The JAK1/2 inhibitor ruxolitinib in patients with COVID-19 triggered hyperinflammation: the RuxCoFlam trial.

Dysregulated hyperinflammatory response is key in the pathogenesis in patients with severe COVID-19 leading to acute respiratory distress syndrome and multiorgan failure. Whilst immunosuppression has been proven to be effective, potential biological targets and optimal timing of treatment are still conflicting. We sought to evaluate efficacy and safety of the Janus Kinase 1/2 inhibitor ruxolitinib, employing the previously developed COVID-19 Inflammation Score (CIS) in a prospective multicenter open label phase II trial (NCT04338958). Primary objective was reversal of hyperinflammation (CIS reduction of ≥25% at day 7 in ≥20% of patients). In 184 patients with a CIS of ≥10 (median 12) ruxolitinib was commenced at an initial dose of 10 mg twice daily and applied over a median of 14 days (range, 2-31). On day 7, median CIS declined to 6 (range, 1-13); 71% of patients (CI 64-77%) achieved a ≥25% CIS reduction accompanied by a reduction of markers of inflammation. Median cumulative dose was 272.5 mg/d. Treatment was well tolerated without any grade 3-5 adverse events related to ruxolitinib. Forty-four patients (23.9%) died, all without reported association to study drug. In conclusion, ruxolitinib proved to be safe and effective in a cohort of COVID-19 patients with defined hyperinflammation.

[Hemophagocytic lymphohistiocytosis in critically ill patients]. / Die hämophagozytische Lymphohistiozytose bei kritisch kranken Patienten.

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammation syndrome. In adults, secondary HLH is mostly observed. HLH is often triggered by infections, malignancies or autoimmune disorders. However, HLH cases in association with immunotherapies have been described recently. HLH in critically ill patients is often difficult to differentiate from sepsis. Both conditions can also be present at the same time. Early diagnosis and timely initiation of an adequate immunosuppressive therapy are essential for the further course and the prognosis of HLH. Therefore, HLH should represent a differential diagnosis in critically ill patients with persistent fever and additional symptoms (e.g. enlarged spleen, neurologic symptoms) or laboratory parameters (e.g. hyperferritinemia, cytopenia, increased transaminases) compatible with HLH. The diagnosis of HLH is made using the HLH-2004 criteria. The probability of the presence of HLH can be calculated using the HScore. High-dose corticosteroids represent the cornerstone of HLH treatment. Etoposide, immunoglobulins, anakinra or other drugs are added depending on the trigger. The course of HLH is influenced by the time of treatment initiation, the underlying trigger and the response to treatment. Generally, the prognosis of critically ill HLH patients is poor.

[Interdisciplinary COVID board for patients with SARS-CoV-2-triggered hyperferritinemic Inflammation]. / Interdisziplinäres COVID-Board bei SARS-CoV-2-getriggerter hyperferritinämischer Inflammation.

BACKGROUND: Patients with severe COVID-19 develop hyperferritinemic inflammation, a rare sepsis-like immune dysregulation syndrome. METHODS: Stratified treatment decisions in a cross-location telemedical interdisciplinary case conference were assessed in this retrospective cohort study. A standardized treatment algorithm including continuous positive airway pressure and noninvasive ventilation was implemented. A locally developed COVID inflammation score (CIS) defined patients at risk for severe disease. Patients with life-threatening inflammation were offered off-label treatment with the immune modulator ruxolitinib. RESULTS: Between 4 March 2020 and 26 June 2020 COVID-19 patients (n = 196) were treated. Median patient age (70 years) and comorbidity were high in interstudy comparison. Mortality in all patients was 17.3%. However, advance care planning statements and physician directives limited treatment intensity in 50% of the deceased patients. CIS monitoring of ruxolitinib-treated high-risk patients (n = 20) on days 5, 7, and15 resulted in suppression of inflammation by 42% (15-70), 54% (15-77) and 60% (15-80). Here, mortality was 20% (4/20). Adjusted for patients with a maximum care directive including ICU, total mortality was 8.7% (17/196). CONCLUSION: Severe COVID-19 pneumonia with hyperferritinemic inflammation is related to macrophage activation syndrome-like sepsis. An interdisciplinary intensive care teleconference as a quality tool for ICUs is proposed to detect patients with rare sepsis-like syndromes.

First-line treatment with R-CHOP or rituximab-bendamustine in patients with follicular lymphoma grade 3A-results of a retrospective analysis.

Based on centroblast frequency, follicular lymphoma (FL) is subdivided into grades 1-2, 3A, and 3B. Grade FL3A frequently coexists with FL1-2 (FL1-2-3A). Based on clinical trials, FL1-2 is treated with rituximab (R) or obinutuzumab plus bendamustine (B) or CHOP, while FL3B is treated with R-CHOP. In contrast, there are little data guiding therapy in FL3A. We present a retrospective, multicenter analysis of 95 FL3A or FL1-2-3A and 203 FL1-2 patients treated with R-CHOP or R-B first-line. R-CHOP facilitated a higher response rate (95% versus 76%) and longer overall survival (OS) (3-year OS 89% versus 73%, P = 0.008) in FL3A or FL1-2-3A, whereas the difference in progression-free survival (PFS) did not reach statistical significance. While transformation rates into aggressive lymphoma were similar between both groups, there were more additional malignancies after R-B compared with R-CHOP (6 versus 2 cases). In FL1-2, R-B achieved a higher 3-year PFS (79% versus 47%, P < 0.01), while there was no significant difference regarding OS or transformation. With the limitations of a retrospective analysis, these results suggest a benefit for R-CHOP over R-B in FL3A or FL1-2-3A. Confirmatory data from prospective clinical trials are needed.

The Janus kinase 1/2 inhibitor ruxolitinib in COVID-19 with severe systemic hyperinflammation.

A subgroup of patients with severe COVID-19 suffers from progression to acute respiratory distress syndrome and multiorgan failure. These patients present with progressive hyperinflammation governed by proinflammatory cytokines. An interdisciplinary COVID-19 work flow was established to detect patients with imminent or full blown hyperinflammation. Using a newly developed COVID-19 Inflammation Score (CIS), patients were prospectively stratified for targeted inhibition of cytokine signalling by the Janus Kinase 1/2 inhibitor ruxolitinib (Rux). Patients were treated with efficacy/toxicity guided step up dosing up to 14 days. Retrospective analysis of CIS reduction and clinical outcome was performed. Out of 105 patients treated between March 30th and April 15th, 2020, 14 patients with a CIS ≥ 10 out of 16 points received Rux over a median of 9 days with a median cumulative dose of 135 mg. A total of 12/14 patients achieved significant reduction of CIS by ≥25% on day 7 with sustained clinical improvement in 11/14 patients without short term red flag warnings of Rux-induced toxicity. Rux treatment for COVID-19 in patients with hyperinflammation is shown to be safe with signals of efficacy in this pilot case series for CRS-intervention to prevent or overcome multiorgan failure. A multicenter phase-II clinical trial has been initiated (NCT04338958).

Consensus statement for cancer patients requiring intensive care support.

This consensus statement is directed to intensivists, hematologists, and oncologists caring for critically ill cancer patients and focuses on the management of these patients.

[Rheumatoid symptoms in patients with hematologic neoplasms]. / Rheumatische Krankheitserscheinungen bei hämatologischen Neoplasien.

Paraneoplastic syndromes in lymphatic or myeloid neoplasms can present with musculoskeletal symptoms, vasculitis-like or febrile symptoms. Hematologic diseases are also associated with rheumatic diseases whereas inflammatory rheumatic diseases are often associated with an increased risk for lymphoproliferative disease. Atypical disease characteristics, lack of disease-specific antibodies or therapeutic response are red flags for diagnosing paraneoplastic or coexistent malignant diseases. New onset of systemic symptoms, worsening of general condition, night sweats or weight loss need to be considered during follow-up and differential diagnostics. This article focuses on musculoskeletal, vasculitis-like and systemic signs of lymphatic or myeloid neoplasms either because of coexistency, tumor association or paraneoplastic disease.

[Hemophagocytic lymphohistiocytosis : A diagnostic challenge on the ICU]. / Hämophagozytische Lymphohistiozytose : Diagnostische Herausforderung auf der ITS.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) has well been studied as a genetic disorder in children (primary HLH). Mutations in the regulatory complex of the cellular immune synapse lead to a loss of function of cytotoxic T­cells and natural killer cells with excessive inflammation based on a cytokine storm. During the last decade, an increasing number of adult HLH patients without a family history of HLH (secondary or acquired HLH) have been reported. Various triggers - infections, malignancies or autoimmune diseases - result in an acquired loss of function of these cells and a sepsis-like disease. Missed or late diagnosis is believed to be a major cause of the high mortality. OBJECTIVES: To describe the current knowledge on HLH and to raise awareness. MATERIALS AND METHODS: Analysis of case reports, current studies, and expert recommendations. RESULTS: Increased vigilance in identifying the adult form of HLH resulted in an increasing number of case reports over the past few years. HLH patients typically present with a clinical phenotype resembling severe sepsis or septic shock with fever, cytopenia, and organomegaly, which do not or insufficiently respond to anti-infective treatment. Early recognition of HLH distinction from sepsis, and prompt initiation of treatment - which is fundamentally different from sepsis - are crucial for improved outcome. A promising diagnostic parameter is ferritin, which has gained sufficient specificity, but only in the context of the triad of fever, cytopenia, and organomegaly. Treatment of adult HLH patients requires immunosuppression, with strict therapeutic guidance derived from the triggering disease. CONCLUSIONS: Because of the similar clinical presentation to that of sepsis, HLH is often not recognized, resulting in a fatal outcome. In "sepsis" patients on the ICU with deterioration despite a standard of care, HLH needs to be considered by testing for ferritin when considering differential diagnoses. The complexity of the illness requires interdisciplinary patient care with specific integration of the hematologist in the diagnostic workup and therapeutic management, because of the frequent use of chemotherapy-based immunosuppression.

A case of Brooke-Spiegler syndrome with a novel mutation in the CYLD gene in a patient with aggressive non-Hodgkin's lymphoma.

PURPOSE: Brooke-Spiegler syndrome (BSS, familial cylindromatosis) is a rare hereditary disease characterized by multiple tumors of the skin appendages predominantly located in the head and neck region, such as cylindromas, trichoepitheliomas, or spiradenomas. It is caused by an autosomal dominant mutation in the CYLD gene, mapped on chromosome 16q12-13. Association with secondary malignant neoplasms has been reported. Until now 51 different mutations in 73 families have been reported; 41 % of them constitute frameshift mutations, resulting in an interruption of the expression of the gene product CYLD. CYLD is a deubiquitinating enzyme and plays an important role in (NF)-κB pathway signaling, a central pathway for apoptosis regulation. Mutation-induced loss of function leads to constitutive activation of NF-κB. METHODS: Here, we report the case of a 48-year-old female patient diagnosed with an abdominal aggressive non-Hodgkin's lymphoma. The patient presented with multiple cylindromas of the capillitium. The patient's mother also has a mild form of late-onset cylindromas. Due to the typical clinical features indicating BSS, genotyping from peripheral blood was performed. A c.2465insAACA mutation in exon 17 of the CYLD gene, leading to a frameshift, was detected in the patient and in the patient's mother. RESULTS/CONCLUSIONS: This is the first description of this hereditary mutation in exon 17 of the CYLD gene. There have been several reports on patients with CYLD mutations and different types of malignancies. However, a coincidence with aggressive non-Hodgkin's lymphoma has not been reported yet.

[Chronic myelogenous leukemia]. / Chronische myeloische Leukämie.

The advent of tyrosine kinase inhibitors (TKI) has improved the prognosis and outcome of patients with chronic myelogenous leukemia (CML) considerably. Compared with imatinib, the first-line use of second-generation inhibitors nilotinib and dasatinib has led to faster and deeper molecular remissions accompanied by a differential adverse effect profile. An essential part of the management of CML patients is the guideline-based application of cytogenetics and standardized polymerase chain reaction techniques to regularly assess the remission status. Long-lasting treatment-free remission in a minority of patients led to hopes for the curability of CML in a significant minority of patients. The use of interferon alpha combined with or after TKI therapy is associated with the induction of an immune response toward the leukemic clone. This innovative treatment approach is currently under prospective investigation to improve long-term response. The coordinated cooperation of academic and regional hospitals, office-based hematologists, laboratories, and patient representatives allows for up-to-date patient care and the early use of new therapeutic options in patients at risk.

Fulminant gastrointestinal bleeding caused by EBV-triggered hemophagocytic lymphohistiocytosis: report of a case.

Hemophagocytic lymphohistiocytosis (HLH) is a rare and often fatal hyperinflammatory syndrome characterized by fever, cytopenia, dramatically increased ferritin and hepatosplenomegaly. Here, we describe a previously healthy 39 year old pregnant woman in 30th week of her pregnancy with diarrhoea, intermittent gastrointestinal bleeding and fever of unknown focus. After cesarean section of twins in the 31st week she deteriorated with fulminant upper and lower gastrointestinal bleeding and disseminated intravascular coagulation. Gastro-, ileocolonoscopy and capsule endoscopy identified multiple bleeding punched ulcerations in the stomach, the entire small bowel and in parts of the colon. Emergency surgery with intraoperative endoscopy for uncontrolled hemorrhagic shock resulted in the resection of actively bleeding ulcers in the jejunum which temporally stabilized the critically ill patient. Jejunal histology and in situ hybridisation showed extensive ulcerations, focal lymphohistiocytic infiltration and EBV-positive immunoblasts. The diagnosis fulminant EBV-related HLH was confirmed based on the HLH-2004 diagnostic criteria and through detection of a reactivated EBV infection (up to 3 × 10(7) DNA copies/mL serum). Despite immunosuppressive therapy with steroids, cyclosporine A and etoposide in combination with Rituximab, the patient died from this sepsis-like, hyper-inflammatory syndrome in multiorgan failure with uncontrolled bleeding.

[Tailored management of chronic myeloid leukemia]. / Maßgeschneiderte Therapie der chronischen myeloischen Leukämie.

State of the art management of chronic myeloid leukemia (CML) patients with the selection of best available treatment options requires systematic cytogenetic and molecular monitoring. The choice of the first-line tyrosine kinase inhibitor depends on integration of comorbidities and individual treatment goals. Clinical prognostic scores should be used for cohort comparison and for stratification in randomized trials. Their relevance for individual treatment decisions has not yet been established. Essential for therapeutic decision-making is the achievement of predefined cytogenetic and molecular milestones in the course of the disease. In cases of treatment resistance or relapse the analysis of potential causes is required. After exclusion of compliance issues bone marrow analysis for the accurate characterization of the hematologic disease state and exclusion of clonal evolution is recommended. In parallel, BCR-ABL mutation analysis should be performed. The choice of second-line treatment depends on the predicted sensitivity of any BCR-ABL mutation detected and the clinical history of the patient. Most important is prevention of disease progression as treatment results in advanced disease are still not satisfying. Therefore, allogeneic stem cell transplantation should be considered early in resistant disease, when high-risk parameters (e.g. multiresistant mutations) have been detected.

Current treatment of mantle cell lymphoma: results of a national survey and consensus meeting.

In most patients, mantle cell lymphoma (MCL) shows an aggressive clinical course with a continuous relapse pattern and a median survival of only 3-5 years. In the current study generation of the European MCL Network, the addition of high-dose Ara-C to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone)-like regimen followed by myeloablative consolidation achieved a significant improvement of progression-free survival in younger patients. In elderly patients, rituximab maintenance led to a marked prolongation of remission duration. Emerging strategies include mammalian target of rapamycin (mTOR) inhibitors, proteasome inhibitors, immune modulatory drugs, Bruton's tyrosine kinase inhibitors and others, all based on the dysregulated control of cell cycle machinery and impairment of several apoptotic pathways. Combination strategies are currently being investigated in numerous trials, but their introduction into clinical practice and current treatment algorithms remains a challenge. In the current survey, the application of the molecular targeted compounds were collected and evaluated by a representative national network of 14 haematological institutions. Optimised strategies are recommended for clinical routine. Future studies will apply individualised approaches according to the molecular risk profile of the patient.

Omacetaxine mepesuccinate prevents cytokine-dependent resistance to nilotinib in vitro: potential role of the common ß-subunit c of cytokine receptors.

Overcoming resistance against BCR-ABL-inhibitors in chronic myeloid leukemia (CML) is central to prevent progression to advanced phase disease. Kinase mutations of BCR-ABL and cytokine-mediated modulation of response to tyrosine kinase inhibitors (TKIs) are key mechanisms governing clinical response to imatinib and second generation TKIs. Omacetaxine mepesuccinate is effective in imatinib-resistant CML with reported stem cell activity. We specifically thought to explore omacetaxine in the context of the pan-resistant mutant T315I, and in its potential to modify cytokine-dependent resistance. Omacetaxine was investigated in cell lines and primary CD34+ enriched progenitor cells from patients with CML. Addition of cytokines, shown to revert the efficacy of TKIs in BCR-ABL-positive cells, does not affect omacetaxine mediated antiproliferative activity, neither in cell lines nor in primary CML CD34+ progenitor cells. Looking at potential mechanisms, we found marked downregulation of the common ß-subunit c of the cytokine-receptors (cCRßc) for IL3, IL5 and GM-CSF by omacetaxine in cell lines and primary progenitor cultures. The observed cytokine-independent in-vitro cytotoxicity of omacetaxine may be explained by downregulation of cCRßc. Whether this can be used clinically as a means to optimize the stem cell activity of TKIs merits further evaluation.

Choosing the best treatment strategy for chronic myeloid leukemia patients resistant to imatinib: weighing the efficacy and safety of individual drugs with BCR-ABL mutations and patient history.

For patients with chronic myeloid leukemia who become or are inherently resistant to imatinib therapy, including dose escalation, several important factors must be considered when deciding which strategy to attempt next. The second-generation tyrosine kinase inhibitors (TKIs) dasatinib and nilotinib offer improved potency and a high likelihood of success for these patients. Overall, the efficacy data are comparable for these two agents, and so physicians should consider the BCR-ABL mutation profile and the patient's history to make an educated decision on the best choice. Only a few BCR-ABL mutations seem to be less responsive to either nilotinib or dasatinib and it is recommended to choose the second-line TKI that has shown clinical activity against the specific mutation in these cases. For patients with all other mutations, and for patients with no mutations, it is recommended to choose the second-generation TKI based on the patient's disease history. It is important to choose an agent that minimizes the likelihood of exacerbating the patient's past tolerability issues to imatinib, or comorbid conditions. Here, we propose a treatment algorithm for imatinib-resistant patients based on BCR-ABL mutation status and patient history.

Lack of clinical efficacy of imatinib in metastatic melanoma.

This two-centre phase-II trial aimed at investigating the efficacy of imatinib in metastasised melanoma patients in correlation to the tumour expression profile of the imatinib targets c-kit and platelet-derived growth factor receptor (PDGF-R). The primary study end point was objective response according to RECIST, secondary end points were safety, overall and progression-free survival. In all, 18 patients with treatment-refractory advanced melanoma received imatinib 800 mg day(-1). In 16 evaluable patients no objective responses could be observed. The median overall survival was 3.9 months, the median time to progression was 1.9 months. Tumour biopsy specimens were obtained from 12 patients prior to imatinib therapy and analysed for c-kit, PDGF-Ralpha and -Rbeta expression by immunohistochemistry. In four cases, cell lines established from these tumour specimens were tested for the antiproliferative effects of imatinib and for functional mutations of genes encoding the imatinib target molecules. The tumour specimens stained positive for CD117/c-kit in nine out of 12 cases (75%), for PDGF-Ralpha in seven out of 12 cases (58%) and for PDGF-Rbeta in eight out of 12 cases (67%). The melanoma cell lines showed a heterogenous expression of the imatinib target molecules without functional mutations in the corresponding amino-acid sequences. In vitro imatinib treatment of the cell lines showed no antiproliferative effect. In conclusion, this study did not reveal an efficacy of imatinib in advanced metastatic melanoma, regardless of the expression pattern of the imatinib target molecules c-kit and PDGF-R.

Imatinib therapy in chronic myelogenous leukemia: strategies to avoid and overcome resistance.

Imatinib is a molecularly targeted therapy that inhibits the oncogenic fusion protein BCR-ABL, the tyrosine kinase involved in the pathogenesis of chronic myelogenous leukemia (CML). Selective inhibition of BCR-ABL activity by imatinib has demonstrated efficacy in the treatment of CML, particularly in chronic phase. Some patients, however, primarily those with advanced disease, are either refractory to imatinib or eventually relapse. Relapse with imatinib frequently depends not only on re-emergence of BCR-ABL kinase activity but may also indicate BCR-ABL-independent disease progression not amenable to imatinib inhibition. Results from phase 2/3 trials suggest that rates of resistance and relapse correlate with the stage of disease and with the monitoring parameters--hematologic, cytogenetic and molecular response. These observations and more recent trials with imatinib, combined with insights provided by an increased understanding of the molecular mechanisms of resistance, have established the rationale for strategies to avoid and overcome imatinib resistance in the management of CML patients. To prevent resistance, early diagnosis and prompt treatment with appropriate initial dosing is essential. Management of resistance may include therapeutic strategies such as dose escalation to achieve individual optimal levels, combination therapy, as well as treatment interruption.

Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy.

Selective inhibition of the BCR-ABL tyrosine kinase by imatinib (STI571, Glivec/Gleevec) is a promising new therapeutic strategy in patients with chronic myelogenous leukemia (CML). Despite significant hematologic and cytogenetic responses, resistance occurs, particularly in patients with advanced disease. We sought to determine the underlying mechanisms. Sixty-six patients with CML in myeloid blast crisis (n = 33), lymphoid blast crisis (n = 2), accelerated phase (n = 16), chronic phase (n = 13), and BCR-ABL-positive acute lymphoblastic leukemia (n = 2) resistant to imatinib were investigated. Median duration of imatinib therapy was 148 days (range 6-882). Patients were evaluated for genomic amplification of BCR-ABL, overexpression of BCR-ABL transcripts, clonal karyotypic evolution, and mutations of the imatinib binding site in the BCR-ABL tyrosine kinase domain. Results were as follows: (1) Median levels of BCR-ABL transcripts, were not significantly changed at the time of resistance but 7/55 patients showed a >10-fold increase in BCR-ABL levels; (2) genomic amplification of BCR-ABL was found in 2/32 patients evaluated by fluorescence in situ hybridization; (3) additional chromosomal aberrations were observed in 19/36 patients; (4) point mutations of the ABL tyrosine kinase domain resulting in reactivation of the BCR-ABL tyrosine kinase were detected in 23/66 patients. In conclusion, although the heterogeneous development of imatinib resistance is challenging, the fact that BCR-ABL is active in many resistant patients suggests that the chimeric oncoprotein remains a good therapeutic target. However, patients with clonal evolution are more likely to have BCR-ABL-independent mechanisms of resistance. The observations warrant trials combining imatinib with other agents.