Prospective assessment of white matter integrity in adult stem cell transplant recipients.

Hematopoietic stem cell transplantation (HSCT) is often used in the treatment of hematologic disorders. Although it can be curative, the pre-transplant conditioning regimen can be associated with neurotoxicity. In this prospective study, we examined white matter (WM) integrity with diffusion tensor imaging (DTI) and neuropsychological functioning before and one year after HSCT in twenty-two patients with hematologic disorders and ten healthy controls evaluated at similar intervals. Eighteen patients received conditioning treatment with high-dose (HD) chemotherapy, and four had full dose total body irradiation (fTBI) and HD chemotherapy prior to undergoing an allogeneic or autologous HSCT. The results showed a significant decrease in mean diffusivity (MD) and axial diffusivity (AD) in diffuse WM regions one year after HSCT (p-corrected <0.05) in the patient group compared to healthy controls. At baseline, patients treated with allogeneic HSCT had higher MD and AD in the left hemisphere WM than autologous HSCT patients (p-corrected <0.05). One year post-transplant, patients treated with allogeneic HSCT had lower fractional anisotropy (FA) and higher radial diffusivity (RD) in the right hemisphere and left frontal WM compared to patients treated with autologous HSCT (p-corrected <0.05).There were modest but significant correlations between MD values and cognitive test scores, and these were greatest for timed tests and in projection tracts. Patients showed a trend toward a decline in working memory, and had lower cognitive test scores than healthy controls at the one-year assessment. The findings suggest a relatively diffuse pattern of alterations in WM integrity in adult survivors of HSCT.

Human rhinovirus infections of the lower respiratory tract in hematopoietic stem cell transplant recipients.

BACKGROUND: Human rhinoviruses (HRVs) are a common cause of upper respiratory infection (URI) in hematopoietic stem cell transplant (HSCT) recipients; yet, their role in lower respiratory illness is not well understood. METHODS: We performed a retrospective chart review of HSCT recipients with HRV infection from the time molecular detection methods were implemented at our institution in 2008. Factors associated with proven or possible HRV pneumonia at the first HRV detection were evaluated by univariate and multivariate analysis. We then characterized all episodes of proven and possible HRV pneumonia from the initial HRV infection through a 1-year follow-up period. RESULTS: Between 2008 and 2011, 63 HSCT recipients had ≥1 documented HRV infections. At first HRV detection, 36 (57%) patients had HRV URI and 27 (43%) had proven or possible HRV pneumonia; in multivariate analysis, hypoalbuminemia (odds ratio [OR] 9.5, 95% confidence interval [CI] 1.3-71.7; P = 0.03) and isolation of respiratory co-pathogen(s) (OR 24.2, 95% CI 2.0-288.4; P = 0.01) were independently associated with pneumonia. During the study period, 22 patients had 25 episodes of proven HRV pneumonia. Fever (60%), cough (92%), sputum production (61%), and dyspnea (60%) were common symptoms. Fifteen (60%) episodes demonstrated bacterial (n = 7), fungal (n = 5), or viral (n = 3) co-infection. Among the remaining 10 (40%) cases of HRV monoinfection, patients' oxygen saturations ranged from 80% to 97% on ambient air, and computed tomography scans showed peribronchiolar, patchy, ground glass infiltrates. CONCLUSIONS: HRV pneumonia is relatively common after HSCT and frequently accompanied by bacterial co-infection. As use of molecular assays for respiratory viral diagnosis becomes widespread, HRV will be increasingly recognized as a significant cause of pneumonia in immunocompromised hosts.

A prospective evaluation of changes in brain structure and cognitive functions in adult stem cell transplant recipients.

Hematopoietic stem cell transplantation (HSCT) is an efficacious treatment for many hematologic malignancies. However, the conditioning regimen of high-dose (HD) chemotherapy with or without total body irradiation (TBI) can be associated with neurotoxicity. In this prospective study, we used quantitative neuroimaging techniques to examine regional gray matter and ventricular volumes, and standardized neuropsychological tests to assess cognitive function before and 1 year after HSCT in 28 patients with hematologic malignancies and in ten healthy controls evaluated at similar intervals. Nineteen patients received conditioning treatment with HD chemotherapy alone and nine had both TBI and HD chemotherapy. There was a significant reduction in gray matter volume in the middle frontal gyrus bilaterally and in the left caudate nucleus in the patient group (all patients combined) but not among healthy controls over the 1-year follow-up period. There was a significant increase in left lateral ventricle volume and in total ventricle volume in the patient group, relative to healthy controls. Similar brain structural changes were seen for patients treated with HD chemotherapy alone. The neuropsychological results showed that 21% of patients could be classified as impaired at baseline. The Reliable Change Index suggested no significantly different rates of cognitive decline between patients and healthy controls. The findings suggest that HSCT patients may be at an increased risk for developing regional brain volume loss, and that subgroups may experience cognitive dysfunction prior to and 1 year following the transplant.

Palifermin for the reduction of acute GVHD: a randomized, double-blind, placebo-controlled trial.

This prospective, randomized, double-blind, placebo-controlled study evaluated the efficacy of palifermin to reduce the incidence of severe (grade 3-4) acute GVHD after myeloablation and allo-SCT. Adults who received allo-SCT for hematologic malignancies received placebo or palifermin 60 µg/kg daily on three consecutive days before conditioning and a single dose of 180 µg/kg after conditioning, but often 1 or 2 days before allo-SCT. Subjects received MTX (plus CYA or tacrolimus) on days 1, 3, 6 and 11. Acute GVHD was evaluated once weekly and oral mucositis was evaluated daily. Subjects were randomly assigned to placebo (n=78) or palifermin (n=77). Conditioning included TBI in approximately half of the subjects (48% placebo, 51% palifermin). The primary efficacy end point, subject incidence of grade 3-4 acute GVHD, was similar between treatment groups (17% placebo, 16% palifermin). Grade 3-4 oral mucositis (73% placebo, 81% palifermin) and other secondary efficacy end points were similar between treatment groups. The most commonly reported treatment-related adverse events were skin/s.c. events such as rash, pruritus, and erythema. This exploratory study of acute GVHD after myeloablation and allo-SCT did not provide evidence of a treatment effect with this dosing regimen of palifermin.

Intensive treatment strategies may not provide superior outcomes in mantle cell lymphoma: overall survival exceeding 7 years with standard therapies.

BACKGROUND: Reported median overall survival (OS) in patients with mantle cell lymphoma (MCL) has been reported to be just 3-4 years. As a consequence, first-line treatment has become more aggressive. Single-center studies with R-Hyper-CVAD and/or autologous stem-cell transplant (ASCT) have produced 3-year OS rates >80%, prompting many to adopt their use. We evaluated outcomes from a single-center cohort managed in a more traditional fashion. METHODS: We identified patients with MCL evaluated at Weill Cornell Medical Center since 1997, and included those with known date of diagnosis. An online social security database was used to verify survival. RESULTS: We identified 181 patients with MCL, and date of diagnosis could be determined in 111. Three-year OS from diagnosis was 86% [95% confidence interval (CI) 78% to 92%]. Median OS was 7.1 years (95% CI 63-98 months). Adequate information on therapy was available for 75 patients. Only five were treated upfront with (R)-Hyper-CVAD or ASCT while an additional four patients received one of these regimens subsequently. Treatment type had no significant effect on OS. CONCLUSION: Outcomes with standard approaches can yield similar survival to that achieved with more intensive approaches. Biases may account for the perceived superiority of aggressive strategies.

Remission induction therapy of untreated acute myeloid leukemia using a non-cytarabine-containing regimen of idarubicin, etoposide, and carboplatin.

BACKGROUND: The safety and efficacy of idarubicin, etoposide, and carboplatin as remission induction therapy for patients younger than 60 years with untreated acute myeloid leukemia was studied as an alternative to standard regimens based on cytarabine plus anthracycline. METHODS: Eligible patients received idarubicin (36-40 mg/m2), etoposide (500 mg/m2), and carboplatin (1000-1500 mg/m2) over 5 days. Those who achieved complete remission received a single course of cytarabine 1.5 gm/m2 every 12 hours for a total of 12 doses. D-xylose absorption was studied as a marker for cytotoxic therapy-induced gut mucosal damage. Cytogenetic and immunophenotyping studies were performed at the time of diagnosis and examined for prognostic importance. RESULTS: Remission was achieved in 29 (67%) of 43 patients with a single induction course. The median leukemia free and overall survival times were 15.4 months (95% CI 6.5-24.2) and 12.5 months (95% CI 5.9-19.1), respectively. Induction mortality was 14%. Karyotype (normal, simple, or complex vs. very complex) was the strongest predictor of remission (79% vs. 25%, P=0.01), leukemia free survival (odds ratio [OR] 19.3, 95% CI 2.7-138.9), and overall survival (OR 5.4, 95% CI 2.1-13.9). Dose-limiting gut mucosal toxicity was greatest during Weeks 2 and 3. Bloodstream infections occurred in 49% of patients at a median of 12 days. Grade 3-4 diarrhea, nausea, stomatitis, esophagitis/dysphagia, and vomiting developed in 33%, 26%, 23%, 9%, and 2% of cases, respectively, at a median of 17, 16, 11, 15.5, and 21 days, respectively. CONCLUSIONS: This regimen was active in adults younger than 60 years with untreated acute myeloid leukemia and normal, simple, or complex karyotypes. Remission duration was confounded by karyotype. Mucosal toxicity limited the tolerability of this regimen. These adverse effects might be overcome by increasing the intensity of postremission therapy and modifying the dosing schedule.

Cytotoxic therapy-induced D-xylose malabsorption and invasive infection during remission-induction therapy for acute myeloid leukemia in adults.

PURPOSE: To study the sequential changes in the intestinal absorption of an oral pentose probe, D-xylose, in patients receiving therapy for untreated acute myeloid leukemia (AML), and to correlate these changes to infectious morbidity. PATIENTS AND METHODS: Serial D-xylose absorption studies were conducted in 110 consecutive adult patients admitted to a university-affiliated tertiary care hospital for remission-induction therapy for untreated newly diagnosed AML. Serial serum D-xylose levels were obtained 1 hour after a 5-g oral dose of D-xylose at baseline and weekly for 4 weeks until marrow recovery. These results were correlated with invasive infection using multivariate techniques. RESULTS: The mean (+/- SEM) serum D-xylose levels were 0.88 +/- 0.03, 0.69 +/- 0.03, 0.58 +/- 0.02, 0.53 +/- 0.02, and 0.73 +/- 0.02 mmol/L at baseline and weeks 1 to 4, respectively (P < .0001, analysis of variance [AN-OVA]). Time to malabsorption varied with induction regimen (P = .007, log-rank test). Bloodstream infections during week 2 correlated with malabsorption (P = .007). Neutropenic enterocolitis correlated independently with induction regimen (P = .009), malabsorption at week 2 (P = .02), and the development of candidemia (P = .005). Hepatosplenic fungal infection correlated with induction regimen (P = .03), malabsorption at week 2 (P = .02), and fever at diagnosis (P = .003). Malabsorption was unrelated to the duration of severe neutropenia and the administration of parenteral nutrition. CONCLUSION: Serial D-xylose absorption studies in subjects with AML produced a characteristic profile of cytotoxic therapy-related damage to the functional integrity of the intestinal epithelium that was regimen dependent, myelosuppression independent, and predictive for invasive infectious complications. Further study to validate these observations appears warranted.

Therapy of untreated acute myeloid leukemia in the elderly: remission-induction using a non-cytarabine-containing regimen of mitoxantrone plus etoposide.

PURPOSE: The University of Manitoba Adult Acute Leukemia Study Group sought to examine the safety, efficacy, and impact on quality of life of a non-cytarabine-containing remission-induction regimen followed by intermediate-dose cytarabine (IDARA-C) postremission therapy for the management of untreated acute myeloid leukemia (AML) in patients age 60 to 80 years. PATIENTS AND METHODS: Eligible patients received mitoxantrone 10 mg/m2 and etoposide 100 mg/m2 on days 1 to 5. Complete remitters received a single course of cytarabine 0.5 mg/m2 every 12 hours on days 1 to 6. Cytogenetic and immunophenotyping studies were performed at diagnosis and were examined for prognostic importance. The Functional Living Index-Cancer (FLI-C) was used in the longitudinal assessment of quality of life. RESULTS: A total of 37 (55%) of 67 eligible patients achieved remission, 34 (92%) of whom did so with a single course. The induction mortality rate was 12%. The median disease-free and overall survival times were 8.4 and 9.2 months, respectively. CD34 stem-cell phenotype, poor performance status, and high cytogenetic complexity score were independent covariates of failure to achieve remission. Very complex karotype combined with CD34 stem-cell phenotype to predict induction death in 67% of cases (P = .0003). Cytotoxic therapy-related gut epithelial damage was maximal during weeks 2 and 3 of therapy. Complete remitters and partial responders exhibited significantly improved global FLI-C scores following completion of therapy. CONCLUSION: Mitoxantrone plus etoposide was an effective and well-tolerated first-line induction regimen for AML in the elderly that should be studied further in comparison to the standard cytarabine/anthracycline-based therapy.

Cyclosporine and methylprednisolone for prophylaxis of acute graft-versus-host disease.

Twenty-eight consecutive HLA matched patients undergoing allogeneic bone marrow transplantation received prophylaxis for acute graft-versus-host disease with combined cyclosporine and methylprednisolone. The incidence of grades II-IV acute GVHD was 28.5%, a figure similar to that reported for two other drug regimens. The incidence of chronic GVHD in patients surviving longer than 150 days was 73%. Toxicity, especially renal, was acceptable and a number of potential problems associated with the use of methotrexate were avoided. While this regimen and similar ones have reduced the incidence and severity of acute GVHD the problem remains formidable and newer approaches are clearly needed.