The European landscape on allogeneic haematopoeietic cell transplantation in Chronic Lymphocytic Leukaemia between 2009 and 2019: a perspective from the Chronic Malignancies Working Party of the EBMT.

Allogeneic transplantation (allo-HCT) is a curative treatment in CLL whose efficacy including the most severe forms had led to the 2006 EBMT recommendations. The advent after 2014 of targeted therapies has revolutionized CLL management, allowing prolonged control to patients who have failed immunochemotherapy and/or have TP53 alterations. We analysed the pre COVID pandemic 2009-2019 EBMT registry. The yearly number of allo-HCT raised to 458 in 2011 yet dropped from 2013 onwards to an apparent plateau above 100. Within the 10 countries who were under the EMA for drug approval and performed 83.5% of those procedures, large initial differences were found but the annual number converged to 2-3 per 10 million inhabitants during the 3 most recent years suggesting that allo-HCT remains applied in selected patients. Long-term follow-up on targeted therapies shows that most patients relapse, some early, with risk factors and resistance mechanisms being described. The treatment of patients exposed to both BCL2 and BTK inhibitors and especially those with double refractory disease will become a challenge in which allo-HCT remains a solid option in competition with emerging therapies that have yet to demonstrate their long-term effectiveness.

Introduction of a Comprehensive Diagnostic and Interdisciplinary Management Approach in Haematological Patients with Mucormycosis: A Pre and Post-Intervention Analysis.

Mucormycosis is a life threatening infection in patients with haematological disease. We introduced a Mucorales-PCR and an aggressive, multidisciplinary management approach for mucormycosis during 2016-2017 and evaluated patient outcomes in 13 patients diagnosed and treated in 2012-2019. Management principle: repeated surgical debridement until biopsies from the resection margins were clean as defined by negative Blankophor microscopy, Mucorales-PCR (both reported within 24 h), and cultures. Cultured isolates underwent EUCAST E.Def 9.3.1 susceptibility testing. Antifungal therapy (AFT) (mono/combination) combined with topical AFT (when possible) was given according to the minimal inhibitory concentration (MIC), severity of the infection, and for azoles, specifically, it was guided by therapeutic drug monitoring. The outcome was evaluated by case record review. All patients underwent surgery guided by diagnostic biopsies from tissue and resection margins (195 samples in total). Comparing 2012-2015 and 2016-2019, the median number of patients of surgical debridements was 3 and 2.5 and of diagnostic samples: microscopy/culture/PCR was 3/3/6 and 10.5/10/10.5, respectively. The sensitivity of microscopy (76%) and Mucorales-PCR (70%) were similar and microscopy was superior to that of culture (53%; p = 0.039). Initial systemic AFT was liposomal amphotericin B (n = 12) or posaconazole (n = 1) given as monotherapy (n = 4) or in combination with isavuconazole/posaconazole (n = 3/6) and terbinafine (n = 3). Nine patients received topical amphotericin B. All received isavuconazole or posaconazole consolidation therapy (n = 13). Mucormycosis related six month mortality was 3/5 in 2012-2015 and 0/7 patients in 2016-2019 (one patient was lost for follow-up). Implementation of combination therapy (systemic+topical AFT/combination systemic AFT) and aggressive surgical debridement guided by optimised diagnostic tests may improve the outcome of mucormycosis in haematologic patients.

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.

Wage-subsidised employment as a result of permanently reduced work capacity in a nationwide cohort of patients diagnosed with haematological malignancies.

BACKGROUND: Patients with haematological malignancies have a poorer labour market prognosis than the general population. We have previously found that they have low rates of return to work, and a higher risk of being granted disability pension, than individuals without a history of these diseases. The aim of this study was to further investigate the labour market prognosis for these patients, by comparing the risk of being granted wage-subsidised (WS) employment as a result of permanently reduced work capacity among patients diagnosed with haematological malignancies to a reference cohort, and to determine if relative risks differ between subtypes of haematological malignancies. 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 they were granted WS employment, disability pension, anticipatory pension, old age pension, emigration, death or until 26 February 2012, whichever came first. RESULTS: A total of 310 (10%) patients and 795 (3%) reference individuals had their work capacity permanently reduced to an extent that they were granted WS employment during the follow-up period. Age- and gender-adjusted relative risks differed significantly between the subgroups of haematological malignancies, and four years after diagnosis they ranged from 2.47 (95% CI 1.46-4.16) for patients with Hodgkin lymphoma to 10.83 (95% CI 7.15-16.40) for patients with chronic myeloid leukaemia. CONCLUSION: All eight subtypes of haematological malignancies were associated with an increased risk of being granted WS employment due to permanently reduced work capacity compared to the reference cohort. The relative risks differed according to haematological malignancy subtype, and the highest was found for patients with chronic myeloid leukaemia.

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

OBJECTIVES: 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. METHODS: Questionnaire-based data on fatigue, depression and anxiety were obtained at baseline. In all, 196 patients returned the questionnaire. Of these, 106 patients were on sick leave and 90 patients were working. They were all followed prospectively for 1 year using register-based data on labour market participation. RESULTS: At baseline, high levels of fatigue, depression and anxiety were more prevalent among sickness absent patients than in those working. Half of the sickness absent patients returned to work during follow-up, and only 10 (11%) working patients experienced LTSA. Sickness absent patients with highest scores of physical fatigue were less likely to RTW than those with lowest scores (RRadj 0.43, 95% CI 0.23-0.78). Similar, we found an association between symptoms of anxiety and RTW (p = 0.048). This association was though non-significant in multivariable analyses (p = 0.068). No significant association was found between depression and RTW. CONCLUSION: Half of sickness absent patients returned to work, and only a few of working patients experienced LTSA during follow-up. Patients reporting high levels of physical fatigue were less likely to RTW. There was a similar tendency for anxiety, whereas we found no association between depression and RTW. Larger prospective studies are needed.

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

UNLABELLED: 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.

Type of hematological malignancy is crucial for the return to work prognosis: a register-based cohort study.

PURPOSE: The aims of this study were to determine the proportion of return to work (RTW) among sick-listed patients diagnosed with one of eight subtypes of hematological malignancies; to evaluate the influence of type of hematological malignancy, comorbidity, use of anxiolytics and antidepressants, socioeconomic and demographic factors on RTW; and to investigate if these associations differ between genders. METHODS: We combined data from national registers on all Danish patients diagnosed with hematological malignancies between 2000 and 2007. A total of 1,741 patients on long-term sick leave were followed until RTW, emigration, permanent withdrawal from the labor market, death, or February 2012, whichever came first. RESULTS: A total of 1,140 (65 %) patients returned to work. A strong association was found between type of diagnosis and RTW (p < 0.001), and the proportion of RTW was lowest for patients with multiple myeloma or acute leukemia compared to patients with Hodgkin lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, chronic myeloid leukemia, and chronic lymphoid leukemia. Use of antidepressants or anxiolytics after diagnosis, gender, age, and educational level were also associated with RTW. Surprisingly, comorbidity was not associated with RTW (p = 0.94); gender only modified the association between age and RTW. CONCLUSION: Two thirds of patients with hematological malignancies on sick leave RTW. A number of factors seem to lead to a poor prognosis, the hematological diagnosis being the most important, and these should be taken into account when performing studies on work outcome for patients with hematological malignancies. IMPLICATIONS FOR CANCER SURVIVORS: Knowledge in this area should assist in identification of hematological cancer patients at risk of not returning to work so that early targeted rehabilitation interventions can be initiated.

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.

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

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 unusual 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.

Expression levels of hsc70 and hsp60 are developmentally regulated during B-cell maturation and not associated to childhood c-ALL at presentation or relapse.

Heat shock proteins are potent regulators of apoptosis, and so they may also be involved in normal cellular differentiation and cancerogenesis. We used quantitative two-dimensional gel electrophoresis for determining whether either the constitutive chaperonic heat shock cognate protein 70 (hsc70) or heat shock protein 60 (hsp60) contribute to B-cell differentiation and leukemogenesis. We compared the expression of these hsps in normal peripheral blood (PB) CD19+ B-cells, in pediatric bone marrow (BM) CD19+ CD10+ B-cell precursors (BCPs) from normal donors, and in BCPs from common acute lymphoblastic leukemia (c-ALL) patients at diagnosis and at relapse. We found that the mean levels of hsc70 in c-ALL BCPs at initial presentation and at relapse failed to differ significantly. Likewise, they failed to differ significantly from the level in high-expressing normal BM BCPs or from that in low-expressing PB B-cells. Mean levels of hsp60 expression in c-ALL BCPs at initial presentation and at relapse were similar and not distinguishable from that in normal BM BCPs, however, elevated (by a factor of 2-3) compared with that in PB B-cells. Hsc70 and Hsp60 expressions were increased (by a factor of 2 of mean levels) in populations of normal BM BCPs as compared with populations of PB B-cells. Thus, no abnormal levels of hsc70 and hsp60 were detectable in populations of pediatric c-ALL BCPs neither at diagnosis nor at relapse. In contrast, our data were in support of developmentally regulated levels of hsc70 and hsp60 expression during B-cell ontogenesis.