Nathan Cantoni

Evidence for a Bidirectional Relationship between Cytomegalovirus Replication and acute Graft-versus-Host Disease

Cytomegalovirus (CMV) infection and graft-versus-host disease (GVHD) are important complications after allogeneic hematopoietic stem cell transplantation (HSCT) with a clear link. Multiple studies show that GVHD and its treatment put patients at risk for CMV replication. Data on CMV replication as a cause of GVHD, in contrast, are controversial. We analyzed the reciprocal association of CMV replication with acute GVHD (aGVHD) in 515 patients treated with allogeneic HSCT between 1993 and 2008. Cumulative incidences at day 100 were 17% for CMV replication, 68% for aGVHD grade I-IV, and 48% for GVHD grade II-IV. Multivariate time-dependent analyses revealed that the presence of GVHD increased the risk of CMV replication in a dose-dependent manner: hazard ratio (HR) for CMV replication for patients with aGVHD grade I was 1.35 (95% confidence interval [CI] 0.82-2.21); HR for patients with aGVHD grade II-IV was 1.61 (95% CI 1.11-2.36, P-value for trend = .01). During phases of CMV replication, patients were at increased risk of developing aGVHD (HR 2.18, 95% CI 1.30-3.65, P < .01). These data confirm that GVHD and its therapy can induce CMV replication. They further demonstrate the reciprocal novel finding that patients are at significantly increased risk of developing aGVHD during CMV replication.

Lymphocyte subset recovery and outcome after T-cell replete allogeneic hematopoietic SCT.

Rapid recovery of lymphocytes after T-cell depleted hematopoietic SCT (HSCT) protects from relapse of myeloid malignancies. Whether lymphocyte reconstitution has a similar role after non-manipulated transplantation is controversial. We assessed numbers of CD4 and CD8 T-cells, natural killer (NK) cells and B-cells, before and 1, 3, 6, 12 and 24 months after T-cell replete transplantation in 345 patients. Lymphocyte subset counts up to 6 months post transplant had no effect on relapse. Elevated number of NK cells 12 months post transplant protected from relapse. As a novel finding, early recovery of NK cells was associated with significant protection from TRM already at the 3 and 6 months time points (P=0.03, P=0.02). In Cox multivariable models, patients with NK cells above 150/μL were significantly protected from TRM (hazard ratio (HR) 0.45, 95% confidence interval (95% CI) 0.21–0.95, P=0.03), an effect comparable in magnitude with that of carrying >200 CD4 T-cells/μL (HR 0.37, 95% CI 0.19–0.74, P=0.005). CD8 T-cell and B-cell recovery did not affect the rates of relapse or TRM. Early reconstitution of NK cells and CD4 T-cells in patients undergoing T-cell replete HSCT independently protected from TRM. Only a weak protection from disease relapse was noted for patients with high numbers of NK cells, and this occurred only late after transplantation.

Order of application and liver toxicity in patients given BU and CY containing conditioning regimens for allogeneic hematopoietic SCT

BU–CY is the established non-TBI-based myeloablative conditioning regimen for allogeneic hematopoietic SCT. However, liver toxicity and hepatic veno-occlusive disease (VOD) are frequent life-threatening complications. Pharmacological considerations suggest that BU can trigger toxicity of subsequent CY. Recent animal data confirmed this hypothesis. Less liver toxicity and better outcomes were observed when mice were treated with the reversed order of CY and BU. We analyzed in this study liver toxicity and outcome in patients receiving BU–CY (16 patients) or CY–BU (59 patients). Liver function differed significantly with higher levels of liver function tests between day +10 and +30, and a higher cumulative incidence of VOD in the BU–CY cohort (2/16 (12.5%) vs 0/59 (0%), P=0.006). TRM was significantly higher in patients receiving BU–CY (cumulative incidence BU–CY 45%, CY–BU 17%, P=0.02), without yet translating into a significant survival difference (incidence for survival: BU–CY 38%, CY–BU 63%; hazard ratio 1.19 for BU–CY, 95% confidence interval 0.29–4.82, P=0.80). Rates of engraftment and relapse were not different. These data support the concepts derived from animal models in favor of CY–BU compared with traditional BU–CY and form the basis for prospective controlled comparisons.

Infection prevention strategies in a stem cell transplant unit: impact of change of care in isolation practice and routine use of high dose intravenous immunoglobulins on infectious complications and transplant related mortality.

Objective:  Nursing in ‘live islands’ and routine high dose intravenous immunoglobulins after allogeneic hematopoietic stem cell transplantation were abandoned by many teams in view of limited evidence and high costs.

Bendamustine, lenalidomide and dexamethasone (BRd) has high activity as 2nd‐line therapy for relapsed and refractory multiple myeloma – a phase II trial

The combination of lenalidomide (Revlimid®, R) and dexamethasone (d) is a standard regimen for patients with relapsed/refractory multiple myeloma (rrMM). With this regimen, only a small fraction of patients will achieve high quality responses [≥ very good partial response (VGPR)]. The combination of bendamustine (B), lenalidomide and dexamethasone (BRd) has shown high efficacy in patients with advanced rrMM. However, dose‐limiting haematotoxicity restricted its use in extensively pre‐treated patient populations. This prospective, multicentre Phase II study evaluated the efficacy and safety of BRd in rrMM patients with one prior line of therapy. Fifty patients were enrolled (median age 68·5 years [range 46–83]) and were treated with B 75 mg/m2 days 1, 2; R 25 mg days 1–21 and d (40/20 mg) days 1, 8, 15 and 22, for 6 28‐day induction cycles, followed by 12 cycles with Rd alone. Pegfilgrastim was administered according to protocol‐defined criteria. The study aimed to demonstrate a complete response (CR)/VGPR rate of >40% after induction therapy. Of 45 evaluable patients, 23 (51%) achieved a CR/VGPR. Grade 4 neutropenia or thrombocytopenia occurred in 17 (34%) and 8 (16%) of patients, respectively. BRd is a safe and efficacious regimen as a second line treatment for rrMM, leading to high quality responses in a considerable proportion of patients.

Recommendations for the diagnosis and treatment of patients with polycythaemia vera

To present the Central European Myeloproliferative Neoplasm Organisation (CEMPO) treatment recommendations for polycythaemia vera (PV).

Promising activity of nelfinavir-bortezomib-dexamethasone (NeVd) in proteasome inhibitor-refractory multiple myeloma

TO THE EDITOR: Treatment of proteasome inhibitor (PI)–refractory multiple myeloma (MM) is challenging, with response rates of only 15% to 35% being achieved with next-generation drugs such as pomalidomide, carfilzomib, and daratumumab, alone or in combination.[1][1][⇓][2]-[3][3] The oral HIV

Role of liver magnetic resonance imaging in hyperferritinaemia and the diagnosis of iron overload

Hyperferritinaemia is a frequent clinical problem. Elevated serum ferritin levels can be detected in different genetic and acquired diseases and can occur with or without anaemia. It is therefore important to determine whether hyperferritinaemia is due to iron overload or due to a secondary cause. The main causes of iron overload are intestinal iron hyperabsorption disorders and transfusion-dependent disorders. Iron homeostasis and iron overload are quantified by different diagnostic approaches. The evaluation of serum ferritin and transferrin saturation is the first diagnostic step to identify the cause of hyperferritinaemia. The assessment of liver iron concentration by liver biopsy or magnetic resonance imaging (MRI) may guide the further diagnostic and therapeutic workup. Liver biopsy is invasive and poorly accepted by patients and should only be carried out in selected patients with hereditary haemochromatosis. As a non-invasive approach, MRI is considered the standard method to diagnose and to monitor both hepatic iron overload and the effectiveness of iron chelation therapy in many clinical conditions such as thalassaemia and myelodysplastic syndromes. Accurate evaluation and monitoring of iron overload has major implications regarding adherence, quality of life and prognosis. There are different technical MRI approaches to measuring the liver iron content. Of these, T2 and T2* relaxometry are considered the standard of care. MRI with cardiac T2* mapping is also suitable for the assessment of cardiac iron. Currently there is no consensus which technique should be preferred. The choice depends on local availability and patient population. However, it is important to use the same MRI technique in subsequent visits in the same patient to get comparable results. Signal intensity ratio may be a good adjunct to R2 and R2* methods as it allows easy visual estimation of the liver iron concentration. In this review a group of Swiss haematologists and radiologists give an overview of different conditions leading to primary or secondary iron overload and on diagnostic methods to assess hyperferritinaemia with a focus on the role of liver MRI. They summarise the standard practice in Switzerland on the use of liver iron concentration MRI as well as disease-specific guideline recommendations.

Black hole in the lung

We have read with great interest the recent article by Martino et al. about lower respiratory tract virus infections as a risk factor for invasive aspergillosis. The established risk factors for aspergillosis in patients after allogeneic hematopoietic SCT (HSCT) include duration of neutropenia, use of steroids, donor type, underlying disease, age, and presence and treatment of GVHD. The authors of this study analyzed the incidence and risk factors for the occurrence of invasive aspergillosis among 219 recipients of allogeneic HSCT after a reduced-intensity conditioning regimen. They showed that steroid therapy for GVHD and the occurrence of a lower respiratory tract infection caused by a respiratory virus were independent risk factors for the development of invasive aspergillosis. Here we report the case of a 45-year-old woman with a history of extensive chronic GVHD of the lungs (bronchiolitis obliterans), gastrointestinal tract, liver and skin following myeloablative allogeneic HSCT for AML 3 years earlier. She was under triple immunosuppression with prednisolone, tacrolimus and mycophenolate when she developed rhinitis, productive cough and chest pain. Influenza A virus was isolated from a nasopharyngeal swab and treatment with oseltamivir and i.v. Igs was initiated. A computed tomography (CT) of the chest done at this time was normal. However, treatment symptoms persisted and another CT scan was performed 1 week later. The picture was suggestive of pulmonary aspergillosis (Figure 1a). Treatment with voriconazole was added and the symptoms improved. The follow-up CT 2 weeks later revealed the formation of a massive cavitation (Figure 1b). Treatment was empirically changed to liposomal amphotericin B and meropenem, and partial resection of the right lower pulmonary lobe was performed. Histological and microbiological investigations showed a polymicrobial infection with the presence of zygomyceteRhizopus microsporus (Figures 2a and b), Enterococcus faecium and coagulasenegative staphylococci. On treatment with liposomal amphotericin B and antibiotics, the infections resolved. This case is in line with the paper by Martino et al. and illustrates how influenza virus triggered this rapidly progressive polymicrobial disease in a severely immunocompromised patient with active chronic GVHD late