Lars-Olof Mügge

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.

Treatment with lenalidomide induces immunoactivating and counter-regulatory immunosuppressive changes in myeloma patients

Lenalidomide activates the immune system, but the exact immunomodulatory mechanisms of lenalidomide in vivo are poorly defined. In an observational study we assessed the impact of lenalidomide on different populations of immune cells in multiple myeloma patients. Lenalidomide therapy was associated with increased amounts of a CD8+ T cell subset, phenotypically staged between classical central memory T cells (TCM) and effector memory T cells (TEM), consequently termed TCM/TEM. The moderate expression of perforin/granzyme and phenotypical profile of these cells identifies them as not yet terminally differentiated, which makes them promising candidates for the anti‐tumour response. In addition, lenalidomide‐treated patients showed higher abundance of CD14+ myeloid cells co‐expressing CD15. This population was able to inhibit both CD4+ and CD8+ T cell proliferation in vitro and could thus be defined as a so far undescribed novel myeloid‐derived suppressor cell (MDSC) subtype. We observed a striking correlation between levels of TCM/TEM, mature regulatory T cells (Tregs) and CD14+CD15+ MDSCs. In summary, lenalidomide induces both activating and inhibitory components of the immune system, indicating the existence of potential counter‐regulatory mechanisms. These findings provide new insights into the immunomodulatory action of lenalidomide.

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).

Impact of early NK cell recovery on development of GvHD and CMV reactivation in dose-reduced regimen prior to allogeneic PBSCT

Summary:Dose-reduced allogeneic peripheral blood stem cell transplantation (PBSCT) is a therapeutic approach for patients with haematological malignancies who are not eligible for conventional allogeneic PBSCT. We analysed early development of lymphocyte subpopulations and the occurrence of cytomegalovirus (CMV) reactivation and acute graft-versus-host reaction (GvHD) in patients undergoing the protocol according to Slavin vs conventionally treated patients. Lymphocyte status prior to conditioning and at day +30 after allogeneic PBSCT was determined in 24 out of 51 patients who received conventional allogeneic PBSCT (eg cyclophosphamide plus total body irradiation) and compared with 27 patients being treated according to the Slavin protocol (fludarabine, busulphan and ATG). There is a significant delay in CD4 (T helper) cell development and consecutive lower CD4/CD8 ratios and a better reconstitution of CD8 (T cytotoxic) and NK (natural killer) cells after the Slavin protocol. Patients undergoing this protocol and no, or only grade I, acute GvHD show an even better NK cell reconstitution compared to patients with grade II–IV GvHD. A low CD4/CD8 ratio represents a CMV risk factor only in conventionally treated patients with grade 0–I GvHD, while after preparative regimen according to the Slavin protocol, the NK/CD8 ratio might be a marker for the prediction of CMV reactivation in addition to CMV risk status.

IKZF1 expression is a prognostic marker in newly diagnosed standard-risk multiple myeloma treated with lenalidomide and intensive chemotherapy: a study of the German Myeloma Study Group (DSMM)

Lenalidomide is an immunomodulatory compound with high clinical activity in multiple myeloma. Lenalidomide binding to the Cereblon (CRBN) E3 ubiquitin ligase results in targeted ubiquitination and degradation of the lymphoid transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) leading to growth inhibition of multiple myeloma cells. Recently, Basigin (BSG) was identified as another protein regulated by CRBN that is involved in the activity of lenalidomide. Here, we analyzed the prognostic value of IKZF1, IKZF3, CRBN and BSG mRNA expression levels in pretreatment plasma cells from 60 patients with newly diagnosed multiple myeloma uniformly treated with lenalidomide in combination with intensive chemotherapy within a clinical trial. We found that IKZF1 mRNA expression levels are significantly associated with progression-free survival (PFS). Patients in the lowest quartile (Q1) of IKZF1 expression had a superior PFS compared with patients in the remaining quartiles (Q2–Q4; 3-year PFS of 86 vs 51%, P=0.01). This translated into a significant better overall survival (100 vs 74%, P=0.03). Subgroup analysis revealed a significant impact of IKZF1, IKZF3 and BSG expression levels on PFS in cytogenetically defined standard-risk but not high-risk patients. Our data suggest a prognostic role of IKZF1, IKZF3 and BSG expression levels in lenalidomide-treated multiple myeloma.

Benefit of continuous treatment for responders with newly diagnosed multiple myeloma in the randomized FIRST trial

The phase 3, randomized Frontline Investigation of Revlimid and Dexamethasone Versus Standard Thalidomide (FIRST) trial investigating lenalidomide plus low-dose dexamethasone until disease progression (Rd continuous) vs melphalan, prednisone and thalidomide for 12 cycles (MPT) and Rd for 18 cycles (Rd18) in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM) showed that Rd continuous prolonged progression-free survival and overall survival compared with MPT. A subanalysis of the FIRST trial was conducted to determine the benefits of Rd continuous in patients with NDMM based on depth of response. Patients randomized 1:1:1 to Rd continuous, Rd18 or MPT were divided into subgroups based on best response: complete response (CR; n=290), ⩾very good partial response (VGPR; n=679), ⩾partial response (PR; n=1 225) or ⩽stable disease (n=299). Over 13% of patients receiving Rd continuous who achieved ⩾VGPR as best response did so beyond 18 months of treatment. Rd continuous reduced the risk of progression or death by 67%, 51% and 35% vs MPT in patients with CR, ⩾VGPR and ⩾PR, respectively. Similarly, Rd continuous reduced the risk of progression or death by 61%, 54% and 38% vs Rd18 in patients with CR, ⩾VGPR and ⩾PR, respectively. In patients with CR, ⩾VGPR or ⩾PR, 4-year survival rates in the Rd continuous arm (81.1%, 73.1% or 64.6%, respectively) were higher vs MPT (70.8%, 59.8% or 57.2%, respectively) and similar vs Rd18 (76.5%, 67.7% and 62.5%, respectively). Rd continuous improved efficacy outcomes in all responding patients, including those with CR, compared with fixed duration treatment.

Clonal T-LGL population mimicking leukemia in Felty’s syndrome—part of a continuous spectrum of T-LGL proliferations?

Dear Editor, Large granular lymphocyte leukemia (LGL leukemia) is characterized by expansion of LGL-cells in the peripheral blood and may be associated with the triad rheumatoid arthritis, splenomegaly, and neutropenia [1–3]. The disease resembles Felty’s syndrome in many aspects, which is usually associated with persistent rheumatoid arthritis [4]. Aberrant signal transducer and activator of transcription 3 (STAT3) signaling was shown to be involved in the pathogenesis of LGL leukemia [5] and the Src homology 2 (SH2) dimerization, and activation domain of STAT3 encoded by exon 20 and 21 of the STAT3 gene is frequently mutated in patients with LGL leukemia. Patients with LGL leukemia and somatic STAT3 mutation are at higher risk for accompanying neutropenia and rheumatoid arthritis [6, 7]. Here, we present and discuss cases of three patients with Felty’s syndrome which show clonal LGL proliferations. In two patients, somatic mutations of the STAT3 gene were found. Patient 1 was a 36-year-old male presented with swelling and morning stiffness in the metacarpophalangeal and proximal interphalangeal joints as well as splenomegaly with 12×5.6 cm. The majority of cells in an immunophenotyping of the peripheral blood cells were CD3/CD8/CD7-positive, and a 50–60 % infiltration of CD3/CD8-positive T lymphocytes in the bone marrow was detected. Only a few cells were CD57-positive (Fig. 1a–c). Multiplex PCR showed a monoclonal T-cell rearrangement supporting the diagnosis of T-cell large granular lymphocyte (T-LGL) leukemia (Fig. 1k). STAT3 analysis showed a mutation in exon 21 in peripheral blood cells as well as in bone marrow cells. By the time final diagnosis was made, the symptoms of rheumatoid arthritis had disappeared after 5 months without any specific treatment, while splenomegaly and severe neutropenia persisted. Therapy was started with prednisone 1 mg/ kg day 1–3 and weekly methotrexate (MTX) injections of 15 mg s.c. One week after the second MTX injection, peripheral blood count demonstrated a sudden increase in total leukocyte and neutrophil counts to normal levels. Patient 2 was a 61-year-old female with a history of seropositive rheumatoid arthritis, secondary Sjögren syndrome, neutropenia for 15 years, and splenomegaly of 13 cm. Cytology of the bone marrow demonstrated a hypocellular bone marrow with an increase of CD57-positive cells (Fig. 1d–f). Analysis of T cell receptor showed a dominant T cell clone in a polyclonal background (Fig. 1l). STAT3 analysis of the peripheral blood revealed a mutation in exon 21. The patient was started on weekly MTX 20 mg s.c. and prednisone of 5 mg per day was continued. Neutrophil count increased >1000/ μl after a period of 6 months. Patient 3 was a 74-year-old female with rheumatoid arthritis for 13 years. At the time of presentation, she had K. G. Schrenk (*) : L.-O. Mügge :A. Hochhaus Abteilung für Hämatologie und internistische Onkologie, Klinik für Innere Medizin II, Universitätsklinikum Jena, Erlanger Allee 101, 07747 Jena, Germany e-mail: karin.schrenk@med.uni-jena.de

Lenalidomide, adriamycin, dexamethasone for induction followed by stem-cell transplant in newly diagnosed myeloma

Lenalidomide, adriamycin, dexamethasone for induction followed by stem-cell transplant in newly diagnosed myeloma

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

ABSTRACT 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.

Lower gastrointestinal bleeding in a patient with Crohn's disease and plasma cell leukemia in remission.

Dear Editor, We report on a patient with plasma cell leukemia following successful treatment with a lenalidomide-containing regimen who presented with recurrent severe gastrointestinal bleeding. Due to a history of Crohn’s disease, activation of chronic inflammatory bowel disease induced by the immunomodulatory effect of lenalidomide was suspected. Biopsy of colon ulcerations demonstrates the very rare extramedullary manifestation of plasma cell leukemia in the large bowel. In August 2014, a 57-year-old woman with multiple myeloma was admitted with leukocytosis (40 Gpt/L) and 40 % of partially immature plasma cells in the peripheral blood differential. Flow cytometry analysis confirmed the clonality of these lymphatic cells (Fig. 1a, b). Previous treatment of multiple myeloma (IgG kappa) diagnosed in 2013 included bortezomib-based induction therapy and high-dosed chemotherapy with melphalan and consecutive autologous stem cell transplantation in first remission. Until diagnosis of plasma cell leukemia, the patient had not received an anthracyclin or lenalidomide. Because of several life-threatening thromboembolic events and a family history describing a genetic predisposition for thromboembolic complications, induction chemotherapy of plasma cell leukemia was performed with cyclophosphamide, adriamycin, and dexamethasone (CAD) without significant response [1]. Thus, we continued treatment of plasma cell leukemia according to the RAD regimen (lenalidomide, adriamycin, dexamethasone) resulting in a VGPR after two cycles (Fig. 1c) [2]. Subsequently, the patient suffered from diarrhea with high frequency (>10 times a day) being associated with lower gastrointestinal bleeding as well as abdominal pain and cramping. Colonoscopy revealed ulcerations with diffuse signs of bleeding indicative for reactivation of Crohn’s disease following immunomodulating chemotherapy containing lenalidomide [3]. Biopsy and histopathological findings confirmed this differential diagnosis. In consideration of the good remission of plasma cell leukemia, high-dosed prednisolone was initiated and slowly tapered within the following weeks. This approach led to a significant reduction of symptoms and enabled discharge from hospital. Because of delayed hematopoietic reconstitution after RAD, weekly bortezomib application was chosen as a maintenance regimen of plasma cell leukemia aiming at bridging to allogeneic stem cell transplantation. Unfortunately, stepwise reduction of oral prednisolone resulted in a recurrence of severe lower gastrointestinal bleeding and hemorrhagic shock. Re-colonoscopy demonstrated ulcerations and numerous colonic polyps (Fig. 1d). Histopathology of polyp biopsies showed a dense infiltrate of lymphatic cells (Fig. 1e), and immunohistochemistry revealed a strong expression of both the plasma cell surface * Sebastian Scholl sebastian.scholl@med.uni-jena.de