Bendt Nielsen

Autologous stem cell transplantation in multiple myeloma: outcome in patients with renal failure.

Abstract:  The impact of renal failure on prognosis of multiple myeloma patients treated with high‐dose chemotherapy and stem cell support is incompletely studied. A total of 137 patients received high‐dose chemotherapy with autologous transplantation at our centre. The patient population was divided into three groups based on their estimated creatinine clearance (Ccr); renal failure defined as Ccr < 60 mL/min: Group A: normal renal function both at diagnosis and at transplant (n = 78), Group B: renal failure at diagnosis but normal renal function at transplant (n = 30), Group C: renal failure both at diagnosis and at transplant (n = 29). There were no differences in the number of stem cells harvested, time to engraftment or response to transplantation between the groups. Ten of the patients in Group C had a normalisation of renal function post‐transplant. Significantly longer hospitalisation, increased use of blood products and increased number of infections were seen in Group C compared to Groups A and B. The transplant‐related mortality was 17% in Group C compared to 0% and 1% in Groups B and A respectively. Eight patients were on dialysis during transplant and four of these died within the first 100 d post‐transplant. Disease response was similar in the three groups. Overall survival was significantly longer in Group A than in Groups B and C. High‐dose chemotherapy with autologous transplantation is feasible in MM with renal failure. Whereas patients with moderate renal insufficiency seem to benefit from this treatment, patients in need for dialysis at the time of transplant must be carefully evaluated before proceeding to high‐dose chemotherapy.

A narrow deletion of 7q is common to HCL, and SMZL, but not CLL

To further characterise the genetic background of the two closely related B‐lymphocytic malignancies hairy cell leukaemia (HCL), and splenic marginal zone lymphoma (SMZL) we have identified characteristic copy number imbalances by comparative genomic hybridisation (CGH). Based on these findings, areas of special interest were fine mapped, and relevant probes constructed for use in interphase‐fluorescence in situ hybridisation (FISH) investigations. Thus, using the CGH data from 52 HCL and 61 SMZL patients, we identified the characteristic profiles of copy number imbalances for both diseases. These were a gain of 5q13‐31 (19%) and loss of 7q22‐q35 (6%) for HCL, and gain of 3q25 (28%), loss of 7q31 (16%), and gain of 12q15 (16%) for SMZL. A partial loss of 7q unsual for low‐malignant B‐cell diseases was found to be common to the two diseases. This loss was therefore fine mapped with BAC/PAC clones. Fine mapping revealed that in SMZL the minimal lost region covers 11.4 Mb spanning from 7q31.33 to 7q33 located between sequence tagged site (STS)‐markers SHGC‐3275 and D7S725. This area was distinct from the commonly deleted 7q region of myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML). A FISH probe specific for the 7q region was constructed. Using this probe in an interphase‐FISH investigation we showed the minimal lost 7q‐region of HCL and SMZL to be one and the same. In one HCL case, this investigation furthermore showed the extent of the deleted region to be below the detection limit of CGH, whereas interphase‐FISH screening of 36 chronic lymphocytic leukaemia (CLL) cases showed no deletion of the 7q area. In conclusion, we have identified characteristic profiles of copy number imbalances in HCL and SMZL and fine mapped the minimal extent of a commonly lost 7q area of special interest. We hypothesise that this region may contain (a) gene(s) important for the pathology of HCL and SMZL.

Recombinant interferon-alpha-2b treatment of hairy-cell leukaemia: experience with a low-dose schedule.

50 patients with hairy cell leukaemia (HCL) were treated with recombinant interferon (IFN) alpha‐2b 2.0 × 106 IU/m2 subcutaneously three times weekly to evaluate the efficacy of low‐dose IFN therapy in inducing and maintaining remission of the disease. At the time of this report 48 patients, of whom 22 were splenectomized, had been treated for at least 3 months and were considered evaluable for response. The median observation time on IFN‐alpha‐2b was 11 months (range 3 to 20). 4 cases with atypical disease (spongy lymphoid myelofibrosis) were also included. All patients responded to IFN. After 3 months 11/48 patients (23%) had achieved a partial remission (PR) with normalization of peripheral blood values. After 6 months 27/43 patients (63%) had achieved a favourable response; complete remission (CR) was recorded in 4 and PR in 23 patients. The proportion of patients with favourable responses (CR + PR) increased with the duration of therapy and after 12 months of therapy 23/28 (82 %) patients showed CR or PR, 9 patients (32 %) being in CR. Splenectomized patients disclosed a trend towards a more rapid response. It is concluded that IFN‐alpha‐2b is a highly effective first‐line therapy for HCL

Factors associated with work outcome for survivors from haematological malignancies – a systematic literature review

Recent years have seen a growing number of survivors from haematological malignancies. As biology and treatment for these malignancies differ from other malignancies, we performed a systematic literature review of factors associated with work outcome for these survivors. A systematic literature search was conducted. Eight studies with different methodology and characteristics met the inclusion criteria. Three prospective studies agreed, to a high extent, on their findings, whereas results of five cross-sectional studies collectively were inconclusive. Overall, this review - like reviews on other cancer survivors - found no certain association of single factors with work outcome. However, based on possible explanations of the converging findings, this review pinpointed a number of issues that may inform future studies. The design should preferably be prospective, including comparison with age-paired cancer-free individuals. The role of co-morbidity and of differences between haematological diagnoses ought to be established, and work outcomes must be well defined and recorded with valid methods. To establish cause-effect relations, factors possibly associated to work outcome should be evaluated at an early time point after diagnosis. Such studies would assist identification of individuals at increased risk of encountering work-related problems and would hence help establish knowledge on which rehabilitation measures could rest.

Interferon-α-induced changes in surface antigens in a hairy-cell leukemia (JOK-1)‘ and a Burkitt's lymphoma cell line (Daudi) during in vitro culture

Abstract: In further studying the mechanism of action of IFN‐α in HCL, we cultured the HCL cell line JOK‐1 and the IFN‐sensitive Burkitt cell line Daudi with and without IFN‐a and investigated the changes in density of a number of surface antigens by use of mAb and flow cytometry analyses. During culture with IFN‐α, reproducible changes were induced in both cell lines, which were qualitatively similar but differed quantitatively with small and transient changes in JOK‐1. Significant decreases in surface antigen expression were observed for CD 19, 23, 37, and for IgM on both cell lines. Moreover, decreases were seen for CD 10, 22, 45, and MHC class I1 on Daudi, and for CD 20, 21, 27, and 40 on JOK‐1. By contrast, only a few antigens increased in density, including CD 39, A96/G8 and SC9, on both cell lines, CD 22 on JOK‐1, and CD 21 on Daudi. The increase in CD 39, A96/G8 and SC9 was probably directly related to the mechanism of action of IFN‐a, whereas the other changes were most consistent with an unspecific inhibition of protein synthesis, possibly due to an accumulation of cells in Go, even though a differentiating effect cannot be ruled out. Thus, the unique in vivo effect of IFN‐α in HCL was not parallelled by a specific direct effect on JOK‐1 in vitro. Our findings therefore do not support the theory that IFNs mechanism of action in vivo is a direct effect on HC, but suggest that indirect effects are involved.

Risk of disability pension for patients diagnosed with haematological malignancies: a register-based cohort study.

Abstract Patients with haematological malignancies are at increased risk of experiencing work-related problems. The aims of this study were to compare the risk of disability pension (DP) among patients diagnosed with eight subtypes of haematological malignancies to a reference cohort, and to determine if relative risks differ between these subtypes; to evaluate the influence of socioeconomic factors, demographic factors, and clinical factors on the risk of DP; and to investigate if these associations differ between the reference cohort and the patient cohort. Material and methods. We combined data from national registers on Danish patients diagnosed with haematological malignancies between 2000 and 2007 and a reference cohort without a history of these diseases. A total of 3194 patients and 28 627 reference individuals were followed until DP, emigration, old age pension or anticipatory pension, death or 26 February 2012, whichever came first. Results. A total of 550 (17%) patients and 1511 (5%) reference individuals were granted DP. Age- and gender-adjusted relative risks differed significantly between the subgroups of haematological malignancies and ranged from 2.64 (95% CI 1.84–3.78) for patients with Hodgkin lymphoma to 12.53 (95% CI 10.57–14.85) for patients with multiple myeloma. In the patient cohort we found that gender, age, comorbidity, ethnicity, educational level, household income, history of long-term sick leave, and need of treatment with anxiolytics or antidepressants after diagnosis were associated with receiving DP. However, most of these associations were stronger in the reference cohort. Conclusion. All eight subtypes of haematological malignancies were associated with an increased risk of DP compared to the reference cohort. The relative risks differed according to subtype, and patients with multiple myeloma had the highest risk of DP. Furthermore, most socioeconomic, demographic and clinical factors had a stronger impact on the risk of DP in the reference cohort than in the patient cohort.

Three years' continuous low-dose interferon-α treatment of hairy-cell leukaemia: Evaluation of response and maintenance dose

Abstract:  Thirty‐six HCL patients were treated with 2 × 106 U/m2 IFN‐α‐2b three times weekly for 24 months, followed by 12 months of treatment with one of three doses ranging from 0.5 × 106 U to 2 × 106 U/m2. For most patients the response continued to improve during the whole treatment period, and there were no cases of disease progression during treatment. Patients with disease of short duration before IFN treatment and/or non‐splenectomized patients seemed to respond more slowly than others, but there were no differences between patients treated with the different IFN doses. Toxicity was usually WHO grade 1 or 2. The continued improvement in a large number of patients even with very small IFN doses might indicate that only a small number of true complete responses are reached after 24 months of treatment, thus explaining the reported high relapse rate after early discontinuation of treatment. It therefore seems worthwhile — also from a cost/benefit point of view — to test long‐term or continuous IFN‐α treatment at other centres.

Are fatigue, depression and anxiety associated with labour market participation among patients diagnosed with haematological malignancies? A prospective study

The objectives of this study are to examine levels of fatigue, depression and anxiety following diagnosis of a haematological malignancy, to determine the incidence of return to work (RTW) and long‐term sickness absence (LTSA) during 1‐year follow‐up and to examine whether fatigue, depression and anxiety are associated with RTW and LTSA in this group of cancer patients.

Increased expression of CD69 on T cells as an early immune marker for human cytomegalovirus reactivation in chronic lymphocytic leukemia patients.

Reactivation of human cytomegalovirus (HCMV) remains a serious problem in immunosuppressed individuals. To investigate whether a change in the immune status can be used as an earlier marker for HCMV reactivation than the traditional PCR analysis, eight chronic lymphocytic leukemia (CLL) patients at risk for reactivation due to commencement of alemtuzumab (anti-CD52) treatment were longitudinally followed. Five series of consecutive weekly blood samples were immunophenotyped by flow cytometry to cover both the innate and adaptive immune responses. Concurrently, patients were monitored by PCR for HCMV reactivation. We found a minor upregulation of the early activation marker CD69 on NK cells immediately before HCMV was detected in circulation by PCR. Interestingly, for the specific immune response, CD69 was highly upregulated on CD3(+) T cells, especially for the CD8(+) subset, in the two patients experiencing an HCMV reactivation between 6 and 20 d before HCMV viremia was measured by PCR. Moreover, a CD4(+):CD8(+) ratio lower than 0.6 may indicate a trend toward an increased risk for viral reactivation. In conclusion, an increase in CD69 expression is a promising candidate as an early predictor of HCMV reactivation.

Impact of Allogeneic Stem Cell Transplantation in First Complete Remission in Acute Myeloid Leukemia: A National Population-Based Cohort Study

To examine the outcomes of allogeneic stem cell transplantation (HSCT) in first complete remission (CR1) compared with chemotherapy alone in a population-based setting, we identified a cohort of patients with acute myeloid leukemia (AML) aged 15 to 70 years diagnosed between 2000 and 2014 in Denmark. Using the Danish National Acute Leukemia Registry, we compared relapse risk, relapse-free survival (RFS), and overall survival (OS) between patients with unfavorable cytogenetic features receiving postremission therapy with conventional chemotherapy only versus those undergoing HSCT in CR1. To minimize immortal time bias, we performed Cox proportional hazards regression, included date of allogeneic HSCT as a time-dependent covariate, and stratified the results by age (<60 or ≥60 years) and cytogenetic risk group. Overall, 1031 patients achieved a CR1. Of these, 196 patients (19%) underwent HSCT. HSCT was associated with a lower relapse rate (24% versus 49%) despite a similar median time to relapse (287 days versus 265 days). In all subgroups, the risk of relapse was lower and both RFS and OS were superior in recipients of HSCT (OS, adjusted mortality ratios: all patients, .54 [95% confidence interval (CI), .42-.71]; patients age <60 years, .58 [95% CI, .42-.81]; patients age ≥60 years, .42 [95% CI, .26-.69]; patients with intermediate-risk cytogenetics, .63 [95% CI, .43-.87]; patients with adverse-risk cytogenetics, .40 [95% CI, .24-.67]). In conclusion, in this population-based nationwide cohort study, HSCT was associated with improved survival in both younger and older patients and in patients with both intermediate and adverse cytogenetic risk.