQ-5D health questionnaire values were mapped from the European Organization for Research and Treatment of Cancer qlq-C30 survey, and SF-6D scores were mapped from the Short Form 12, elicited from 191 and 43 patients in two different trials. RESULTS: In the base case, azacitidine had an incremental cost-effectiveness ratio (icer) of $86,182 (95% confidence limits: $69,920, $107,157) per quality-adjusted life year (qaly) gained relative to ccr. Comparing azacitidine with bsc, low-dose chemotherapy plus bsc, and standard-dose chemotherapy plus bsc, the icers were, respectively, $86,973, $84,829, and $2,152 per qaly gained. Results were most sensitive to the utility for azacitidine after 6 months of treatment and to overall survival. CONCLUSIONS: The prolonged 9-month median overall survival with azacitidine relative to ccr fills a gap w hen treating patients with higher-risk mds and aml with 20%-30% blasts. The economic value of azacitidine is within the threshold of willingness-to-pay for third-party public payers for oncology treatments in Canada.

Older age is associated with similar quality of life and physical function compared to younger age during intensive chemotherapy for acute myeloid leukemia.

We examined the quality of life (QOL) and physical function over the first three cycles of intensive chemotherapy in 103 newly diagnosed younger (18-59 years, n=64) and older adults (age 60 or older, n=39) with acute myeloid leukemia. Both QOL and physical function were worse than normative data. QOL was fairly stable over time and similar in both age groups, whereas physical function generally improved over time, although the improvement was somewhat greater in younger than older adults. Compared to younger adults, older adults tolerate intensive chemotherapy quite well from QOL and physical function perspectives.

An international phase II trial of single-agent lenalidomide for relapsed or refractory aggressive B-cell non-Hodgkin's lymphoma.

BACKGROUND: Lenalidomide is an immunomodulatory agent with antitumor activity in B-cell malignancies. This phase II trial aimed to demonstrate the safety and efficacy of lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular grade 3 lymphoma (FL-III), or transformed lymphoma (TL). METHODS: Patients received oral lenalidomide 25 mg on days 1-21 every 28 days as tolerated or until progression. The primary end point was overall response rate (ORR). RESULTS: Two hundred and seventeen patients enrolled and received lenalidomide. The ORR was 35% (77/217), with 13% (29/217) complete remission (CR), 22% (48/217) partial remission, and 21% (45/217) with stable disease. The ORR for DLBCL was 28% (30/108), 42% (24/57) for MCL, 42% (8/19) for FL-III, and 45% (15/33) for TL. Median progression-free survival for all 217 patients was 3.7 months [95% confidence interval (CI) 2.7-5.1]. For 77 responders, the median response duration lasted 10.6 months (95% CI 7.0-NR). Median response duration was not reached in 29 patients who achieved a CR and in responding patients with FL-III or MCL. The most common adverse event was myelosuppression with grade 4 neutropenia and thrombocytopenia in 17% and 6%, respectively. CONCLUSION: Lenalidomide is well tolerated and produces durable responses in patients with relapsed or refractory aggressive non-Hodgkin's lymphoma.

Rituximab purging and maintenance combined with auto-SCT: long-term molecular remissions and prolonged hypogammaglobulinemia in relapsed follicular lymphoma.

We enrolled 23 patients with relapsed follicular lymphoma (FL) in a prospective single-arm study of auto-SCT combined with in vivo rituximab graft purging and post transplant rituximab maintenance. Minimal residual disease was monitored with quantitative PCR testing. With a median follow-up of 74.2 months, neither median overall survival (OS) nor PFS has been reached. Here, 5-year OS and 5-year PFS are 78% (95% confidence interval (CI) 61-95%) and 59% (95% CI 38-80%), respectively. Time to progression (TTP) with the experimental regimen was significantly improved compared with TTP with the last prior treatment (P<0.001). Durable molecular remissions occurred in 11 of 13 assessable patients. PFS was significantly longer in patients who achieved a molecular remission by 3 months post-auto-SCT (P=0.001). Prolonged hypogammaglobulinemia occurred in most patients; however, no increase in major infections was observed.

Phase II testing of sunitinib: the National Cancer Institute of Canada Clinical Trials Group IND Program Trials IND.182-185.

Sunitinib (SU11248) is an orally bioavailable inhibitor that affects the receptor tyrosine kinases involved in tumour proliferation and angiogenesis, including vascular endothelial growth factor (VEGF) receptors 1, 2, 3, and platelet-derived growth factor receptors alpha (PDGFRA) and beta (PDGFRB). Because angiogenesis is necessary for the growth and metastasis of solid tumours, and VEGF is believed to have a pivotal role in that process, SUNITINIB treatment may have broad-spectrum clinical utility. In the present article, we discuss the biologic and clinical rationales that have recently led the Investigational New Drug Program of the National Cancer Institute of Canada Clinical Trials Group to initiate four phase ii trials testing this agent in the following four different tumour types: relapsed diffuse large cell lymphoma, malignant pleural mesothelioma, locally advanced or metastatic cervical cancer and recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma.

Intensive chemotherapy and autologous stem-cell transplantation plus rituximab is superior to conventional chemotherapy for newly diagnosed advanced stage mantle-cell lymphoma: a matched pair analysis.

BACKGROUND: The outcome of 20 patients with newly diagnosed mantle-cell lymphoma (MCL) treated on a prospective trial of autologous stem-cell transplantation (ASCT) and rituximab immunotherapy was compared with the outcome of 40 matched historical control patients treated with standard combination chemotherapy. PATIENTS AND METHODS: Control patients with MCL were identified from a lymphoma database, and pairs were matched with patients receiving ASCT-rituximab for stage of disease, gender and age (+/-5 years). Only patients treated with an anthracycline- or cyclophosphamide-fludarabine-based regimen were included. RESULTS: Seventeen of 20 patients who received ASCT-rituximab remain alive in remission at a median of 30 months from diagnosis; one patient relapsed 2 years post-ASCT, and two died at 7 and 11 months post-ASCT without evidence of lymphoma. Of 40 patients treated with conventional chemotherapy, with a median follow-up of 80 months, 33 have relapsed or progressed and 29 have died. Overall (OS) and progression-free (PFS) survival were superior in patients treated with ASCT-rituximab compared with those treated with conventional chemotherapy (PFS at 3 years, 89% versus 29%, P <0.00001; OS at 3 years, 88% versus 65%, P = 0.052). CONCLUSIONS: This matched-pair analysis suggests that patients with advanced-stage MCL treated with ASCT-rituximab had statistically significantly better PFS and a trend toward better OS than patients treated with conventional chemotherapy. Longer follow-up will determine response duration and the true impact of this treatment strategy on PFS and OS.

Follow-up of patients with Hodgkin's disease following curative treatment: the routine CT scan is of little value.

A total of 10-40% of patients with Hodgkin's disease relapse following initial curative therapy. Intensive follow-up is resource intensive and may identify false relapses. We performed a retrospective review of all patients with Hodgkin's disease treated at our centre between 1990 and 1999 to evaluate the utility of the components of follow-up. A total of 107 patients met the inclusion and exclusion criteria. The median age was 33 years and the median duration of follow-up 38 months. The total number of follow-up visits was 1209 and total number of CT scans 283. There were 109 suspected relapses of which 22 proved to be true relapses. Of the latter, 14 were identified clinically, six radiologically and two via lab testing. The routine CT scan detected only two relapses (9%), yet accounted for 29% of the total follow-up costs. Based on data from our centre, the cost per true relapse was $6000 US, 49% incurred by radiological tests. The majority of the cost of follow-up was incurred by routine follow-up (84%) as opposed to the investigation of suspected relapses (16%). We conclude that most true relapses are clinically symptomatic and that the routine CT is an expensive and inefficient mode of routine follow-up.

Pharmacokinetic study of patients with follicular or mantle cell lymphoma treated with rituximab as 'in vivo purge' and consolidative immunotherapy following autologous stem cell transplantation.

BACKGROUND: Little is known about the pharmacokinetics of rituximab in an autologous stem cell transplant (ASCT) setting. PATIENTS AND METHODS: We evaluated serum rituximab levels in 26 patients with follicular or mantle cell lymphoma treated with a combination of ASCT and immunotherapy. Patients received nine infusions of rituximab (375 mg/m(2)): one dose as an 'in vivo purge' prior to stem cell collection, and two 4-week cycles at 8 and 24 weeks following ASCT. Pre- and post-infusion serum rituximab levels were measured during the purging dose, with doses 1 and 4 of both sets of maintenance rituximab cycles, and 12 weeks and 24 weeks following treatment. RESULTS: Rituximab levels were detectable after the first infusion, and peaked at a mean concentration of 463.8 micro g/ml after the final dose. Levels remained detectable 24 weeks after completion of treatment. There was a trend toward higher rituximab levels in patients with follicular lymphoma. Serum concentrations achieved during the maintenance cycles were similar to levels observed in patients with measurable lymphoma treated during 'the pivotal trial'. No correlation was observed between serum rituximab levels achieved in the minimal disease state and the risk of later clinical relapse, nor with the ability to achieve a molecular remission following ASCT. CONCLUSIONS: The finding that patients treated in minimal disease states and at the time of active disease both achieve similar final serum rituximab concentrations after four infusions suggests that the pharmacokinetics are complex, and may not necessarily correlate with disease burden. The precise factors influencing rituximab clearance in patients with lymphoma are unresolved, and this remains an area of active research.

The development of marked elevation in white blood cell count does not predict inferior outcome in chronic lymphocytic leukemia.

Although elevation of the white blood cell (WBC) count at diagnosis of chronic lymphocytic leukemia (CLL) appears to predict shortened survival, its significance later in the course of the disease remains unclear. We reviewed all cases of CLL seen in our center between 1980 and 1999 to evaluate the frequency and clinical significance of WBC elevation > 100 x 10(9)/L. CLL was confirmed according to standard diagnostic criteria and data was collected from diagnosis, occurrence of WBC > 100 x 10(9)/L, and last follow-up. 235 consecutive patients with CLL were identified; 94 were excluded. 141 included patients had a median age of 61 years and median WBC 19.7 x 10(9)/L at diagnosis. Median follow-up for all patients was 56 months, and median survival was 104 months. 41 patients (29%) had > or = 1 episode of WBC > 100 x 10(9)1/L, occurring at a median of 38 months from diagnosis. Compared to controls matched for modified Rai stage, development of a WBC > 100 x 10(9)/L did not predict inferior survival (median 107 vs. 101 months, p = 0.72). We conclude that the occurrence of a WBC count > 100 x 10(9)/L in patients with CLL does not shorten the survival, and patients require therapy only if other indications for treatment are present.

Bcl-2 clearance: optimising outcomes in follicular non-Hodgkin's lymphoma.

The long median survival time of patients with follicular non-Hodgkin's lymphoma (NHL), means that the efficacy of new treatments are difficult to assess in the short term. Bcl-2 is an inhibitor of apoptosis and overexpression of the bcl-2 gene in the blood or bone marrow is a feature in up to 85% of patients with follicular NHL. Levels of bcl-2(+) cells in the peripheral blood or bone marrow therefore are a useful measure of disease status in such patients and can be detected by polymerase chain reaction (PCR). Complete bcl-2 clearance from the bone marrow (molecular remission) following autologous stem cell transplant (ASCT) for follicular NHL is considered to be an important prognostic factor for disease-free survival. Tumour cell contamination of the stem cell grafts used in ASCT is commonly associated with relapse. This can be addressed by purging the stem cell harvest prior to transplantation. Various methods of in vitro purging after stem cell collection have been shown to reduce the level of contamination but yield is invariably reduced and grafts remain bcl-2 positive. However, in vivo purging with rituximab during the process of collection has been used to obtain bcl-2-negative stem cell harvests without compromising the yield. Rituximab is a monoclonal antibody licensed for treatment of relapsed and refractory low-grade or follicular NHL. Rituximab targets the CD20 antigen, which is found on cells of the B cell lineage. When used for in vivo purging it depletes the peripheral blood of CD20-positive cells and prevents contamination by lymphoma cells. Molecular remission, as measured by bone-marrow bcl-2 clearance, has been achieved in 7/7 patients with follicular NHL at 1 year after treatment with ASCT using rituximab as an 'in vivopurse', followed by rituximab maintenance. Early clinical outcomes are also encouraging.