Christoph Groth

Letermovir for Cytomegalovirus Prophylaxis in Hematopoietic-Cell Transplantation

BACKGROUND Cytomegalovirus (CMV) infection is a leading cause of illness and death in patients who have undergone allogeneic hematopoietic-cell transplantation. Available treatments are restricted by clinically significant toxic effects and drug resistance. METHODS In this phase 2 study, we evaluated the effect of letermovir (also known as AIC246), a new anti-CMV drug with a novel mechanism of action, on the incidence and time to onset of prophylaxis failure in CMV-seropositive recipients of allogeneic hematopoietic-cell transplants from matched related or unrelated donors. From March 2010 through October 2011, we randomly assigned 131 transplant recipients in a 3:1 ratio to three sequential study cohorts according to a double-blind design. Patients received oral letermovir (at a dose of 60, 120, or 240 mg per day, or matching placebo) for 12 weeks after engraftment. The primary end point was all-cause prophylaxis failure, defined as discontinuation of the study drug because of CMV antigen or DNA detection, end-organ disease, or any other cause. Patients underwent weekly surveillance for CMV infection. RESULTS The reduction in the incidence of all-cause prophylaxis failure was dose-dependent. The incidence of prophylaxis failure with letermovir, as compared with placebo, was 48% versus 64% at a daily letermovir dose of 60 mg (P=0.32), 32% at a dose of 120 mg (P=0.01), and 29% at a dose of 240 mg (P=0.007). Kaplan-Meier time-to-onset profiles for prophylaxis failure showed a significant difference in the comparison of letermovir at a dose of 240 mg per day with placebo (P=0.002). The safety profile of letermovir was similar to placebo, with no indication of hematologic toxicity or nephrotoxicity. CONCLUSIONS Letermovir, as compared with placebo, was effective in reducing the incidence of CMV infection in recipients of allogeneic hematopoietic-cell transplants. The highest dose (240 mg per day) had the greatest anti-CMV activity, with an acceptable safety profile. (Funded by AiCuris; ClinicalTrials.gov number, NCT01063829.).

Control of Multidrug-Resistant Pseudomonas aeruginosa in Allogeneic Hematopoietic Stem Cell Transplant Recipients by a Novel Bundle Including Remodeling of Sanitary and Water Supply Systems

Background Infections by multidrug-resistant Pseudomonas aeruginosa (MDRPa) are an important cause of morbidity and mortality in patients after allogeneic hematopoietic stem cell transplantation (HSCT). Humid environments can serve as a reservoir and source of infection by this pathogen. To minimize the risk of infection from these reservoirs, we performed extensive remodeling of sanitation and water installations as the focus of our hygiene bundle. Methods During the reconstruction of our transplantation unit (April 2011-April 2014) we implemented several technical modifications to reduce environmental contamination by and subsequent spreading of MDRPa, including a newly designed shower drain, disinfecting siphons underneath the sinks, and rimless toilets. During a 3-year study period (2012-2014), we tracked the number of patients affected by MDRPa (colonized and/or infected) and the outcome of infected patients, and monitored the environmental occurrence of this pathogen. We further performed whole-genome sequencing of nosocomial MDRPa strains to evaluate genotypic relationships between isolates. Results Whereas 31 (9.2%; 18 colonized, 13 infected) patients were affected in 2012 and 2013, the number decreased to 3 in 2014 (17%; 3 colonized, 0 infected). Lethality by MDRPa similarly decreased from 3.6% to 0%. Environmental detection of MDRPa decreased in toilets from 18.9% in 2012-2013 to 6.1% in the following year and from 8.1% to 3.0%, respectively, in shower outlets. Whole-genome sequencing showed close relationships between environmental and patient-derived isolates. Conclusions Hospital construction measures aimed at controlling environmental contamination by and spread of MDRPa are effective at minimizing the risk of highly lethal MDRPa infections.

Epileptic seizures and rhinocerebral mucormycosis during blinatumomab treatment in a patient with biphenotypic acute leukemia

Dear Editor, InMarch 2010, a 22-year-old female patient was admitted to our hospital for progressive dyspnea and weakness. The past medical history included a respiratory infection 2 weeks before admission treated with amoxicillin. Physical examination and laboratory findings revealed a severe anemia (hemoglobin 4 g/ dL) and neutropenia (460/μL). A subsequent bone marrow aspiration displayed a 90 % infiltration with lymphoblastic cells. According to the immunophenotype, which was characterized by positive staining of the blasts for CD79a, CD19, and TdT, as well as aberrant expression of CD13, CD33, and CD15, the leukemia was defined as an acute lymphoblastic leukemia (ALL). Cytogenetic evaluation showed a normal karyotype. Clonal rearrangements of the immunoglobulin light chain genes IGL (VL2-JL2) and IGK (IntronRSS-KDE)were identified and used as clone-specific markers for minimal residual disease quantification (MRD). According to the therapy recommendations of the German Multicenter Study Group for Adult ALL, a high risk subtype was defined and therapy initiated in March 2010 [1]. In the first complete remission (MRD positive with level <10), an allogeneic stem cell transplantation (SCT) from an unrelated donor (9/10 HLAmatched donor, one antigen mismatch in HLA-DQ) was performed in July 2010 following a myeloablative conditioning regimen with fractionated total body irradiation (12 Gy), cyclophosphamide, and antithymocyte globulin. The patient developed an acute graft versus host disease (GvHD) of the skin (grade 2) and the upper gastrointestinal tract 10 and 84 days after transplantation, respectively, which responded to corticosteroid therapy. In May 2011, a significant decrease of donor cell chimerism in the CD34 and the CD19 subpopulation was observed, until in July 2011 a relapse with 5 % blasts in the peripheral blood was diagnosed. Since the achievement of a complete remission before a potential second allogeneic SCT confers a prognostic impact and seemed to be unlikely to reach by using conventional treatment regimens [2], the patient was enrolled in the MT 103–206 trial evaluating the efficacy of blinatumomab in relapsed/ refractory ALL [3]. In August 2011, the patient developed generalized tonic-clonic seizures 24 h after the start of the continuous infusion of the antibody construct (5 μg/m per day), which stopped after termination of blinatumomab and the application of dexamethasone and diazepam. The patient had received a corticosteroid pretreatment for 3 days (18 mg dexamethasone per day) and corticosteroid premedication (16 mg dexamethasone) prior to start of blinatumomab infusion. * Matthias Stelljes stelljes@uni-muenster.de

High‐dose melphalan‐based sequential conditioning chemotherapy followed by allogeneic haematopoietic stem cell transplantation in adult patients with relapsed or refractory acute myeloid leukaemia

Considering the unsatisfactory results of salvage therapies for patients with relapsed/refractory acute myeloid leukaemia (R/R‐AML), their value before allogeneic haematopoietic stem cell transplantation (HSCT) remains questionable. However, direct allogeneic HSCT following established conditioning regimens applied in patients with R/R‐AML during active disease has been equally disappointing. In this retrospective observational study, high‐dose melphalan, as part of a sequential preparative regimen, followed by a total body irradiation (4 × 2 Gy)‐based or a treosulfan‐based dose‐adapted conditioning therapy for allogeneic HSCT was administered to 292 adult patients (median age 56 years, range 17–74) with primary refractory (144 patients), secondary refractory (97 patients) or relapsed AML (51 patients). Overall survival rates at 3 years were 34%, 29% and 41%, respectively. Risk factors associated with an inferior survival were higher age, transplantation from a human leucocyte antigen‐mismatched donor and high disease burden. Patients transplanted with blast infiltration <20% showed a notable survival rate of 51% at 3 years. In particular, patients with primary refractory AML showed a more favourable outcome when transplanted early during their disease course. Thus, high‐dose melphalan‐based sequential conditioning chemotherapy followed by an allogeneic HSCT is feasible and enables long‐term remission to be achieved in a substantial proportion of patients with active R/R‐AML.

Relative Impact of HLA Matching and Non-HLA Donor Characteristics on Outcomes of Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndrome

Increasing donor-recipient HLA disparity is associated with negative outcomes of allogeneic hematopoietic stem cell transplantation (HSCT), but its comparative relevance amid non-HLA donor characteristics is not well established. We addressed this question in 3215 HSCTs performed between 2005 and 2013 in Germany for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Donors were HLA-matched related (MRD; n = 872) or unrelated (10/10 MUD, n = 1553) or HLA-mismatched unrelated (<10/10 MMUD, n = 790). Overall survival (OS) was similar after MRD compared with 10/10 MUD HSCT, reflecting opposing hazards of relapse (hazard ratio [HR], 1.32; P < .002) and nonrelapse mortality (HR, .63; P < .001). After UD HSCT, increasing HLA disparity was associated with inferior OS (HR, 1.21 [P < .02] and HR, 1.57 [P < .001] for 9/10 and ≤8/10 MMUD, respectively, compared with 10/10 MUD). Among non-HLA donor characteristics, age, sex mismatching (male recipient-female donor), and cytomegalovirus (CMV) mismatching (positive recipient-negative donor) impacted OS. Multivariate subgroup analysis showed that OS was similar after HSCT from the youngest 9/10 MMUD (<30 years) compared with the oldest 10/10 MUD (>40 years) (HR, 1.18; P = .25) and also in male patients transplanted from female 10/10 MUD compared with male 9/10 MMUD (HR, .89; P = .46). In contrast, OS of CMV-positive patients tended to be better with CMV-negative 10/10 MUDs compared with CMV-positive 9/10 MMUDs (HR, 1.31; P = .04). Because of low patient numbers in subgroups, definite conclusions and establishment of a hierarchy among HLA matching and non-HLA donor characteristics could not be made. Our data suggest that the impact of donor age and sex mismatch but not CMV mismatch on outcome of allogeneic HSCT may be comparable with that of single HLA disparity.

Successful second allogeneic stem cell transplantation in a patient with T-lymphoblastic leukemia (T-ALL) relapsed as myeloid sarcoma

Dear Editor, Lineage switch between myeloid and lymphoblastic leukemia is a rare but interesting event as its exploration might give insights into pathways responsible for lineage assignment and development of leukemia. Lineage switch describes an acute leukemia that meets French-American-British (FAB) criteria for one lineage but converts to the opposite lineage upon relapse. Lineage switches are associated with poor prognosis and resistance to therapy [1, 2]. Here, we describe a linage switch from a T-cell acute lymphoblastic leukemia (T-ALL) to a myeloid sarcoma in a patient who was cured by second allogeneic stem cell transplantation (SCT). The 32-year-old male patient was first diagnosed with a cortical T-ALL. He had been treated with polychemotherapy according to the German Multicenter Study Group (GMALL) 07/2003 protocol, during which a relapse had occurred. After salvage chemotherapy with cladribine, etoposide, and cytarabine, he had achieved a second complete remission (CR) and a first allogeneic SCTwas performed (conditioning: cyclophosphamide/12 Gy TBI). The patient presented 7 years later with a mediastinal tumor and lymphadenopathy. A biopsy obtained from the mediastinal tumor revealed a blast cell infiltrate positive for CD34, CD10, and CD45. In contrast to the previous T-ALL (Fig. 1a–c), the infiltrate showed positivity for the myeloid antigens CD33 and intracellular myeloperoxidase and negativity for T cell antigens (Fig. 1e–g). The clonal relation of the myeloid sarcoma to the initial disease was proven by detection of the same biallelic clonal T cell receptor gamma-chain rearrangements (Fig. 1d, h). Chimerism analyses of blood and bone marrow showed a complete donor cell chimerism. Despite intensive salvage therapies with cytarabine/daunorubicin, cytarabine/mitoxantrone, and nelarabine/ifosfamide, no remission could be achieved, and a second allogeneic SCT from a different donor (conditioning: fludarabine, busulfane, cyclophosphamide) followed by a consolidating mediastinal radiotherapy was performed. These therapies led to an ongoing CR confirmed by PET-CT. Actually, after 2 years, the patient is well in a sustained CR. Reasons for lineage switches remain unclear. Either an emergence of a minor subclone which had already been present at initial diagnosis or a phenotypic shift of the original clone are the two main explanations. Mutations in early hematopoietic progenitor cells before lineage differentiation, e.g., of the DNMT3A gene, can lead to a preleukemic state [3]. However, due to poor sample quality, we were not able to detect any mutations. So far, there are only two more cases described in literature in which the clonal relation of a lineage switch from T-lymphoblastic to myeloid lineage was proven by analysis of molecular markers [4, 5], while in several other cases, the clonal relation was proven by conventional cytogenetic analyses [6–8]. In our patient, the disease was refractory to chemotherapy and only responded to a second allogeneic SCT, suggesting that allogeneic SCT may represent a * Matthias Stelljes stelljes@uni-muenster.de