Allogeneic stem cell transplant recipients surviving at least 2 years without relapse: outcome and risk factors.

Outcomes of 2-year survivours undergoing allo-haematopoietic stem cell transplantation at Oslo University Hospital were retrospectively assessed with the objectives of identification of risk factors for late death as possible means for precautionary measures and interventions to improve long-term survival. 421 patients with haematological malignancy, transplanted between 2005 and 2019, alive and free of disease after 2 years were included with data reported from The OUS-HSCT registry. Median follow-up was 6.2 years (2.016.1), and 232 patients (55%) were observed for minimum 5 years. The probability of being alive 5 and 10 years after HSCT was 86% and 76%. Primary risk factors for late death included initial diagnosis of age ≥ 60 years, chronic lymphocytic leukaemia (CLL), previous blood stream- or invasive fungal infection (BSI, IFI), and chronic graft-versus-host disease (cGVHD). Transplant-related mortality (TRM) and relapse at 5 years were 9.0% and 7.7%, respectively. Two factors were associated with the latter: cytomegalovirus (CMV) seronegative donor and CLL. Compared with the age- and gender-matched Norwegian general population, life expectancy was lower for each disease, except for CML. The prospect for the long-term survival is good for 2-year survivors of the allogeneic hematopoietic stem cell transplantation. However, life expectancy remains inferior to the age- and gender-matched general population. Optimising prophylaxis and treatment for chronic GVHD, BSI and IFI are needed along with the improved adherence to guidelines for early detection of secondary malignancies. Measures to improve immune reconstitution, possibly the microbiota, and the use of CMV seropositive donors regardless of recipient sero-status may be warranted and should be addressed in further studies.

The prognostic value of patient-reported outcomes in allogeneic hematopoietic stem cell transplantation: exploratory analysis of a randomized nutrition intervention trial.

Whether patient-reported outcomes (PROs) can predict overall survival (OS) and non-relapse mortality (NRM) among recipients of allogeneic stem cell transplantation (allo-HSCT), is unclear. We performed an exploratory analysis of the prognostic value of patient-reported outcomes (PROs) among 117 recipients of allogeneic stem cell transplantation (allo-HSCT) who participated in a randomized nutrition intervention trial. Cox proportional hazards models were used to investigate possible associations between PROs collected pre-allo-HSCT (baseline) using scores from the EORTC Quality of Life Questionnaire-Core 30 (QLQ-C30) and 1-year overall survival (OS), whereas logistic regression was used to study associations between these PROs and 1-year non-relapse mortality (NRM). Multivariable analyses indicated that only the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) and the European Bone Marrow Transplantation (EBMT) risk score were associated with 1-year OS. In the multivariable model including clinical-sociodemographic factors for 1-year NRM, our analysis showed that living alone (p=0.009), HCT-CI (p=0.016), EBMT risk score (p=0.002), and stem cell source (p=0.046) could be associated with 1-year NRM. Moreover, in the multivariable model, our analysis showed that only appetite loss from the QLQ-C30 was associated with 1-year NRM (p=0.026). In conclusion, in this specific setting, our analysis suggests that the commonly used HCT-CI and EBMT risk scores could be predictive for both 1-year OS and 1-year NRM, whereas baseline PROs in general were not.

Allogeneic stem cell transplantation in adults 2015-21. / Allogen stamcelletransplantasjon hos voksne 2015­21.

BACKGROUND: Allogeneic stem cell transplantation is the only curative treatment for several malignant and non-malignant haematological diseases, and is associated with a risk of serious complications. In recent years, several changes have been introduced with the aim of reducing treatment-related complications. This retrospective study reviews quality indicators for patients who underwent transplantation in the period 2015-21. MATERIAL AND METHOD: The study included 589 adult patients who were treated with allogeneic stem cell transplantation for the first time at Oslo University Hospital in the period May 2015 to May 2021. Three two-year periods are compared using descriptive methods. RESULTS: In the period 2015-2021, the number of first-time transplant patients per year increased from 85 to 113. One-year survival increased from 68 % in the first two-year period to 74 % in the second period and 82 % in the last period. Both acute and chronic GVHD were reduced, and one-year GVHD-free and relapse-free survival increased from 42 % to 60 % during the study period. INTERPRETATION: Since 2015, the number of transplants has increased, while survival has improved and the risk of complications is lower.

Graft-Versus-Host-Disease and Health-Related Quality of Life in Young Long-term Survivors of Cancer and Allogeneic Hematopoietic Stem Cell Transplantation.

Purpose: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an established treatment predominantly for malignancies. Chronic graft-versus-host disease (cGVHD) is the leading long-term complication after allo-HSCT, but knowledge on cGVHD and health-related quality of life (HRQOL) in long-term survivors of allo-HSCT performed in childhood, adolescence, and young adulthood (CAYA) is scarce. Therefore, we aimed to (1) assess prevalence and risk factors of active cGVHD using the 2014 National Institutes of Health-Consensus criteria, (2) investigate associations between cGVHD severity, patient-reported symptom burden, and HRQOL, and (3) compare HRQOL of survivors to population norms. Methods: We conducted a nationwide cross-sectional study in long-term survivors of CAYA allo-HSCT combining clinical examinations and patient-reported outcome measures. Results: We included 103 survivors, 55 (53%) females, median age of 19.6 years [range 0.3-29.9] at HSCT, 16.8 years [6.0-32.0] from HSCT, and 77 (75%) with underlying malignancy. Overall, 32 (31%) survivors were diagnosed with active cGVHD. The risk of active cGVHD was increased with prior acute GVHD and reduced with in vivo T cell depletion. cGVHD severity was associated with increased symptom burden, but not with adverse HRQOL. Compared to Norwegian population norms, allo-HSCT survivors reported significantly lower HRQOL. Conclusion: These results indicate a high prevalence of cGVHD in long-term survivors of CAYA allo-HSCT. Although we did not find an association between cGVHD severity and HRQOL, survivors reported significantly poorer HRQOL compared to population norms. Knowledge on the long-term consequences of cGVHD will be important for optimizing treatment and long-term follow-up care after CAYA allo-HSCT.

Meiotic drive in chronic lymphocytic leukemia compared with other malignant blood disorders.

The heredity of the malignant blood disorders, leukemias, lymphomas and myeloma, has so far been largely unknown. The present study comprises genealogical investigations of one hundred and twelve Scandinavian families with unrelated parents and two or more cases of malignant blood disease. For comparison, one large family with related family members and three hundred and forty-one cases of malignant blood disease from the Faroese population was included. The inheritance is non-Mendelian, a combination of genomic parental imprinting and feto-maternal microchimerism. There is significantly more segregation in maternal than in paternal lines, predominance of mother-daughter combinations in maternal lines, and father-son combinations in paternal lines. Chronic lymphocytic leukemia is the most frequent diagnosis in the family material, and chronic lymphocytic leukemia has a transgenerational segregation that is unique in that inheritance of susceptibility to chronic lymphocytic leukemia is predominant in males of paternal lines. Male offspring with chronic lymphocytic leukemia in paternal lines have a birth-order effect, which is manifest by the fact that there are significantly more male patients late in the sibling line. In addition, there is contravariation in chronic lymphocytic leukemia, i.e. lower occurrence than expected in relation to other diagnoses, interpreted in such a way that chronic lymphocytic leukemia remains isolated in the pedigree in relation to other diagnoses of malignant blood disease. Another non-Mendelian function appears in the form of anticipation, i.e. increased intensity of malignancy down through the generations and a lower age at onset of disease than otherwise seen in cases from the Cancer Registers, in acute lymphoblastic leukemia, for example. It is discussed that this non-Mendelian segregation seems to spread the susceptibility genes depending on the gender of the parents and not equally to all children in the sibling line, with some remaining unaffected by susceptibility i.e. "healthy and unaffected", due to a birth order effect. In addition, anticipation is regarded as a non-Mendelian mechanism that can amplify, «preserve¼ these vital susceptibility genes in the family. Perhaps this segregation also results in a sorting of the susceptibility, as the percentage of follicular lymphoma and diffuse large B-cell lymphoma is lower in the family material than in an unselected material. Although leukemias, lymphomas and myelomas are potentially fatal diseases, this non-Mendelian distribution and amplification hardly play any quantitative role in the survival of Homo sapiens, because these diseases mostly occur after fertile age.

A family with cytotoxic T-lymphocyte-associated protein 4 haploinsufficiency presenting with aplastic anaemia.

Acquired aplastic anaemia is a rare disease, and occurrence in more than one member of the same family is uncommon. With this case report, we wish to highlight the importance of searching for an underlying genetic cause when this occurs. It may have consequences for future generations in affected families. CTLA4 haploinsufficiency is a heterogeneous disease entity with severe systemic immune dysregulation associated with several autoimmune diseases including aplastic anaemia.

T cells targeted to TdT kill leukemic lymphoblasts while sparing normal lymphocytes.

Unlike chimeric antigen receptors, T-cell receptors (TCRs) can recognize intracellular targets presented on human leukocyte antigen (HLA) molecules. Here we demonstrate that T cells expressing TCRs specific for peptides from the intracellular lymphoid-specific enzyme terminal deoxynucleotidyl transferase (TdT), presented in the context of HLA-A*02:01, specifically eliminate primary acute lymphoblastic leukemia (ALL) cells of T- and B-cell origin in vitro and in three mouse models of disseminated B-ALL. By contrast, the treatment spares normal peripheral T- and B-cell repertoires and normal myeloid cells in vitro, and in vivo in humanized mice. TdT is an attractive cancer target as it is highly and homogeneously expressed in 80-94% of B- and T-ALLs, but only transiently expressed during normal lymphoid differentiation, limiting on-target toxicity of TdT-specific T cells. TCR-modified T cells targeting TdT may be a promising immunotherapy for B-ALL and T-ALL that preserves normal lymphocytes.

Successful Control of Hepatitis B Virus Reactivation following Restart of Ibrutinib in Chronic Lymphocytic Leukaemia.

Ibrutinib is a targeted therapy drug that blocks the activity of Bruton's tyrosine kinase, and it is an approved treatment for several mature B-cell malignancies including chronic lymphocytic leukaemia (CLL). Side effects include infections, cytopenia, nausea, and diarrhoea. In this report, we describe a case of hepatitis B reactivation in a female CLL patient undergoing treatment with ibrutinib. Diagnosis was confirmed with highly elevated hepatitis B virus DNA and a prior blood sample confirmed previous exposure. Ibrutinib was paused, and antiviral therapy was initiated with prompt clinical improvement. Ibrutinib was reinitiated shortly after clinical improvement. Thus, our case report demonstrates that systematic HBV screening is essential before starting treatment with ibrutinib. We suggest that antiviral prophylaxis is considered for patients at risk of reactivation, and ibrutinib may be continued following HBV reactivation with proper antiviral treatment.

Tissue factor pathway inhibitor upregulates CXCR7 expression and enhances CXCL12-mediated migration in chronic lymphocytic leukemia.

The infiltration of chronic lymphocytic leukemia (CLL) cells into lymphoid organs correlates with disease severity. CXCL12 is a key chemotactic factor for the trafficking of CLL. Tissue factor pathway inhibitor (TFPI) is a serine protease inhibitor and plays a role in CXCL12-mediated hematopoietic stem cell homing. We aim to explore the role of TFPI in CXCL12-mediated migration of CLL cells. In this study, plasma TFPI concentrations were measured by ELISA. CLL cells were isolated from patients and used for trans-endothelial migration (TEM) assays. Quantitative RT-PCR and Western blotting were used to detect the expression of CXCR7, CXCR4 and ß-catenin. Immunofluorescence and co-immunoprecipitation was used to detect the binding of TFPI and glypican-3 (GPC3). We found that plasma TFPI levels in CLL patients were higher than in healthy controls, particularly in the patients with advanced disease. TFPI enhanced CXCL12-mediated TEM of CLL cells by increasing the expression of the CXCL12 receptor CXCR7, but not of the CXCL12 receptor CXCR4. The effect of TFPI on TEM was abolished by the CXCR7 inhibitor, CCX771, while the CXCR4 inhibitor AMD3100 strongly increased TEM. TFPI co-localized with GPC3 on the cell surface. An antibody to GPC3, HS20, decreased CXCR7 expression and abolished the effect of TFPI on TEM. TFPI activated ß-catenin and the Wnt/ß-catenin inhibitor IWP4 repressed the effect of TFPI on CXCR7 expression and TEM. We conclude that TFPI may contribute to organ infiltration in CLL patients.

HLA class I depletion by citric acid, and irradiation of apheresis platelets for transfusion of refractory patients.

BACKGROUND: Patients can form antibodies to foreign human leukocyte antigen (HLA) Class I antigens after exposure to allogeneic cells. These anti-HLA class I antibodies can bind transfused platelets (PLTs) and mediate their destruction, thus leading to PLT refractoriness. Patients with PLT refractoriness need HLA-matched PLTs, which require expensive HLA typing of donors, antibody analyses of patient sera and/or crossmatching. An alternative approach is to reduce PLT HLA Class I expression using a brief incubation in citric acid on ice at low pH. METHODS AND MATERIALS: Apheresis PLT concentrates were depleted of HLA Class I complexes by 5 minutes incubation in ice-cold citric acid, at pH 3.0. Surface expression of HLA Class I complexes, CD62P, CD63, phosphatidylserine, and complement factor C3c was analyzed by flow cytometry. PLT functionality was tested by thromboelastography (TEG). RESULTS: Acid treatment reduced the expression of HLA Class I complexes by 71% and potential for C3c binding by 11.5-fold compared to untreated PLTs. Acid-treated PLTs were significantly more activated than untreated PLTs, but irrespective of this increase in steady-state activation, CD62P and CD63 were strongly upregulated on both acid-treated and untreated PLTs after stimulation with thrombin receptor agonist peptide. Acid treatment did not induce apoptosis over time. X-ray irradiation did not significantly influence the expression of HLA Class I complexes, CD62P, CD63, and TEG variables on acid treated PLTs. CONCLUSION: The relatively simple acid stripping method can be used with irradiated apheresis PLTs and may prevent transfusion-associated HLA sensitization and overcome PLT refractoriness.

Transformation to plasmablastic lymphoma in CLL upon ibrutinib treatment.

Chronic lymphatic leukaemia (CLL) is the most common leukaemia in the Western world. Ibrutinib, a tyrosine kinase inhibitor, is the treatment of choice on relapse or p53-dysfunction. Richter's transformation to diffuse large B cell lymphoma is most often seen. However, transformation to other aggressive lymphomas as plasmablastic lymphoma (PBL) does occur. PBL is an extremely aggressive lymphoma and is usually treated using a CHOP-like regimen (cyclophosphamide, doxorubicin, vincristine and prednisone/dexamethasone), but with poor outcome. The only curative treatment is allogeneic stem cell transplant (ASCT).We report on a case of CLL treated with ibrutinib that underwent transformation to PBL. Due to high expression of CD138, we added daratumumab to the chemotherapy with a good, but transitory response. The case did not make it to an ASCT. Targeting CD138 by daratumumab may be added to chemoimmune therapy for PBL.

Antitumor, Anti-Inflammatory and Antiallergic Effects of Agaricus blazei Mushroom Extract and the Related Medicinal Basidiomycetes Mushrooms, Hericium erinaceus and Grifola frondosa: A Review of Preclinical and Clinical Studies.

Since the 1980s, medicinal effects have been documented in scientific studies with the related Basidiomycota mushrooms Agaricus blazei Murill (AbM), Hericium erinaceus (HE) and Grifola frondosa (GF) from Brazilian and Eastern traditional medicine. Special focus has been on their antitumor effects, but the mushrooms' anti-inflammatory and antiallergic properties have also been investigated. The antitumor mechanisms were either direct tumor attack, e.g., apoptosis and metastatic suppression, or indirect defense, e.g., inhibited tumor neovascularization and T helper cell (Th) 1 immune response. The anti-inflammatory mechanisms were a reduction in proinflammatory cytokines, oxidative stress and changed gut microbiota, and the antiallergic mechanism was amelioration of a skewed Th1/Th2 balance. Since a predominant Th2 milieu is also found in cancer, which quite often is caused by a local chronic inflammation, the three conditions-tumor, inflammation and allergy-seem to be linked. Further mechanisms for HE were increased nerve and beneficial gut microbiota growth, and oxidative stress regulation. The medicinal mushrooms AbM, HE and GF appear to be safe, and can, in fact, increase longevity in animal models, possibly due to reduced tumorigenesis and oxidation. This article reviews preclinical and clinical findings with these mushrooms and the mechanisms behind them.

Two Consecutive Episodes of Severe Delayed Hemolytic Transfusion Reaction in a Sickle Cell Disease Patient.

Patients with sickle cell disease (SCD) suffer from anemia and painful vaso-occlusive crisis (VOC) and sometimes need blood transfusions. Delayed hemolytic transfusion reaction (DHTR) is a rare life-threatening complication observed in SCD and mimics VOC. We describe a female SCD patient undergoing three surgical procedures during which DHTR developed following the first two. Prior to a planned tonsillectomy, she received transfusion and three days after surgery developed severe hemolysis as well as pain and respiratory symptoms. On suspicion of VOC, she received additional transfusions and became hemodynamically unstable, and her hemolytic anemia worsened. Gradually, she recovered and could be discharged after two weeks; DHTR was not suspected. Sixteen months later, an arthroplasty was performed due to avascular necrosis, and again she was transfused preoperatively. Similar to the initial surgery, she developed symptoms and signs of VOC after three days, but this time, DHTR was suspected and further transfusions were withheld. Although immunosuppressive medication did not alleviate the condition, she improved on combined treatment with darbepoietin, rituximab, and eculizumab. Six months later, a second arthroplasty was performed uneventfully after prophylaxis with rituximab and without transfusion. DHTR should be considered in the presence of severe, unexplained hemolysis following a recent transfusion, and additional transfusions in this setting should be given only on vital indication.

Chronic lymphocytic leukemia and secondary hematological malignancies: A nation-wide cancer registry study.

OBJECTIVE: Chronic lymphocytic leukemia (CLL) treatment has changed dramatically, and landscape of second hematologic malignancies (SHM) evolves in the new era of targeted therapy. No data were available about the real-world burden of SHM. METHODS: All 2631 patients with CLL in the Cancer registry of Norway registered 2003-2012 were included. RESULTS: After median follow-up of 6.6 years, 103 patients (4%) developed SHM. Diffuse large B-cell lymphoma (DLBCL) was most common (n = 65; 63%). Median survival was 9.3 years (95% CI; 8.9-9.8) in non-SHM patients and 1.7 years in DLBCL, 0.8 years in Hodgkin lymphoma (n = 12), and 2.8 years in myeloid neoplasia (n = 15; 95% CI: 0.3-2.6, 0.6-2.9, and 0.4-5.3, respectively; P < .001). Outcomes were poorest for SHM patients treated for CLL (HR 2.76, 95% CI 1.4-5.5, P = 0.003). A higher proportion of men and younger age were found in SHM patients (median age 66 vs 72 years in non-SHM; P < .001; men 68% vs 57%, P = .03). Myeloid neoplasia was rare (incidence rate 1/1000 person-years; 95% CI: 0.6-1.5) and tended to occur later than DLBCL in patients treated for CLL (median time from CLL to SHM 62 vs 45 months; P = .09). CONCLUSIONS: SHM and especially myeloid malignancies were rare in chemoimmunotherapy era.

The Systemic Metabolic Profile Early after Allogeneic Stem Cell Transplantation: Effects of Adequate Energy Support Administered through Enteral Feeding Tube.

Patients undergoing allogeneic stem cell transplantation usually require nutritional support. There is no consensus on whether enteral support through tube feeding should be preferred. A recent randomized study could not detect any difference between enteral and parenteral feeding with regard to post-transplant outcomes, whereas 2 retrospective studies described an association between enteral feeding and a favorable post-transplant outcome. We compared pre- and post-transplant plasma metabolomic profiles for 10 patients receiving mainly enteral nutritional support and 10 patients receiving mainly parenteral support. Samples were collected before conditioning and 3 weeks post-transplant; 824 metabolites were analyzed using mass spectrometry. The pretransplant metabolite profiles showed a significant overlap between the 2 groups. Post-transplant samples for both patient groups showed an increase of secondary bile acids and endocannabinoids, whereas reduced levels were seen for food preservatives, plasmalogens, and retinol metabolites. The main post-transplant differences between the groups were decreased levels of fatty acids and markers of mitochondrial activation in the control group, indicating that these patients had insufficient energy intake. A significant effect was also seen for heme/bilirubin metabolism for the parenteral support. To conclude, allotransplant recipients showed altered metabolic profiles early after transplantation; this was mainly due to the conditioning/transplantation/reconstitution, whereas the type of nutritional support had minor effects.

Richter syndrome epidemiology in a large population based chronic lymphocytic leukemia cohort from Norway.

BACKGROUND: Transformation to aggressive lymphoma (Richter syndrome, RS) occurs in a substantial subset of patients who must discontinue targeted therapy for chronic lymphocytic leukemia (CLL). RS has an extremely poor prognosis. METHODS: Using the nation-wide database of The Cancer Registry of Norway of 7664 CLL patients registered between 1953-2012, we identified 107 patients experiencing RS. RESULTS: Seventy seven (72%) of RS patients were identified among 2631 CLL patients diagnosed between 2003-2012; diffuse large B-cell lymphoma (DLBCL) was identified in 65 (84%), Hodgkin lymphoma (HL) in 12 (16%) patients and the diagnosis was confirmed in 50 (65%) available biopsy specimens. The incidence rate in this period was 4.7/1000 person-years (95% CI: 3.8-5.9). The median survival from CLL diagnosis was 1.7 years (95% CI: 0.34-2.3) for RS patients while it was 10.3 years (95% CI: 9.5-10.9) for the remaining CLL patients. Male gender predominated among RS patients (69%) compared to CLL population (58%) and RS patients were diagnosed with CLL at a significantly younger age than the remaining patients (65 vs. 72 years). Median time from diagnosis of CLL to RS was 2 years (Range, 0-13 years). No CLL treatment was administered in 25 (33%) patients prior RS diagnosis; a median of 1 treatment line was administered to pretreated patients. The median duration of survival after RS diagnosis was 27 months (95% CI; 9-88). CONCLUSIONS: Collectively, RS was a rare complication of CLL in the chemoimmunotherapy era, occurred early in the CLL course in younger, and both treatment naïve and pretreated patients, and shortened survival substantially.

A Case of Posttransfusion Purpura with Severe Refractory Thrombocytopenia but No Cutaneous Manifestations.

Posttransfusion purpura is a serious adverse effect of transfusion due to HPA-antibodies. A young female was diagnosed with acute leukaemia, and treatment commenced. Severe thrombocytopenia ensued. No platelet increment was achieved despite transfusions with buffy coat, HLA-compatible, and HPA-1a negative platelets. The workup indicated the presence of anti-HPA-1a. When the diagnosis of posttransfusion purpura was sufficiently substantiated, she had experienced a fatal intracerebral haemorrhage.

STIM1 R304W causes muscle degeneration and impaired platelet activation in mice.

STIM1 and ORAI1 regulate store-operated Ca2+ entry (SOCE) in most cell types, and mutations in these proteins have deleterious and diverse effects. We established a mouse line expressing the STIM1 R304 W gain-of-function mutation causing Stormorken syndrome to explore effects on organ and cell physiology. While STIM1 R304 W was lethal in the homozygous state, surviving mice presented with reduced growth, skeletal muscle degeneration, and reduced exercise endurance. Variable STIM1 expression levels between tissues directly impacted cellular SOCE capacity. In contrast to patients with Stormorken syndrome, STIM1 was downregulated in fibroblasts from Stim1R304W/R304W mice, which maintained SOCE despite constitutive protein activity. In studies using foetal liver chimeras, STIM1 protein was undetectable in homozygous megakaryocytes and platelets, resulting in impaired platelet activation and absent SOCE. These data indicate that downregulation of STIM1 R304 W effectively opposes the gain-of-function phenotype associated with this mutation, and highlight the importance of STIM1 in skeletal muscle development and integrity.

Improved outcome in patients following autologous stem cell transplantation for multiple myeloma in south eastern Norway 2001-2010: a retrospective, population based analysis.

BACKGROUND: With the advent of novel drugs improved overall survival in patients with multiple myeloma, including patients who received up-front autologous stem cell transplantation (ASCT), has been reported from several centers. Here we report on overall survival in a population-based cohort of patients receiving ASCT as first line treatment and in whom novel agents were an option for second and later lines of treatment. METHODS: Patients with multiple myeloma ≤ 65 years of age who were considered for ASCT from 01.01.2001-31.06.2005 (period 1) and from 01.07.2005 until 31.12.2009 (period 2) at Oslo University Hospital (OUH) were identified. Relevant data were collected from the patients' medical records. RESULTS: Altogether, 293/355 patients received ASCT. In all, median OS was 82.9 months in patients ≤ 60 years of age and 59.0 months in patients 61-65 years. For patients ≤ 60 years of age median OS increased from 70.6 months to 87.7 months (p = 0. 22) and median survival after start of second line therapy increased from 34.5 months to 46.5 months (p = 0.015) between the two periods. For patients 61-65 years of age median OS increased from 57.3 months to 61.2 months (p = 0. 87) and median survival after start of second line therapy was practically unchanged (32.6 months vs. 33.1 months (p = 0.97) between the periods. In patients ≤ 60 years of age salvage ASCT was used in 34% of the patients while in patients 61-65 years of age salvage ASCT was used in 7.3% of the patients. The use of salvage ASCT and novel drugs, as well as the number of treatment lines, were higher in patients ≤ 60 years of age and increased during the study period. CONCLUSION: In patients ≤ 60 years of age an increased median OS of 17 months between the two periods were noted, but the difference failed to reach statistical significance. However, a statistically significant difference in median survival of 12 months after start of second line therapy was found in this age group, which may be explained by a more active second line treatment. In patients 61-65 years only a slight increase of survival, not statistically significant, was noted between the periods.