[Combined immunosuppression with cyclosporin A, mycophenolate mofetil (MMF) and dexamethasone for activity control of recurrent secondary hemophagocytic lymphohistiocytosis (sHLH) with underlying systemic lupus erythematosus (SLE)]. / Kombinierte Immunsuppression mit Cyclosporin A, Mycophenolatmofetil (MMF) und Dexamethason zur Aktivitätskontrolle einer rezidivierten, sekundären hämophagozytischen Lymphohistiozytose (sHLH) auf dem Boden eines systemischen Lupus erythematodes (SLE).

A 42-year-old female patient was admitted to hospital due to acute neurological symptoms (dysarthria, disorientation). After exclusion of cerebral ischemia and hemorrhage an autoimmune encephalitis was diagnosed. Shortly before as an outpatient the suspicion of the presence of systemic lupus erythematosus (SLE) was voiced. The patient showed a constellation of high levels of inflammatory laboratory parameters and within a few days developed a severe pancytopenia. In the presence of all diagnostic criteria a secondary hemophagocytic lymphohistiocytosis (sHLH) was diagnosed and confirmed by a kidney biopsy during the course of the underlying SLE. The immunosuppressive treatment with etoposide and high-dose dexamethasone according to the HLH-94 protocol only showed temporary success. After 3 weeks of treatment with a protocol-conform dose reduction, under running treatment a new exacerbation of symptoms was confirmed. A renewed dose escalation of the drugs used did not lead to control of the symptoms. The inflammatory activity could only be sustainably controlled by the use of cyclosporin A in combination with mycophenolate mofetil (MMF) and dexamethasone. After stabilization of the condition of the patient, an outpatient follow-up care was possible.

Different treatment strategies versus a common standard arm (CSA) in patients with newly diagnosed AML over the age of 60 years: a randomized German inter-group study.

A randomized inter-group trial comparing more intensive treatment strategies to a common standard arm 3 + 7 (CSA) was conducted in patients with non-M3 AML. Untreated patients ≥ 60 years were allocated to the CSA (n = 132) or to the study group arms (n = 1154) of the AMLCG (TAD/HAM versus HAM/HAM ± G-CSF followed by TAD and maintenance) and the OSHO (intermediate-dose ara-C/mitoxantrone followed by ara-C/mitoxantrone). Median age of the 1147 eligible patients was 69 (range 60-87) years. CR/CRi status at 90 days was not significantly different between the CSA (54% (95%CI: 45-64)) and the study group arms (53% (95%CI: 47-60) and 59% (95%CI: 58-63)). The five-year event-free survival (EFS) probability (primary endpoint) was 6.2% (95%CI: 2.7-14.0) in the CSA, 7.6% (95%CI: 4.5-12.8) in study group A and 11.1% (95%CI: 9.0-13.7) in B. The 5-year OS was 17.2% (95%CI: 11.0-26.9), 17.0% (95%CI: 2.0-23.9), and 19.5% (95%CI: 16.7-22.8) in CSA, study group A and B, respectively. Neither study group differed significantly from the CSA regarding EFS, OS, or relapse-free survival. In multivariate analyses, allocation to the treatment strategy was not significantly associated with the time-to-event endpoints. The evaluation of more intensive treatment strategies did not show clinically relevant outcome differences when compared to CSA.

Sex-Disaggregated Analysis of Biology, Treatment Tolerability, and Outcome of Multiple Myeloma in a German Cohort.

INTRODUCTION: Multiple myeloma (MM) is a plasma cell disease that affects more men than women. Although there is an obvious imbalance in incidence, knowledge of differences in biology and outcome between the sexes is surprisingly rare. METHODS: We performed a unicentric retrospective analysis of patients with MM treated at a tertiary cancer centre between 2003 and 2018. RESULTS: We present a sex-disaggregated analysis of the characteristics and outcome of MM in a cohort of 655 patients (median age at diagnosis 62 years; 363 men with a median age at diagnosis 62 years and 292 women with a median age at diagnosis 63 years, p = 0.086). Most patients (n = 561, 86%) received myeloma-specific treatment. Median overall survival was 76 months (95% CI 63-89) (72 months in men [95% CI 54-90] and 83 months in women [95% CI 66-100], p = ns). Apart from a higher incidence of moderate and severe anaemia in women (p < 0.001), there were no statistically significant differences in the biology of the underlying MM. Similarly, in the group of patients who received high-dose therapy with autologous stem-cell transplantation (ASCT, n = 313), no statistically significant differences apart from more frequent anaemia in women were detected regarding the biology of the disease. However, there was a trend toward a higher plasma cell infiltration of the bone marrow and toward more frequent high-risk features in women. In contrast, relevant comorbidities were significantly more common in men (for example, coronary heart disease in 13% of men vs. 2% of women, p < 0.001). Toxicities after ASCT were not significantly different between the sexes with the exception of severe mucositis, which occurred in 22% of men versus 40% of women (p = 0.001). CONCLUSION: In conclusion, this first sex-disaggregated analysis of MM patients in Germany supports previous findings that survival is comparable amongst sexes, but women experience more toxicity of high-dose therapy. The higher incidence of clinically relevant anaemia in women warrants further investigation to exclude underlying treatable causes.

Kinetics of Renal Function during Induction in Newly Diagnosed Multiple Myeloma: Results of Two Prospective Studies by the German Myeloma Study Group DSMM.

BACKGROUND: Preservation of kidney function in newly diagnosed (ND) multiple myeloma (MM) helps to prevent excess toxicity. Patients (pts) from two prospective trials were analyzed, provided postinduction (PInd) restaging was performed. Pts received three cycles with bortezomib (btz), cyclophosphamide, and dexamethasone (dex; VCD) or btz, lenalidomide (len), and dex (VRd) or len, adriamycin, and dex (RAD). The minimum required estimated glomerular filtration rate (eGFR) was >30 mL/min. We analyzed the percent change of the renal function using the International Myeloma Working Group (IMWG) criteria and Kidney Disease: Improving Global Outcomes (KDIGO)-defined categories. RESULTS: Seven hundred and seventy-two patients were eligible. Three hundred and fifty-six received VCD, 214 VRd, and 202 RAD. VCD patients had the best baseline eGFR. The proportion of pts with eGFR <45 mL/min decreased from 7.3% at baseline to 1.9% PInd (p < 0.0001). Thirty-seven point one percent of VCD versus 49% of VRd patients had a decrease of GFR (p = 0.0872). IMWG-defined "renal complete response (CRrenal)" was achieved in 17/25 (68%) pts after VCD, 12/19 (63%) after RAD, and 14/27 (52%) after VRd (p = 0.4747). CONCLUSIONS: Analyzing a large and representative newly diagnosed myeloma (NDMM) group, we found no difference in CRrenal that occurred independently from the myeloma response across the three regimens. A trend towards deterioration of the renal function with VRd versus VCD may be explained by a better pretreatment "renal fitness" in the latter group.

Melphalan 200 mg/m2 does not increase toxicity and improves survival in comparison to reduced doses of melphalan in multiple myeloma patients.

Autologous stem cell transplantation (ASCT) conditioned with melphalan 200 mg/m2 (Mel200) is standard of care for young multiple myeloma (MM) patients. Lower doses of melphalan (MelRed) have been used to reduce toxicity, although data regarding their efficacy are not concordant. We retrospectively evaluated 313 MM patients receiving ASCT at Jena University Hospital between 2003 and 2017. Patients receiving MelRed were on average older (p < 0.001), had a worse renal function (p < 0.001) and more comorbidities (p < 0.001). No differences were seen in treatment response before ASCT between the two groups, whilst after ASCT the rate of at least very good partial responses (VGPR) was significantly higher for patients receiving Mel200 (93% vs. 76%, p < 0.001). PFS (39 vs. 20 months, p < 0.001) and OS (103 vs. 59 months, p = 0.001) were longer with Mel200. Toxicities were comparable in the two groups. After adjusting for age and clinical characteristics using the propensity score, for VGPR before and after ASCT and for double ASCT strategy in a Cox regression analysis, Mel200 was still associated with a lower risk of disease progression (HR = 0.40, 95% CI = 0.40-0.96) and of death (HR = 0.61, 95% CI = 0.35-1.07). Our results confirm that Mel200 is still the standard of care for ASCT eligible myeloma patients.

Frailty impairs the feasibility of induction therapy but not of maintenance therapy in elderly myeloma patients: final results of the German Maintenance Study (GERMAIN).

PURPOSE: The German Maintenance Study (GERMAIN) was designed to evaluate the impact of lenalidomide maintenance after induction therapy with bortezomib, melphalan and prednisolone (VMP) in transplant-ineligible newly diagnosed multiple myeloma (MM) patients. METHODS: Due to poor accrual and high dropout rate, only 85 patients (planned 286) entered the trial and 40 (planned 200) were randomized to lenalidomide maintenance (n = 19) vs. observation (n = 21). RESULTS: The primary endpoint, improved progression-free survival, was not met (p = 0.3572). After a median follow-up of 12.9 months, median progression-free survival in the lenalidomide arm was 14.4 months and 11.4 months with placebo. The hazard ratio 0.621 (95% confidence interval: [0.224, 1.725]) was about the same as expected (0.625). However, with only 40 patients randomized, the actual power to detect a difference was 11%. Of patients receiving at least one dose of induction, 54% were frail according to a modified International Myeloma Working Group frailty score. Discontinuations were high during induction (47%), and affected mainly frail patients (54%). Despite a higher rate of adverse events in the lenalidomide arm (p = 0.0061), only 2 patients discontinued lenalidomide due to toxicity. CONCLUSION: A frailty assessment with appropriate dose modification for induction therapy should be mandatory for all elderly non-transplant-eligible myeloma patients.

The risk of infections in multiple myeloma before and after the advent of novel agents: a 12-year survey.

Infections represent a major cause of morbidity and mortality in multiple myeloma and are linked to both therapy- and disease-related factors. Although it has been suggested that the rate of infections increased since the introduction of novel agents, controversies still exist. To better assess the risk factors associated with infections in the era of novel agents, we conducted a large retrospective analysis of 479 myeloma patients treated at Jena University Hospital over a period of 12 years. During their disease history, 65% of patients developed at least one infection, and 37% of therapies were associated with at least one infectious episode. The rate of infections was constant over the years, with no increase in infectious complications after the routine implementation of novel agents. Infections were mainly bacterial and strongly associated with high disease burden, relapsed disease, and treatment with high-dose chemotherapy. Varicella zoster virus (VZV) reactivations occurred late during treatment (median time between high-dose chemotherapy and VZV reactivation 6 months, range 0-44 months), and fewer patients developed a VZV reactivation after 2009 (p = 0.001). Infections are still one of the major causes of morbidity in myeloma patients, and prophylactic measures are urgently needed to reduce this potentially lethal complication.

Lenalidomide in combination with bendamustine and prednisolone in relapsed/refractory multiple myeloma: results of a phase 2 clinical trial (OSHO-#077).

INTRODUCTION: While lenalidomide monotherapy is established for relapsed and/or refractory multiple myeloma (MM) treatment, combination therapies including lenalidomide are still under investigation in a number of phase 2/3 studies. In the current study, a treatment regime of lenalidomide (Revlimid®), bendamustine and prednisolone (RBP) was tested in patients with relapsed/refractory MM. METHODS: In the previously completed phase 1 study RBP with a dose of 75 mg/m2 bendamustine days 1-2, prednisolone 100 mg days 1-4 and 25 mg lenalidomide days 1-21 was well tolerated. RESULTS: Between July 2011 and September 2013, 25 patients were included in this analysis. The median number of previous treatments was 1 (range 1-2). Twenty-two patients (88%) responded after at least two cycles of RBP (one sCR, five nCR, eight VGPR and eight PR). The median time to first haematological response was 28 days, and median time to best response was 56 days. Due to increased haematological toxicity a dose reduction in most patients required in subsequent cycles of therapy. The median progression-free and overall survival was 22 and 38 months, respectively. In conclusion RBP is a highly effective therapy for patients with relapsed/refractory MM. In contrast to our phase 1 study, dose reduction was necessary in many patients because of haematological toxicity.

Safety issues and management of toxicities associated with new treatments for multiple myeloma.

INTRODUCTION: In the last decade, the availability of new drugs for the treatment of Multiple Myeloma (MM) significantly improved patients' outcomes, but also raised attention towards a new spectrum of adverse events. Recently, four novel agents with different mechanisms of action (carfilzomib, elotuzumab, daratumumab and panobinostat) have been approved for the treatment of MM. This review aims at providing physicians with the tools to recognize and handle toxicity issues related with these new treatments. Areas covered: This review focuses on the management of drug related adverse events of the latest approved drug combinations. New drug combinations under development and still in the phase of approval will be briefly discussed. PubMed was searched using the terms 'toxicity', 'carfilzomib', 'elotuzumab' 'daratumumab' and 'panobinostat'. Phase II and III clinical trials and previously published analyses on toxicities were reviewed. For new drug combination abstracts presented at the latest ASH, ASCO and EHA meetings as well as clinicaltrial.gov website was searched and reviewed. Expert commentary: With the development of newer drugs and the availability of different treatment options for MM patients, an accurate evaluation of treatment side effects, their prompt recognition and management is mandatory for all clinical hematologists.

Comparison of two dose levels of cyclophosphamide for successful stem cell mobilization in myeloma patients.

INTRODUCTION: Even in the era of proteasome inhibitors and immunomodulatory drugs, the autologous stem cell transplantation after high-dose melphalan continues to represent a standard approach for myeloma patients in first-line therapy. Different mobilization chemotherapies before stem cell apheresis have been published while cyclophosphamide at a dose level of up to 4 g/m2 has been evaluated and is commonly applied. In contrast, lower dose levels of cyclophosphamide (e.g., 1.5 g/m2) did not result in a sufficient collection of stem cells. METHODS: We retrospectively analyzed the impact of "intermediate-dose" (ID-CY, 2.5 g/m2) versus "high-dose" (HD-CY, 4 g/m2) cyclophosphamide in 101 (48 vs. 53) consecutively evaluable myeloma patients (median age 59 years, range 32-72 years) who underwent stem cell mobilization after induction chemotherapy. Successful stem cell harvest was defined as a stem cell yield of at least 5 million CD34 cells per kg bodyweight. Evaluation of toxicity especially considered infectious complications and hematological toxicity in both subgroups. RESULTS: Successful stem cell mobilization was achieved in 40 of 48 (83 %) and 44 of 53 (83 %) patients, respectively. The median time to apheresis (11 vs. 12 days) and the median CD34 content of stem cell harvest (8.3 vs. 7.6 million CD34 cells per kg bodyweight) did not differ significantly between both groups. There was a significant difference of WBC nadir in favor of the cyclophosphamide regimen with 2.5 g/m2 (0.8 vs. 0.3 Gpt/L, p = 0.021), and neutropenic fever was more often observed in patients who received 4 g/m2 cyclophosphamide (34 vs. 15 %, p = 0.078). Importantly, after induction chemotherapy using the VCD regimen (bortezomib, cyclophosphamide, dexamethasone), successful stem cell mobilization was achieved in 26 of 29 (90 %) patients treated with 2.5 g/m2 and 21 of 25 (84 %) patients receiving 4 g/m2 cyclophosphamide, respectively. CONCLUSIONS: ID-CY is safe and highly effective for stem cell mobilization in patients with newly diagnosed myeloma and associated with a reduced toxicity compared to HD-CY.

A retrospective review of diagnosis and treatment modalities of neuroendocrine tumors (excluding primary lung cancer) in 10 oncological institutions of the East German Study Group of Hematology and Oncology (OSHO), 2010-2012.

RATIONALE: There is a paucity of data on the incidence of neuroendocrine tumors (NET) outside pulmonary primaries and on treatment modalities applied to patients with NET in clinical practice. Only very little therapeutic progress has been made with respect to response and overall survival, particularly among patients with poorly differentiated, WHO grade 3 neuroendocrine carcinomas (G3-NEC). We sought to document the incidence and treatment modalities in patients with NET/NEC within a period of 2 years. METHODS: We conducted a retrospective data analysis using a simple documentation file to be completed in written form or electronically, including localization, WHO grading, treatment modalities, and specific therapeutic regimens applied. Primary lung cancer was excluded. The time period to be covered was 2010 through 2012. Individual patient data such as names or age were not documented, so that no ethics committee approval was required. RESULTS: Ten different hospital- or practice-based institutions contributed their data. One to 35 patients were documented per institution, summing up to 149 patients with 154 tumor localizations. Midgut (n = 46), foregut (n = 42), hindgut (n = 17), lung (n = 9), bladder (n = 8), unknown primary (n = 11), and other including prostate and liver (n = 21) were documented as tumor sites. Histological gradings were G1 (n = 71), G2 (n = 27), G3 (n = 34), undifferentiated "G4" (n = 4), and not specified (n = 13). Treatment modalities were surgical resection (n = 102), chemotherapy (n = 49), somatostatin analogs (n = 39), radiotherapy (n = 22), receptor-directed radionuclide therapy (n = 12), and systemic tyrosine kinase inhibition (n = 5). Chemotherapy was given to patients not only with G3-NEC (n = 31), but also with G2 (n = 12) and G1 NET (n = 7). Somatostatin analogs as well as receptor-directed radionuclides were applied to patients throughout all gradings. CONCLUSIONS: NET and NEC are not very rare tumor entities, but are diagnosed with very different frequencies, possibly depending upon the alertness of pathologists and clinicians. Chemotherapy, receptor-directed radionuclide application, and somatostatin analog therapy are applied without a clear correlation to different histologic gradings. Diagnostic and therapeutic progress in the field of NETs/carcinomas is urgently needed.

A case with coincidental diagnosis of primary central nervous system lymphoma and lymph node sarcoidosis.

Primary central nervous system lymphoma (PCNSL) is rare. Clinical and histological differential diagnosis of systemic lymphoma and sarcoidosis continues to be a challenge. The first case report in the German and English literature of PCNSL and synchronous sarcoidosis is presented. Synchronous mediastinal lymphadenopathy suggestive of non-Hodgkin's lymphoma (NHL) or sarcoidosis was noted. Both conditions require alternative therapeutic and prognostic considerations to PCNSL. A regime of intrathecal and adjuvant systemic chemotherapy led to transient clinical improvement prior to the patient's demise through overwhelming sepsis and multiorgan failure. Post mortem findings confirmed synchronous PCNSL with mediastinal lymph node sarcoidosis.

Clinical impact of nucleophosmin mutations and Flt3 internal tandem duplications in patients older than 60 yr with acute myeloid leukaemia.

BACKGROUND: Nucleophosmin (NPM1) and Flt3 internal tandem duplications (Flt3-ITD mutations) represent the most frequent molecular aberrations in patients with acute myeloid leukemia (AML). While NPM1 mutations are associated with favourable prognosis in younger AML patients, Flt3-ITD mutations reflect an unfavourable prognostic factor in these patients. So far, especially NPM1 mutations have not yet been evaluated exclusively in older patients. PATIENTS AND METHODS: We retrospectively analysed the prevalence of NPM1 and Flt3-ITD mutations and its association with complete remission (CR), and survival in 99 elderly patients (median age 71 yr, range 60-85 yr) newly diagnosed for AML. Primary treatment approach was curative in 54, and palliative in 38 patients, while seven patients received best supportive care only. The mean follow-up of surviving patients was 600 d. RESULTS: Sixty-seven patients were tested negative for NPM1 and Flt3-ITD mutations (group 1), 16 patients carried only a NPM1 mutation (group 2) and nine patients had only a Flt3-ITD mutation (group 3) while additional seven patients were positive for both aberrations (group 4). We can demonstrate a significant higher rate of CR comparing wildtype vs. NPM1 positive patients (40.5% for group 1 vs. 80.0% for group 2, P = 0.03) for patients receiving curative therapy. Interestingly, there is no significant difference in overall survival between group 1 and group 2 (Log-rank test P = 0.22, median 440 d vs. 1125 d). In contrast, patients carrying a Flt3-ITD mutation had a significant worse overall survival compared to wildtype patients (P = 0.03, median 210 d for group 3 + 4 vs. 634 d for group 1 + 2) while no difference of CR rate could be observed (42.8% vs. 48.9%, P = 0.91). CONCLUSION: As elderly but medically fit patients with AML carrying a NPM1 mutation have a high CR rate, age itself should not be a barrier for induction treatment. However, new therapeutic concepts of postremission therapy (e.g. allogeneic stem cell transplantation after dose-reduced conditioning) should be considered for these patients in first CR.

Safety and impact of donor-type red blood cell transfusion before allogeneic peripheral blood progenitor cell transplantation with major ABO mismatch.

BACKGROUND: Changes within the ABO system are regularly observed phenomena in allogeneic bone marrow transplantation (BMT) and peripheral blood progenitor cell transplantation (PBPCT). Major ABO mismatch can lead to different clinical problems including acute hemolysis after infusion of the allograft, delay of red blood cell (RBC) engraftment, or even manifestation of pure red cell aplasia (PRCA). STUDY DESIGN AND METHODS: This retrospective study demonstrates the safety and the impact of donor-type RBC transfusion before allogeneic PBPCT in major ABO settings as routinely performed at our transplantation unit. This study reports on transfusion of mismatched RBCs at the end of the conditioning period in 35 patients who underwent allogeneic PBPCT, which led to a decrease in isoagglutinin titers in most cases. RESULTS: A decrease of isoagglutinin titer after donor-type RBC transfusion can significantly reduce the demand of RBC transfusion between transplantation and Day +30 (p = 0.003). Interestingly, patients who developed PRCA were not observed, a complication being regularly documented by other groups. CONCLUSION: A decrease of isoagglutinin titers by in vivo immunoadsorption before allogeneic PBPCT does not only lack severe complication but also leads to a reduction in demand of RBC transfusion after engraftment and may reduce the incidence of PRCA in these patients.

Increase of interleukin-18 serum levels after engraftment correlates with acute graft-versus-host disease in allogeneic peripheral blood stem cell transplantation.

PURPOSE: Acute graft-versus-host disease (GvHD) is a constant and severe complication after allogeneic stem cell transplantation regularly involving skin, liver, gut, and lungs. The cytokine interleukin-18 (IL-18) has been shown to increase in patients who develop acute GvHD after bone marrow tranplantation (BMT). MATERIALS AND METHODS: Here, we measured IL-18 serum levels after peripheral blood stem cell transplantation (PBSCT) at several characteristic time points in 24 patients (median age 46 years). Patients received a median of 7.3 x 10(6)/kg bodyweight CD34-positive blood stem cells from HLA-matched family donors (n = 5), matched unrelated donors (n = 18), and one mismatched unrelated donor. GvHD prophylaxis consisted of cyclosporin A alone or combined with methotrexate and/or mycophenolate mofetil. RESULTS: In 14 patients we observed no GvHD or only GvHD grade I whereas ten patients developed GvHD grade II-IV post transplant. Low, intermediate, and high levels of serum IL-18 were found in patients after allogeneic PBSCT independently of GvHD after transplantation. In contrast to GvHD arising after BMT, there was no clear correlation between absolute IL-18 serum levels and GvHD grade after PBSCT. However, the individual time course of IL-18 serum level after engraftment correlates with acute GvHD after PBSCT. In detail, an increase of serum IL-18 of at least 1.6-fold after engraftment is associated with acute GvHD II or higher with a sensitivity of three out of four. Using the 1.6 "cut-off" for IL-18 increase after engraftment, a specificity of up to 100% can be achieved. CONCLUSION: The time course of IL-18 serum levels might be used for GvHD prediction after PBSCT comparable to absolute serum levels after BMT.