Paw Jensen

Non‐invasive assessment of tissue iron overload in the liver by magnetic resonance imaging

Summary. We investigated the clinical usefulness of a standard magnetic resonance imaging (MRI) system for non‐invasive determination of the liver iron concentration in 38 patients with iron overload and 15 normal controls by measurement of the signal intensity ratio between liver and skeletal muscle (SIR). However, SIR was found dependent on the applied repetition time (TR) of the MRI system, which led us to investigate this relationship in autopsy material of liver and muscle tissue specimens with various iron content. Based on these results, adjustment of SIR measurements to a constant value of TR was achieved. By use of this technique we found a close correlation between MRI and chemically determined liver iron concentration (r2= 0.98) as well as the serum ferritin concentration (r2= 0.86). The reproducibility was sufficiently good for the use of MRI in the follow‐up of iron reductive treatment. The use of iron store parameters in serum was found insufficient as indicators of endpoint for venesection therapy, if 20 μmol Fe/g dry weight was applied as the upper reference limit of the liver iron concentration.

Real world data on primary treatment for mantle cell lymphoma: a Nordic Lymphoma Group observational study.

There is consensus that young patients with mantle cell lymphoma (MCL) should receive intensive immunochemotherapy regimens, but optimal treatment of elderly patients as well for as patients with limited or indolent disease is not defined. Our aim was to evaluate and compare outcome in relation to prognostic factors and first-line treatment in patients with MCL in a population-based data set. Data were collected from the Swedish and Danish Lymphoma Registries from the period of 2000 to 2011. A total of 1389 patients were diagnosed with MCL. During this period, age-standardized incidence MCL increased, most prominently among males. Furthermore, male gender was associated with inferior overall survival (OS) in multivariate analysis (hazard ratio [HR] = 1.36; P = .002). Forty-three (3.6%) patients with stage I-II disease received radiotherapy with curative intent, showing a 3-year OS of 93%. Twenty-nine (2.4%) patients followed a watch-and-wait approach and showed a 3-year OS of 79.8%. Among patients receiving systemic treatment, rituximab (n = 766; HR = 0.66; P = .001) and autologous stem cell transplant (n = 273; HR = 0.55; P = .004) were independently associated with improved OS in multivariate analysis. Hence, by a population-based approach, we were able to provide novel data on prognostic factors and primary treatment of MCL, applicable to routine clinical practice.

Role of routine imaging in detecting recurrent lymphoma; a review of 258 patients with relapsed aggressive non-Hodgkin and Hodgkin lymphoma

After first‐line therapy, patients with Hodgkin lymphoma (HL) and aggressive non‐HL are followed up closely for early signs of relapse. The current follow‐up practice with frequent use of surveillance imaging is highly controversial and warrants a critical evaluation. Therefore, a retrospective multicenter study of relapsed HL and aggressive non‐HL (nodal T‐cell and diffuse large B‐cell lymphomas) was conducted. All included patients had been diagnosed during the period 2002–2011 and relapsed after achieving complete remission on first‐line therapy. Characteristics and outcome of imaging‐detected relapses were compared with other relapses. A total of 258 patients with recurrent lymphoma were included in the study. Relapse investigations were initiated outside preplanned visits in 52% of the patients. Relapse detection could be attributed to patient‐reported symptoms alone or in combination with abnormal blood tests or physical examination in 64% of the patients. Routine imaging prompted relapse investigations in 27% of the patients. The estimated number of routine scans per relapse was 91–255 depending on the lymphoma subtype. Patients with imaging‐detected relapse had lower disease burden (P = 0.045) and reduced risk of death following relapse (hazard ratio = 0.62, P = 0.02 in multivariate analysis). Patient‐reported symptoms are still the most common factor for detecting lymphoma relapse and the high number of scans per relapse calls for improved criteria for use of surveillance imaging. However, imaging‐detected relapse was associated with lower disease burden and a possible survival advantage. The future role of routine surveillance imaging should be defined in a randomized trial. Am. J. Hematol. 89:575–580, 2014.

Fracture risk in patients with monoclonal gammopathy of undetermined significance

Little information is available on the risk of fractures in patients with monoclonal gammopathy of undetermined significance (MGUS). We identified 1535 patients with MGUS between 1978 and 2003 in North Jutland County, Denmark. The population control group consisted of 15 350 persons selected from the Danish Central Population Registry, matched by age and sex. Data on fractures in the two groups were obtained from the regional Hospital Discharge Registry. In the MGUS cohort, 187 first‐time fractures were identified during 9754 person‐years of follow‐up, corresponding to an incidence rate of 19/1000 person‐years. The adjusted relative risk for fractures among MGUS patients compared with population controls was 1·4 [95% confidence interval (CI), 1·2–1·6]. After 5 years of follow‐up, the risk difference was 1·8% (95% CI, 0·5–3·0). Six of the 187 MGUS patients with fractures were later diagnosed with malignant transformation. Relative risks for fractures were increased in IgG‐type MGUS [1·3 (95% CI,1·1–1·6)], IgM‐type MGUS [1·6 (95% CI, 1·1–2·2)] and MGUS with kappa light chain [1·4 (95% CI, 1·1–1·7)]. MGUS patients had an increased risk of fractures, which could not be explained by comorbidity, advanced age, gender or malignant transformation.

Evaluation of transfusional iron overload before and during iron chelation by magnetic resonance imaging of the liver and determination of serum ferritin in adult non-thalassaemic patients.

The ability to quantitate transfusional iron overload is crucial for determining the need for and the efficacy of chelation therapy in patients with long‐standing transfusion‐dependent anaemias. We evaluated the usefulness of some indirect measures of iron overload in estimating the iron concentration in the liver ‐ the most important iron storage organ ‐ in 26 non‐chelated adult non‐thalassaemic patients. Liver Iron concentration was determined noninvasively by magnetic resonance imaging (MRI). The standard error of the estimated liver iron concentration was 80 μmol Fe/g dried liver tissue when using the number of transfused blood units, and 93 μmolFe/g when using a serum ferritin assay. Follow‐up in 11 patients (1248 months) revealed that serum ferritin is a poor measure of the liver iron concentration during iron chelation. However, this discrepancy was individually different and seemed to be dependent on the erythropoietic marrow activity. By monitoring the liver iron concentration by MRI. we compared the efficacy of chelation with desferrioxamine given either by subcutaneous continuous infusions or by bolus injections. Depletion of liver iron stores could be achieved efficiently by both regimens.

Heart transplantation in a case of juvenile hereditary haemochromatosis followed up by MRI and endomyocardial biopsies.

Abstract: Cardiac involvement in hereditary haemochromatosis (HH) is a poor prognostic sign and is the main cause of death in the juvenile form. The treatment of choice is iron removal therapy by phlebotomy, but treatment by iron chelation (desferrioxamine) has been recommended in cases with severe cardiac symptoms. We describe here the first case of juvenile HH undergoing heart transplantation, which became necessary despite intensive iron removal therapy by phlebotomy and treatment by desferrioxamine. Throughout the course the myocardial iron content was monitored by endomyocardial biopsies and by magnetic resonance imaging (MRI). At the last follow‐up, 18 months after transplantation, the myocardial iron content in the transplanted heart was still within reference ranges by biochemical determination and MRI and the patients condition was completely satisfactory. In conclusion, heart transplantation should be considered in cases of severe juvenile HH. In the follow‐up of these patients MRI may be a useful supplement.

Monoclonal gammopathy of undetermined significance and risk of venous thromboembolism

Background:  Patients with multiple myeloma are at increased risk of venous thromboembolism (VTE), but little information is available on VTE risk in patients with the precursor condition monoclonal gammopathy of undetermined significance (MGUS).

Cardiac function during iron chelation therapy in adult non-thalassaemic patients with transfusional iron overload.

Abstract: It is well‐documented that iron chelation by desferrioxamine protects/improves the cardiac function in blood transfusion‐dependent children suffering from ß‐thalassaemia. In patients who do not become dependent upon blood transfusion until adulthood (ANT‐patients), iron chelation by desferrioxamine may affect the cardiac function in unknown ways, presumably because age‐related changes in the heart may cause iron chelation to affect the cardiac function in different ways. We therefore followed the left ventricular ejection fraction (LVEF) by multigated radionuclide angiography in 16 iron‐loaded ANT‐patients during iron chelation alone and after increasing the efficacy of chelation by vitamin C supplementation. During 12 months of iron chelation the mean LVEF fell significantly from 63.3% to 58.0% (p = 0.04). Individual changes in LVEF did not correlate significantly with age but with the pretreatment liver iron concentration. After initiation of vitamin C supplementation, the mean LVEF increased from 55.9% to 65.3% (p = 0.01). Our data suggest that in ANT‐patients prolonged desferrioxamine treatment without vitamin C supplementation may be associated with reduced LVEF, whereas vitamin C supplementation seems to benefit the cardiac function. Similar findings have not been described in ß‐thalassaemia and may hence be specific for ANT‐patients. However, our findings have to be confirmed by controlled studies.

Minimal Loss of Lifetime for Patients With Diffuse Large B-Cell Lymphoma in Remission and Event Free 24 Months After Treatment: A Danish Population-Based Study

Purpose The general outlook for patients with diffuse large B-cell lymphoma (DLBCL) in first remission is important information for patients and for planning post-treatment follow-up. The purpose of this study was to evaluate the survival of patients with DLBCL in remission compared with a matched general population. Methods A total of 1,621 patients from the Danish Lymphoma Registry who were newly diagnosed with DLBCL between 2003 and 2011 were included in this study. All patients were ≥ 16 years of age at diagnosis and had achieved complete remission or complete remission unconfirmed after first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or R-CHOP-like therapy. Results The 5-year post-treatment DLBCL survival was inferior to survival in the matched general population (78%; 95% CI, 76 to 80; v 87%; standardized mortality ratio, 1.75; P < .001). Excess mortality was present but reduced for patients achieving post-treatment event-free survival for 24 months (pEFS24; standardized mortality ratio, 1.27; P < .001). In age-stratified analyses, the survival of patients < 50 years of age was normalized to the general population after achieving pEFS24 ( P = .99). During the first 8 years after pEFS24, the average loss of lifetime was 0.31 mo/y (95% CI, 0.11 to 0.50 mo/y). Excess mortality diminished when analyzing death from lymphoma as competing event to death from other causes, suggesting that early and late relapse is responsible for increased mortality in patients with DLBCL. Conclusion Although this population-based study does not support complete normalization of survival for patients with DLBCL achieving pEFS24, the estimated loss of residual lifetime was low for patients in continuous remission 2 years after ending treatment. Therefore, pEFS24 is an appealing and relevant milestone for patient counseling and could be a surrogate end point in clinical trials.

F-18-fluorodeoxyglucose-positron emission tomography/computed tomography after one cycle of chemotherapy in patients with diffuse large B-cell lymphoma: results of a Nordic/US intergroup study

Abstract We evaluated the predictive value of interim positon emission tomography (I-PET) after one course of chemoimmunotherapy in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). One hundred and twelve patients with DLBCL were enrolled. All patients had PET/computed tomography (CT) scans performed after one course of chemotherapy (PET-1). I-PET scans were categorized according to International Harmonization Project criteria (IHP), Deauville 5-point scale (D 5PS) with scores 1–3 considered negative (D 5PS > 3) and D 5PS with scores 1–4 considered negative (D 5PS = 5). Ratios of tumor maximum standardized uptake value (SUVmax) to liver SUVmax were also analyzed. We found no difference in progression-free survival (PFS) between PET-negative and PET-positive patients according to IHP and D 5PS > 3. The 2-year PFS using D 5PS = 5 was 50.9% in the PET-positive group and 84.8% in the PET-negative group (p = 0.002). A tumor/liver SUVmax cut-off of 3.1 to distinguish D 5PS scores of 4 and 5 provided the best prognostic value. PET after one course of chemotherapy was not able to safely discriminate PET-positive and PET-negative patients in different prognostic groups.