Side effects that occurred early in people with multiple sclerosis during the first year of treatment with cladribine tablets: a plain language summary.

People with multiple sclerosis (also shortened to MS) may have difficulties staying on treatment due to side effects. Cladribine tablets, approved for treating relapsing forms of MS, are given by mouth for four short periods over two years. The benefit of convenient dosing may be lost if side effects prevent people with MS from finishing their treatment. This is the summary of a study that examined side effects from cladribine tablets treatment in the first 12 weeks of two clinical studies called CLARITY and ORACLE-MS. Overall, 34.7% of participants who took cladribine tablets experienced drug-related side effects compared to 23.2% of participants who took placebo. Most side effects were mild and were seen in 54.8% of participants taking cladribine tablets and 59.1% taking the placebo. A low number of participants discontinued treatment due to side effects (1.6% of participants who took cladribine tablets; 1.4% of participants who took placebo). The researchers concluded that cladribine tablets are well-tolerated and people with MS are likely to complete the full treatment course. ClinicalTrials.gov NCT numbers: CLARITY study - NCT00213135 and ORACLE-MS study - NCT00725985.

Treatment-emergent adverse events occurring early in the treatment course of cladribine tablets in two phase 3 trials in multiple sclerosis.

BACKGROUND: Treatment-emergent adverse events (TEAEs) that occur close to treatment initiation may negatively affect overall tolerability and adherence. It is important to develop a clear understanding of potential early TEAEs after initiating treatment with cladribine tablets. OBJECTIVE: To identify TEAEs that begin early in the course of treatment in patients enrolled in CLARITY and ORACLE-MS studies. METHODS: This post hoc analysis of CLARITY and ORACLE-MS safety populations assessed the incidence of TEAEs, serious TEAEs, drug-related TEAEs, and TEAEs leading to discontinuation in patients receiving cladribine tablets or placebo within 2, 6, and 12 weeks after treatment initiation. RESULTS: By Week 12, 61.3% of patients treated with cladribine tablets 3.5 mg/kg and 55.2% treated with placebo experienced a TEAE. More patients receiving cladribine tablets versus placebo experienced a drug-related TEAE by Week 12 (34.7% vs. 23.2%). The most common TEAEs reported with cladribine tablets were: headache (7.2%), lymphopenia (6.8%), and nausea (6.0%). Patients receiving cladribine tablets and placebo reported similar proportions of serious TEAEs (2.2% vs. 1.7%) and TEAEs leading to treatment discontinuation (1.6% vs. 1.4%). CONCLUSION: Cladribine tablets were well tolerated during the first 12 weeks as evidenced by a low incidence of TEAEs leading to treatment discontinuation.

MAGNIMS score predicts long-term clinical disease activity-free status and confirmed disability progression in patients treated with subcutaneous interferon beta-1a.

BACKGROUND: Subcutaneous (sc) interferon (IFN) ß-1a reduces relapse rates and delays disability progression in patients with MS. We examined the association of the year 1 Magnetic Resonance Imaging in MS (MAGNIMS) score with long-term clinical disease activity (CDA) -free status and confirmed disability progression in patients treated with sc IFN ß-1a in PRISMS. METHODS: Patients treated with sc IFN ß-1a three-times-weekly (22 or 44 µg; pooled data) were classified by MAGNIMS score (0, n = 129; 1, n = 108; 2, n = 130) at year 1. Hazard ratios (HR; 95% confidence intervals [CI]) for risk of CDA and confirmed Expanded Disability Status Score (EDSS) progression were calculated by MAGNIMS score for up to 15 years of follow-up. RESULTS: The risk of CDA was higher with a year 1 MAGNIMS score of 1 versus 0 (HR 1.82 [1.38-2.41]), 2 versus 0 (2.63 [2.01-3.45]) and 2 versus 1 (1.45 [1.11-1.89], all p < 0.0001). The same outcome was observed with the risk of confirmed EDSS progression (1 versus 0: 1.93 [1.23-3.02]; 2 versus 0: 2.95 [1.95-4.46]; 2 versus 1: 1.53 [1.05-2.23]; all p < 0.0001). CONCLUSION: In PRISMS, MAGNIMS score at Year 1 predicted risk of CDA and confirmed disability progression in sc IFN ß-1a-treated patients over up to 15 years. PRISMS-15 clinicaltrial.gov identifier: NCT01034644.

Integrated Lymphopenia Analysis in Younger and Older Patients With Multiple Sclerosis Treated With Cladribine Tablets.

Cladribine tablets (CladT) preferentially reduce B and T lymphocyte levels. As aging is associated with a decline in immune function, the effect of CladT on lymphocyte levels may differ by age. This post hoc analysis combined data from the Phase 3 CLARITY, CLARITY Extension, and ORACLE-MS studies to examine the effect of age (≤50 or >50 years) on lymphopenia following CladT 3.5 mg/kg (CladT3.5; cumulative dose over 2 years) treatment over 96 weeks. Both CladT3.5 and placebo were given over Weeks 1 and 5 (Year 1 treatment) and Weeks 48 and 52 (Year 2 treatment) from the start of the studies. Absolute lymphocyte count (ALC) and levels of lymphocyte subsets were examined in 1564 patients (Age ≤50 [placebo: N=566; CladT3.5: N=813]; Age >50 [placebo: N=75; CladT3.5: N=110]). In both age groups, following CladT3.5 treatment, nadir for ALC occurred at Week 9 (8 weeks following start of Year 1 treatment) and Week 55 (7 weeks following start of Year 2 treatment) of the 96-week period; for CD19+ B lymphocytes, nadir occurred at Week 9 (Year 1) and Week 52 (Year 2). For CD4+ T lymphocytes, nadir occurred at Week 16 (Year 1) in both age groups, and at Weeks 60 and 72 (Year 2) in the Age ≤50 and >50 groups, respectively. Nadir for CD8+ T lymphocytes occurred at Week 16 (Year 1) and Week 72 (Year 2) in the Age ≤50 group and levels remained in the normal range; nadir occurred at Week 9 (Year 1) and Week 96 (Year 2) in the Age >50 group. Lymphocyte recovery began soon after nadir following CladT3.5 treatment and median levels reached normal range by end of the treatment year in both age groups. By Week 96, ~25% of patients treated with CladT3.5 reported ≥1 episode of Grade ≥3 lymphopenia (Gr≥3L). The rate of certain infections was numerically higher in older versus younger patients who experienced Gr≥3L. In conclusion, CladT3.5 had a similar effect on ALC and lymphocyte subsets in both younger and older patient groups.

No evidence of disease activity status in patients treated with early vs. delayed subcutaneous interferon ß-1a.

BACKGROUND: Clinically isolated syndrome (CIS) is defined as a monophasic clinical episode highly suggestive of multiple sclerosis (MS). Regardless, studies have shown that treatment at this early stage of MS can delay a second event and prolong the transition to clinically diagnosed MS. The objective of this post-hoc analysis was to determine the effect of early CIS treatment with once weekly (qw) or three times weekly (tiw) subcutaneous interferon (scIFN) ß-1a vs. delayed treatment (DT) on the composite endpoint of no evidence of disease activity (NEDA)-3. METHODS: In REFLEX, patients with CIS were randomized to double-blind scIFN ß-1a 44 µg tiw, qw, or placebo for 24 months. Upon clinically-definite MS, patients switched to open-label scIFN ß-1a tiw. Patients who completed REFLEX entered an extension (REFLEXION). Patients initially randomized to placebo switched to tiw (DT); scIFN ß-1a patients continued their initial qw/tiw regimen for up to 60-months post-randomization. This post-hoc analysis was conducted in the integrated intent-to-treat REFLEX plus REFLEXION population (tiw, n = =171; qw, n = =175; DT, n = =171). All p values are nominal. CIS was defined using the McDonald 2010 criteria. RESULTS: Patients receiving early treatment (ET) with scIFN ß-1a tiw and qw were more likely to achieve NEDA-3 than DT at year 2 (tiw vs. DT: OR 4.26, 95% CI 2.02-8.98, p = =0.0001; qw vs. DT: OR 2.99, 95% CI 1.39-6.43, p = =0.005). Compared with DT, ET with scIFN ß-1a tiw was more likely to achieve NEDA-3 at year 3 (OR 3.73, 95% CI 1.63-8.55, p = =0.002) and year 5 (OR 12.96, 95% CI 1.66-101.04, p = =0.015). Between ET regimens, the odds of achieving NEDA-3 were not significantly improved by scIFN ß-1a 44 µg tiw at year 2 (OR 1.42, 95% CI 0.81-2.50, p = =0.22) but were at year 3 (OR 2.26, 95% CI 1.11-4.60, p = =0.024) and year 5 (OR 3.22, 95% CI 1.01-10.22, p = =0.048), indicating that the beneficial effects of more frequent scIFN ß-1a dosing become more apparent over time in patients with CIS. In the subgroup of patients with Gd+ lesions at baseline the odds for achieving NEDA-3 were higher for ET up to year 2 compared with DT (tiw: OR 10.21, 95% CI 1.23-84.82, p = =0.03; qw: OR 8.97, 95% CI 1.08-74.28, p = =0.04). In patients without Gd+ lesions at baseline, those receiving ET were more likely to achieve NEDA-3 at year 2 (OR 3.56, 95% CI 1.56-8.10, p = =0.003), year 3 (OR 2.54, 95% CI 1.05-6.18, p = =0.04) and year 5 (OR 9.63, 95% CI 1.19-77.79, p = =0.034) than patients who received DT. CONCLUSIONS: ET with scIFN ß-1a tiw was associated with a higher likelihood of achieving NEDA-3 not only at 2 but also at 3 and 5 years.

Subcutaneous Interferon-ß1a Does Not Increase the Risk of Stroke in Patients with Multiple Sclerosis: Analysis of Pooled Clinical Trials and Post-Marketing Surveillance.

INTRODUCTION: Previous studies suggest that multiple sclerosis (MS) patients have a greater stroke risk than the general population but there is limited evidence of stroke risk in patients receiving disease-modifying treatment. We assessed stroke risk in MS patients treated with subcutaneous interferon-ß1a (sc IFN-ß1a) using pooled data from clinical trials and post-marketing surveillance. METHODS: Seventeen phase II-IV Merck KGaA-sponsored trials of sc IFN-ß1a were assessed to estimate the stroke incidence rate (IR) and IR ratio (IRR) per 100 patient-years (PY), and associated 95% confidence intervals (CI). The association of treatment duration with stroke was assessed through a Cox model. IR, IRR, and hazard ratio (HR) were adjusted by age, sex, presence of any comorbidity, and MS duration. Individual case safety reports were retrieved from the Global Patient Safety Database. The reporting rates of stroke were calculated and classified as medically confirmed or non-medically confirmed according to the source of each report. RESULTS: In 17 clinical trials, 4412 patients were treated with sc IFN-ß1a for a total of 10,622 PY and 1055 patients with placebo for 2005 PY. The IR/100 PY (95% CI) of stroke was 0.025 (0.004, 0.150) in sc IFN-ß1a patients and 0.051 (0.008, 0.349) in placebo patients. The IRR for sc IFN-ß1a vs placebo was 0.486 (0.238, 0.995) and the HR was 0.496 (0.235, 1.043) for time to stroke-related event for sc IFN-ß1a treatment at any dose compared with placebo. Among sc IFN-ß1a patients, the IRR in those treated for < 2 years was 0.602 (0.159, 2.277) and for ≥ 2 years 0.469 (0.196, 1.124). Analysis of the safety database showed that the overall reporting rate for stroke was 13.286/10,000 PY. CONCLUSION: Safety data from both clinical trial and post-marketing settings indicate that treatment with sc IFN-ß1a does not increase stroke risk in patients with MS. FUNDING: Merck KGaA, Darmstadt, Germany.

Dyspnea Management of Hospice Patients.

Up to 70% of hospice patients are reported to experience dyspnea at end of life. Despite the high prevalence of this burdensome symptom, there is little in the literature to guide effective treatment. Assessment of subjective symptoms and objective signs as well as physical, psychospiritual, sociocultural, or environmental barriers is critical to an effective plan of care. The purpose of the article is to review the current literature on assessment and management of dyspnea in hospice patients and provide implications for hospice clinicians.

A Phase I Trial of Bortezomib and Sorafenib in Advanced Malignant Melanoma.

LESSONS LEARNED: This study is a rare example of effective doses of both targeted agents being both administered and tolerated.This combination should not be used in melanoma. BACKGROUND: Sorafenib and bortezomib affect BCL family member expression. We previously demonstrated that bortezomib augmented sorafenib-mediated cytotoxicity in melanoma cell lines in vitro. We aimed to combine sorafenib 400 mg b.i.d. with increasing doses of weekly bortezomib. METHODS: Patients with metastatic melanoma were enrolled in dose-escalation cohorts to determine the maximum tolerated dose (MTD) of sorafenib (twice daily) in combination with bortezomib (weekly for 3 of 4 weeks). The MTD was defined as the highest dose level at which less than 33% of patients exhibited a dose-limiting toxicity (DLT). Efficacy, as measured by 6-month progression-free survival and response rate per RECIST, was documented. RESULTS: Eleven patients were enrolled at three dose levels. DLTs (fatigue and rash) were seen in two of three patients at the highest dose level. Five patients were enrolled for sorafenib 400 mg b.i.d. and bortezomib 1.0 mg/m(2) weekly for 3 of every 4 weeks; none had DLTs, and this dose level was defined as the MTD. Of 10 evaluable patients, no responses were seen. Two of 11 patients (18%) remained progression free for longer than 6 months. CONCLUSION: The combination of sorafenib and bortezomib is safe but not active in patients with melanoma.

Reversal of in situ T-cell exhaustion during effective human antileukemia responses to donor lymphocyte infusion.

Increasing evidence across malignancies suggests that infiltrating T cells at the site of disease are crucial to tumor control. We hypothesized that marrow-infiltrating immune populations play a critical role in response to donor lymphocyte infusion (DLI), an established and potentially curative immune therapy whose precise mechanism remains unknown. We therefore analyzed marrow-infiltrating immune populations in 29 patients (22 responders, 7 nonresponders) with relapsed chronic myelogenous leukemia who received CD4(+) DLI in the pre-tyrosine kinase inhibitor era. Immunohistochemical analysis of pretreatment marrow revealed that the presence of >4% marrow-infiltrating CD8(+) (but not CD4(+)) T cells predicted DLI response, even in the setting of high leukemia burden. Furthermore, mRNA expression profiling of marrow-infiltrating T cells of a subset of responders compared with nonresponders revealed enrichment of T-cell exhaustion-specific genes in pretreatment T cells of DLI responders and significant downregulation of gene components in the same pathway in responders in conjunction with clinical response. Our data demonstrate that response to DLI is associated with quantity of preexisting marrow CD8(+) T cells and local reversal of T-cell exhaustion. Our studies implicate T-cell exhaustion as a therapeutic target of DLI and support the potential use of novel anti-PD1/PDL1 agents in lieu of DLI.

Low-dose high-dose-rate brachytherapy in the treatment of facial lesions of cutaneous T-cell lymphoma.

BACKGROUND: The use of many of the standard skin-directed mycosis fungoides (MF) therapies on facial skin may be limited by site-specific increased risks of side effects, excessive inflammation, and ocular toxicity. OBJECTIVE: Our study aimed to describe the levels of erythema, scale, and induration of facial lesions in MF before and after low-dose high-dose-rate surface applicator brachytherapy and to examine the overall clinical response to brachytherapy. METHODS: A total of 23 facial MF lesions in 10 patients were treated with high-dose-rate brachytherapy doses of 4 Gy per session for a total of 2 fractions at our multidisciplinary cutaneous oncology clinic between August 17, 2009, and March 12, 2012. RESULTS: In all 23 lesions, dramatic clinical improvement was observed. Patients were followed up for a median of 6.3 months. No recurrences were reported in the follow-up period. LIMITATIONS: Long-term follow-up is lacking. Reassessment of all included patients at annual intervals for a period of at least 5 years is the authors' goal. CONCLUSION: Low-dose high-dose-rate brachytherapy using custom-made surface molds is a highly efficacious therapy in the treatment of facial lesions in MF.

Young adult daughters of BRCA1/2 positive mothers: what do they know about hereditary cancer and how much do they worry?

OBJECTIVE: The objectives of this study are to determine (i) what daughters, ages 18-24 years, of BRCA1/2 mutation carriers understand about their 50% chance of carrying a BRCA1/2 mutation and about risk reduction or management options for mutation carriers, (ii) the extent and nature of daughters' cancer-related distress, and (iii) the effects of knowing mother's mutation status on daughters' future plans. METHODS: A total of 40 daughters, currently aged 18-24 years, of mothers who tested positive for a mutation in BRCA1/2 were invited by mail to participate (with contact information supplied by their mothers). Daughters participated in a qualitative telephone interview about the impact of learning their mother's mutation status on their understanding of their own cancer risks and their cancer-related distress, and their knowledge of screening strategies, risk-reducing surgery, current health status, and future plans. Participants also completed study-specific demographic and family history questionnaires, the Brief Symptom Inventory-18, Impact of Event Scale (with hereditary predisposition to breast/ovarian cancer as the event), and the Breast Cancer Genetic Counseling Knowledge Questionnaire. RESULTS: Daughters' genetic knowledge is suboptimal; gaps and misconceptions were common. Over 1/3 of the daughters reported high cancer-related distress, despite normal levels of general distress. Disclosed genetic information raised future concerns, especially regarding childbearing. CONCLUSION: Targeted professional attention to this high-risk cohort of young women is critical to inform the next generation of daughters of BRCA1/2 mutation carriers and encourage recommended screening by age 25 years. Improved uptake of screening and risk reduction options could improve survival, and psychoeducation could reduce cancer-related distress.

Communication about standard treatment options and clinical trials: can we teach doctors new skills to improve patient outcomes?

BACKGROUND: The International Breast Cancer Study Group conducted a phase III trial in Australian/New Zealand (ANZ) and Swiss/German/Austrian (SGA) centres on training doctors in clear and ethical information delivery about treatment options and strategies to encourage shared decision making. METHODS: Medical, surgical, gynaecological and radiation oncologists, and their patients for whom adjuvant breast cancer therapy was indicated, were eligible. Doctors were randomised to participate in a workshop with standardised teaching material and role playing. Patients were recruited in the experimental and control groups before and after the workshop. RESULTS: In ANZ centres, 21 eligible doctors recruited a total of 304 assessable patients. In SGA centres, 41 doctors recruited 390 patients. The training was well accepted. There was no overall effect on patient decisional conflict (primary endpoint) 2 weeks after the consultation. Overall, patients were satisfied with their treatment decision, their consultation and their doctors' consultation skills. Considerable variation was observed in patient outcomes between SGA and ANZ centres; the effect sizes of the intervention were marginal (<0.2). CONCLUSIONS: Shared decision making remains a challenge. A sustained training effect may require more intensive training tailored to the local setting. Cross-cultural differences need attention in conducting trials on communication interventions.

Reduced-intensity conditioning stem cell transplantation: comparison of double umbilical cord blood and unrelated donor grafts.

There are little data comparing umbilical cord blood (UBC) and conventional stem cell sources for reduced-intensity conditioning (RIC) hematopoietic stem cell transplantation (HSCT). We performed a retrospective analysis of RIC HCST using double UCB (dUCB) grafts and RIC HSCT using unrelated donor (URD) grafts. The study included 64 dUCB transplantations and 221 URD transplantations performed at Dana-Farber Cancer Institute and Massachusetts General Hospital between 2004 and 2008. The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was 14.1% for dUCB and 20.3% for URD (P = .32). The 2-year cumulative incidence of chronic GVHD was significantly lower in dUCB compared with URD (21.9% versus 53.9%; P < .0001). The 2-year cumulative incidence of nonrelapse mortality was significantly higher in dUCB (26.9% versus 10.4%; P = .0009). In our analysis, dUCB HSCT and URD HSCT had comparable 3-year overall survival (46% in dUCB and 50% in URD; P = .49) and progression-free survival (30% in dUCB and 40% in URD; P = .47). dUCBT was associated with greater nonrelapse mortality despite less chronic GVHD. Our findings suggest that the use of 2 partially matched UCB units appears to be a suitable alternative for patients undergoing RIC HSCT without an HLA-matched donor.

Use of matched unrelated donors compared with matched related donors is associated with lower relapse and superior progression-free survival after reduced-intensity conditioning hematopoietic stem cell transplantation.

As success of reduced-intensity conditioning (RIC) hematopoietic stem cell transplantation (HSCT) relies primarily on graft-versus-leukemia (GVL) activity, increased minor HLA disparity in unrelated compared to related donors could have a significant impact on transplant outcomes. To assess whether use of unrelated donors (URD) engenders more potent GVL in RIC HSCT compared to matched related donors (MRD), we retrospectively studied 433 consecutive T-replete 6/6 HLA matched URD (n = 246) and MRD (n = 187) RIC HSCT for hematologic malignancies at our institution. Diseases included: acute myelogenous leukemia (AML) (127), non-Hodgkin lymphoma (NHL) (71), chronic lymphocytic leukemia (CLL) (68), myelodysplastic syndrome (MDS) (64), Hodgkin disease (HD) (40), chronic myeloid leukemia (CML) (25), multiple myeloma (MM) (23), myeloproliferative disorder (MPD) (12), acute lymphoblastic leukemia (ALL) (7), and other leukemia (1). All received uniform fludarabine and intravenous busulfan conditioning, and GVHD prophylaxis with tacrolimus/mini-methroxate (mini-MTX) or tacrolimus/sirolimus ± mini-MTX. Unrelated donors were younger compared to MRD (median donor age: 33 years versus 52 years, P < .0001), and provided larger CD34(+) products (median CD34(+) cells infused: 8.7 × 10(6)/kg versus 7.5 × 10(6)/kg, P = .002). Distribution of diseases, disease risk, prior transplant, and cytomegalovirus (CMV) status was similar in both cohorts. Cumulative incidence of grade II-IV acute GVHD (at day +180), 2-year chronic GVHD, and 2-year nonrelapse mortality (NRM) were 20% versus 16%, 55% versus 50%, and 8% versus 6% in URD and MRD, respectively (P = NS). Cumulative incidence of relapse at 2 years was lower in URD, 52% versus 65% (P = .005). With median follow-up of 26.5 and 35.8 months, 2-year progression-free survival (PFS) was significantly better in unrelated donor transplants, 39.5% for URD, and 29% for MRD (P = .01). Overall survival (OS) at 2 years were 56% for URD versus 50% for MRD (P = .53). In multivariable analysis, URD was associated with a lower risk of relapse (hazard ratio [HR] 0.67, P = .002) and superior PFS (HR 0.69, P = .002). These results suggest that URD is associated with greater GVL activity than MRD, and could have practice changing impact on future donor selection in RIC HSCT.

Syngeneic donor hematopoietic stem cell transplantation is associated with high rates of engraftment syndrome.

Engraftment syndrome (ES), typically characterized by noninfectious fever, rash, and/or noncardiogenic pulmonary edema, is a complication of autologous and allogeneic hematopoietic stem cell transplantation (HSCT). There are no data on ES after syngeneic HSCT. We retrospectively analyzed syngeneic HSCT outcomes and determined ES incidence, risk factors, and prognostic impact. Thirty-two adult patients with a median age of 46 years (range: 22-60) underwent syngeneic HSCT at our institution between July 1986 and April 2009, primarily for hematologic malignancies (65% lymphoid-including 15% plasma cell; 31% myeloid). The median duration of follow-up was 6.1 years (range: 3.7 months to 18.1 years). Five-year progression-free and overall survival (PFS, OS) was 52% and 67%, respectively. Five-year overall cumulative incidence of relapse and nonrelapse mortality (NRM) was 37.6% and 10.2%, respectively; with increased relapse incidence of 76.3% in myeloid disease (P = .002). Fifteen patients (47%) met diagnostic criteria for ES, 10 (67%) of whom received systemic steroids. Five-year PFS was 47% in patients with ES versus 56% in those without (P = .37). Five-year OS was 63% with ES versus 71% without (P = .80). Five-year cumulative incidence of NRM was 21% with ES versus 0% without (P = .06). Five-year cumulative incidence of relapse was 32% with ES and 44% without (P = .68). Older age (P = .05) and possibly total body irradiation-based conditioning (P = .09) were risk factors for developing ES. In multivariable Cox models only diagnosis (myeloid disease) impaired OS and PFS. In summary, we document a high incidence of ES after syngeneic HSCT. The trend of increased NRM after ES requires reevaluation in a larger syngeneic HSCT cohort.

Cognitive function in postmenopausal breast cancer patients one year after completing adjuvant endocrine therapy with letrozole and/or tamoxifen in the BIG 1-98 trial.

Endocrine therapy for breast cancer may affect cognition. The purpose of this study was to examine whether cognitive function improves after cessation of adjuvant endocrine therapy. Change in cognitive function was assessed in 100 postmenopausal breast cancer patients in the BIG 1-98 trial, who were randomized to receive 5 years of adjuvant tamoxifen or letrozole alone or in sequence. Cognitive function was evaluated by computerized tests during the fifth year of trial treatment (Y5) and 1 year after treatment completion (Y6). Cognitive test scores were standardized according to age-specific norms and the change assessed using the Wilcoxon signed-rank test. There was significant improvement in the composite cognitive function score from Y5 to Y6 (median of change = 0.22, effect size = 0.53, P < 0.0001). This improvement was consistent in women taking either tamoxifen or letrozole at Y5 (P = 0.0006 and P = 0.0002, respectively). For postmenopausal patients who received either adjuvant letrozole or tamoxifen alone or in sequence, cognitive function improved after cessation of treatment.

Prediction of veno-occlusive disease using biomarkers of endothelial injury.

Predicting the development of veno-occlusive disease (VOD) of the liver remains challenging. We hypothesized that biomarkers of endothelial injury in myeloablative allogeneic transplantation recipients could predict VOD occurrence. We evaluated 4 biomarkers-von Willebrand Factor (vWF), thrombomodulin, E-selectin, and soluble intercellular adhesion molecule-1 (sICAM-1)-weekly in the peritransplantation period in an attempt to predict VOD. In the patients who received sirolimus, vWF, thrombomodulin, and sICAM-1 levels were significantly elevated in patients with VOD compared with those without VOD on day -1 (P or=1400 IU/mL and thrombomodulin >or=100 ng/mL on day +7 were both 100% sensitive and 100% specific in predicting VOD. These biomarkers were informative when adjusted for other risk factors for VOD in regression analysis. Among patients not receiving sirolimus, biomarkers of endothelial injury were not informative. We conclude that vWF, thrombomodulin, and sICAM-1 elevations before and early after transplantation may be useful in predicting VOD in patients receiving sirolimus.

Reduced-intensity conditioning hematopoietic stem cell transplantation in patients over 60 years: hematologic malignancy outcomes are not impaired in advanced age.

Reduced-intensity-conditioning (RIC) hematopoietic stem cell transplantation (HSCT) is markedly underutilized in the elderly, in part because the impact of advanced age on outcomes is poorly understood. We retrospectively analyzed outcomes in 158 consecutive hematologic malignancy patients aged > or =60 years (median, 63 years; range: 60-71 years) undergoing fludarabine/busulfan-based RIC, with a median-follow-up of 34 months (range: 12.0-85.7). Multivariate analysis was undertaken for factors having an impact on outcome. For the patients aged > or =60 years, 2-year nonrelapse mortality (NRM) and relapse was 10% and 54.6%, respectively. Two-year overall and progression-free survival (OS, PFS) was 46% and 35%, respectively. Grade II-IV acute and chronic graft-versus-host disease (aGVHD, cGVHD) incidence was 19.6% and 45.9%, respectively. Comparing 110 patients aged 60-64 years versus 48 patients aged > or =65 years, 2-year NRM and relapse was 10.5% versus 8.3% (P = .84) and 53.5% versus 56.3% (P = .31), respectively. Grade II-IV aGVHD and cGVHD incidence was 19.1% versus 22.9% (P = .52) and 51.8% versus 32.5% (P = .01), respectively. Two-year OS and PFS was 49% versus 41% (P = .11) and 36% versus 35% (P = .24), respectively. In a multivariate Cox-model, high-risk disease associated with poorer PFS (hazard ratio [HR] = 2.1, P = .01) and OS (HR = 1.84, P = .03); acute myelogenous leukemia/myelodysplastic syndrome diagnosis (HR = 1.66, P = .03) and matched-related donor (HR = 1.62, P = .03) associated with poorer PFS. RIC HSCT is well tolerated, with reasonable survival in elderly patients. Age is not associated with impaired outcomes. HSCT should not be excluded solely based on advanced patient age.

Busulfan and cyclophosphamide (Bu/Cy) as a preparative regimen for autologous stem cell transplantation in patients with non-Hodgkin lymphoma: a single-institution experience.

High-dose chemotherapy with autologous stem cell transplantation (ASCT) has been established as a standard form of therapy for patients with non-Hodgkin lymphoma (NHL). While many high-dose chemotherapy combinations are used, no single regimen has proved superior over another. Here, we report our single center's experience in patients with NHL undergoing ASCT with the combination of busulfan and cyclophosphamide (Bu/Cy). This study is a retrospective analysis of 78 consecutive patients with NHL who underwent ASCT with Bu/Cy at Massachusetts General Hospital Cancer Center. Data were collected through review of electronic medical records. A total of 78 patients with NHL underwent ASCT with Bu/Cy preparative therapy between 1996 and 2006. Median follow-up for survivors was 5.0 years (range, 6 months to 12 years). Significant transplantation-associated complications included 9 documented bacterial infections, 4 cases of engraftment syndrome, 3 cases of hepatic veno-occlusive disease (VOD), 6 cases of cardiac complications, and 2 cases of pulmonary fibrosis. The 100-day treatment-related mortality (TRM) was 1%. At 3 years, progression-free survival (PFS) was 48% (95% confidence interval [CI]=37% to 59%) and overall survival (OS) was 65% (95% CI=53% to 74%). Our data indicate that in patients with NHL undergoing ASCT, Bu/Cy has efficacy and toxicity comparable to that of other reported regimens.

Comparison of Tacrolimus and Sirolimus (Tac/Sir) versus Tacrolimus, Sirolimus, and mini-methotrexate (Tac/Sir/MTX) as acute graft-versus-host disease prophylaxis after reduced-intensity conditioning allogeneic peripheral blood stem cell transplantation.

Previous studies have shown that adding sirolimus to a tacrolimus/mini-methotrexate regimen (Tac/Sir/MTX) as graft-versus-host disease (GVHD) prophylaxis produces low rates of acute GVHD (aGVHD) after reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (SCT). To assess whether posttransplantation methotrexate MTX can be safely eliminated altogether, we conducted a prospective clinical trial testing the combination of T and Sir alone (tac/sir) as GVHD prophylaxis after RIC SCT from matched related donors. We compared the results with patients who received (Tac/Sir/MTX) as GVHD prophylaxis after RIC SCT from matched related donors in a previous prospective study. Patients in both groups received i.v. fludarabine (Flu) 30 mg/m(2)/day and i.v. busulfan (Bu) 0.8 mg/kg/day on days -5 to -2 as conditioning, followed by transplantation of unmanipulated filgrastim-mobilized peripheral blood stem cells (PBSCS). After transplantation, patients in both groups received Tac and Sir orally starting on day -3, with doses adjusted to achieve trough serum levels of 5 to 10 ng/mL and 3 to 12 ng/mL, respectively. The patients in the Tac/Sir/MTX group also received mini-MTX therapy (5 mg/m(2) i.v.) on days +1, +3, and +6. Filgrastim 5 microg/kg/day s.c. was started on day +1 and continued until neutrophil engraftment. Twenty-nine patients received the Tac/Sir regimen, and 46 patients received the Tac/Sir/MTX regimen. The 2 groups were balanced in terms of age, sex, and disease characteristics. Engraftment was brisk and donor chimerism after transplantation robust in both groups. The cumulative incidence of grade II-IV aGVHD was similar in the 2 groups (17% for Tac/Sir versus 11% for Tac/Sir/MTX; P = .46). There also were no differences between the 2 groups in cumulative incidence of extensive chronic GVHD (cGVHD), treatment-related mortality (TRM), disease relapse, or survival. The Tac/Sir combination for GVHD prophylaxis is well tolerated and associated with a low incidence of aGVHD in matched related donor RIC SCT. The omission of mini-MTX from the Tac/Sir GVHD prophylaxis regimen appears to have no adverse effect on the development of aGVHD.