Ella Willenbacher

Ropeginterferon alfa-2b, a novel IFNα-2b, induces high response rates with low toxicity in patients with polycythemia vera.

In this prospective, open-label, multicenter phase 1/2 dose escalation study, we used a next-generation, mono-pegylated interferon (IFN) α-2b isoform, ropeginterferon alfa-2b. The unique feature of ropeginterferon alfa-2b is a longer elimination half-life, which allows administration every 2 weeks. We present data from 51 polycythemia vera patients. The main goal was to define the maximum tolerated dose and to assess safety and efficacy. A dose range of 50 to 540 µg was tested without the appearance of dose-limiting toxicities. All drug-related adverse events were known toxicities associated with IFN-α. The cumulative overall response rate was 90%, comprising complete response in 47% and partial response in 43% of patients; the best individual molecular response level was a complete response in 21% of patients and partial response in 47%. Notably, we did not observe any correlation between the dose level and the response rate or response duration, suggesting that already low levels of ropeginterferon alfa-2b are sufficient to induce significant hematologic and molecular responses. These data suggest promising efficacy and safety of ropeginterferon alfa-2b and support the development of the drug in a randomized phase 3 clinical trial. The study was disclosed at www.clinicaltrials.gov as #NCT01193699 before including the first patient.

Rituximab plus subcutaneous cladribine in patients with extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue: a phase II study by the Arbeitsgemeinschaft Medikamentöse Tumortherapie

Currently, there is no standard systemic treatment for extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue. Both rituximab and cladribine have shown some activity in this disease, but the combination has not been tested so far. In view of this, we initiated a phase II study to assess the activity and safety of rituximab and cladribine in patients with histologically verified mucosa-associated lymphoid tissue lymphoma. Treatment consisted of rituximab 375 mg/m2 i.v. day 1 and cladribine 0.1 mg/kg s.c. days 1 – 4 every 21 days. In case of complete remission after two courses, another two cycles of therapy were administered, while patients with a partial response or stable disease were scheduled to receive six cycles of treatment. Out of 40 evaluable patients (14 female, 26 male), 39 received treatment as scheduled while one patient died before initiation of therapy and was rated as having progressive disease in the intent-to-treat analysis. Twenty-one patients had gastric lymphoma, while 19 suffered from extragastric mucosa-associated lymphoid tissue lymphoma. Side effects consisted mainly of hematologic toxicity including leukopenia, lymphopenia, anemia and thrombocytopenia. Twenty-three patients had a complete remission (58%) and nine had a partial remission (23%) for an overall response rate of 81%, while five had stable disease (13%) and two progressed during therapy. After a median follow-up of 16.7 months (interquartile range: 15.9 – 18.7 months), 35 patients are alive (88%) while four patients have died and one patient withdrew consent and did not allow further follow up. Our data demonstrate that rituximab plus cladribine is active and safe in patients with mucosa-associated lymphoid tissue lymphoma.

T cells in multiple myeloma display features of exhaustion and senescence at the tumor site

BackgroundMultiple myeloma is an incurable plasma cell malignancy that is mostly restricted to the bone marrow. Cancer-induced dysfunction of cytotoxic T cells at the tumor site may be responsible for immune evasion and therapeutical failure of immunotherapies. Therefore, enhanced knowledge about the actual status of T cells in myeloma bone marrow is urgently needed. Here, we assessed the expression of inhibitory molecules PD-1, CTLA-4, 2B4, CD160, senescence marker CD57, and CD28 on T cells of naive and treated myeloma patients in the bone marrow and peripheral blood and collected data on T cell subset distribution in both compartments. In addition, T cell function concerning proliferation and expression of T-bet, IL-2, IFNγ, and CD107a was investigated after in vitro stimulation by CD3/CD28. Finally, data was compared to healthy, age-matched donor T cells from both compartments.MethodsMulticolor flow cytometry was utilized for the analyses of surface molecules, intracellular staining of cytokines was also performed by flow cytometry, and proliferation was assessed by 3H-thymidine incorporation. Statistical analyses were performed utilizing unpaired T test and Mann-Whitney U test.ResultsWe observed enhanced T cell exhaustion and senescence especially at the tumor site. CD8+ T cells expressed several molecules associated with T cell exhaustion (PD-1, CTLA-4, 2B4, CD160) and T cell senescence (CD57, lack of CD28). This phenotype was associated with lower proliferative capacity and impaired function. Despite a high expression of the transcription factor T-bet, CD8+ T cells from the tumor site failed to produce IFNγ after CD3/CD28 in vitro restimulation and displayed a reduced ability to degranulate in response to T cell stimuli. Notably, the percentage of senescent CD57+CD28− CD8+ T cells was significantly lower in treated myeloma patients when compared to untreated patients.ConclusionsT cells from the bone marrow of myeloma patients were more severely impaired than peripheral T cells. While our data suggest that terminally differentiated cells are preferentially deleted by therapy, immune-checkpoint molecules were still present on T cells supporting the potential of checkpoint inhibitors to reactivate T cells in myeloma patients in combination therapies. However, additional avenues to restore anti-myeloma T cell responses are urgently needed.

Improved accuracy of discrimination between IgM multiple myeloma and Waldenström macroglobulinaemia by testing for MYD88 L265P mutations.

Immunoglobulin M (IgM) myelomas account for <0.5% of all myelomas (De Gramont et al, 1990) and are responsible for only a very small proportion of all IgM paraproteinaemias, estimated not to exceed 0.2% (Owen et al, 2000). In the largest published series, which included 10 patients, IgM myelomas were frequently associated with an immunophenotype negative for CD20, CD56 and CD117, the occurrence of a translocation t(11;14) and an aggressive clinical course with bad prognosis (Feyler et al, 2008), although the universality of these findings have been challenged (Willenbacher et al, 2008). In contrast, Waldenstr€ om Macroglobulinaemia (WM), which accounts for the vast majority of all IgM paraproteinaemias (Kyle & Garton, 1987), has recently been shown to be associated with the MYD88 L265P exon 5 mutation, which triggers interleukin-1 receptor–associated kinase (IRAK)-mediated nuclear factor (NF)-jB signalling in over 90% of cases (Treon et al, 2012). The analysis of the frequency of MYD88 mutations in WM-related lymphoid neoplasms (Varettoni et al, 2013; Xu et al, 2013) showed a positive mutational status in only 16/93 non-WM patients (Xu et al, 2013), and only 44/213 patients in (Varettoni et al, 2013), but included only 3 cases of IgM MM (Xu et al, 2013). To clarify whether MYD88 mutational analysis could help to make the clinically critical distinction between IgM MM and WM, we analysed 4 further cases of IgM MM with appropriate control samples and extended the analysis to exon 3 and exon 4 of the MYD88 gene. Patients with IgM Myeloma were identified by a search of the Austrian Myeloma Registry (AMR) database (www. myeloma.at), as well as an arrangement within the local pathology repository for sample availability. Clinical charts were reviewed for plausibility of the diagnosis (e.g. confirmation of lytic bone disease), together with analysis of the cytogenetic and immunophenotypic profile of the neoplasms for myeloma characteristics. Control samples with an established diagnosis of WM were taken from clinical routine diagnostics. DNA from 4 patients with IgM MM and 7 WM patients was extracted from formalin-fixed paraffin-embedded samples using the QIAGEN DNA easy kit (Qiagen, Hilden, Germany). For Sanger sequencing of the relevant exons, primers were used as described elsewhere (Pham-Ledard et al, 2012). Amplified polymerase chain reaction (PCR) products were isolated by the High Pure PCR-Product Purification kit (Roche, Vienna, Austria). For sequencing of the amplified fragments, the Big Dye Terminator v1.1 ready reaction cycle

Molecular responses and chromosomal aberrations in patients with polycythemia vera treated with peg‐proline‐interferon alpha‐2b

Fifty‐one polycythemia vera (PV) patients were enrolled in the phase I/II clinical study PEGINVERA to receive a new formulation of pegylated interferon alpha (peg‐proline‐IFNα‐2b, AOP2014/P1101). Peg‐proline‐IFNα‐2b treatment led to high response rates on both hematologic and molecular levels. Hematologic and molecular responses were achieved for 46 and 18 patients (90 and 35% of the whole cohort), respectively. Although interferon alpha (IFNα) is known to be an effective antineoplastic therapy for a long time, it is currently not well understood which genetic alterations influence therapeutic outcomes. Apart from somatic changes in specific genes, large chromosomal aberrations could impact responses to IFNα. Therefore, we evaluated the interplay of cytogenetic changes and IFNα responses in the PEGINVERA cohort. We performed high‐resolution SNP microarrays to analyze chromosomal aberrations prior and during peg‐proline‐IFNα‐2b therapy. Similar numbers and types of chromosomal aberrations in responding and non‐responding patients were observed, suggesting that peg‐proline‐IFNα‐2b responses are achieved independently of chromosomal aberrations. Furthermore, complete cytogenetic remissions were accomplished in three patients, of which two showed more than one chromosomal aberration. These results imply that peg‐proline‐IFNα‐2b therapy is an effective drug for PV patients, possibly including patients with complex cytogenetic changes. Am. J. Hematol. 90:288–294, 2015.

A phase II study of rituximab plus lenalidomide for mucosa-associated lymphoid tissue lymphoma (MALT lymphoma).

To the editor: Chemotherapy-containing regimens are effective for the treatment of advanced mucosa-associated lymphoid tissue (MALT) lymphoma, and recent data on R -chlorambucil and R -bendamustine may potentially have set new treatment standards for progressive disease.[1][1][⇓][2][⇓][3]-[4][4

Decision-analytic modeling studies: An overview for clinicians using multiple myeloma as an example

PURPOSE The purpose of this study was to provide a clinician-friendly overview of decision-analytic models evaluating different treatment strategies for multiple myeloma (MM). METHODS We performed a systematic literature search to identify studies evaluating MM treatment strategies using mathematical decision-analytic models. We included studies that were published as full-text articles in English, and assessed relevant clinical endpoints, and summarized methodological characteristics (e.g., modeling approaches, simulation techniques, health outcomes, perspectives). RESULTS Eleven decision-analytic modeling studies met our inclusion criteria. Five different modeling approaches were adopted: decision-tree modeling, Markov state-transition modeling, discrete event simulation, partitioned-survival analysis and area-under-the-curve modeling. Health outcomes included survival, number-needed-to-treat, life expectancy, and quality-adjusted life years. Evaluated treatment strategies included novel agent-based combination therapies, stem cell transplantation and supportive measures. CONCLUSION Overall, our review provides a comprehensive summary of modeling studies assessing treatment of MM and highlights decision-analytic modeling as an important tool for health policy decision making.

IgM myeloma: more on a rare entity

If using serum FLC ratio in place of UPE in screening for disease, the published data clearly support the view that the clinical benefit of increased detection of significant disease outweighs the small loss of detection of very small urinary bands of questionable clinical relevance. We accept that there are few studies designed to specifically address this question, that the cost implications and false positive rate of introducing the serum FLC assay as a screening test for plasma cell disorders are not clear but, nevertheless, we believe that the serum FLC assay is an advance over urine screening.

Real-World Use of 3rd Line Therapy for Multiple Myeloma in Austria: An Austrian Myeloma Registry (AMR) Analysis of the Therapeutic Landscape and Clinical Outcomes prior to the Use of Next Generation Myeloma Therapeutics

Objective Clinical trials demonstrate improving survival in patients with multiple myeloma (MM) after treatment. However, it is unclear whether increased survival translates to a similar benefit in a real world setting. Methods We analyzed the overall survival of 347 multiple myeloma patients in Austria by means of a national registry (AMR), focused on results from 3rd and later lines of therapy. This benchmark was chosen to define a baseline prior to the broad application of upcoming 2nd generation drugs (carfilzomib, pomalidomide). Results Projected 10 years survival for patients with MM in Austria is estimated to be 56% in patients diagnosed in between the years 2011–2014, 21% in patients with a diagnosis made between 2000–2005, and 39% in those with a diagnosis made between 2006–2010). For the same intervals a significant increase in the use of both bortezomib, lenalidomide and thalidomide—so called IMiDs (from 2005 onwards) and their simultaneous use in combination therapies (from 2010 onwards) could be shown. The use of autologous transplantation (ASCT) remained more or less constant at ~ 35% of patients in the 1st line setting over the whole period, comparing well to international practice patterns, while the use of 2nd line ASCT increased from 5.5% to 18.7% of patients. Patients in 3rd or later line treatment (n = 105), showed that even in relapsed and refractory disease median survival was 27 months with a considerable proportion of long-term survivors (~20%). Conclusion & Perspective With the expected emergence of additional active anti-myeloma compounds, we aim to assess survival in patients with relapsed and refractory MM.

Bone marrow microenvironmental CD4 + and CD8 + lymphocyte infiltration patterns define overall- and progression free survival in standard risk multiple myeloma – an analysis from the Austrian Myeloma Registry

Wolfgang Willenbacher, Ella Willenbacher, Claudia Zelle-Rieser, Rainer Biedermann, Roman Weger, Karin Jöhrer and Andrea Brunner Internal Medicine V – Hematology and Oncology, Medical University of Innsbruck, Innsbruck, Austria; Area 4 Health Technology Assessment and Bioinformatics, ONCOTYROL – Center for Personalized Cancer Medicine, Innsbruck, Austria; Tyrolean Cancer Research Institute, Innsbruck, Austria; Department of Orthopedic Surgery, Medical University of Innsbruck, Innsbruck, Austria; Department of Pathology, Division of General Pathology, Medical University of Innsbruck, Innsbruck, Austria