Current practice in nutrition after allogeneic hematopoietic stem cell transplantation - Results from a survey among hematopoietic stem cell transplant centers.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (alloHSCT) is frequently associated with impaired oral intake and malnutrition, which potentially increases morbidity and mortality. Therefore, nutrition is one of the major challenges in the post-transplant period. METHODS: To document the current clinical approach in nutritional treatment, we designed a questionnaire concerning the current practice in nutrition after alloHSCT and distributed it to German speaking centers performing alloHSCT in Germany, Austria and Switzerland between November 2018 and March 2020. Twenty-eight (39%) of 72 contacted centers completed the survey, 23 from Germany, two from Austria and three from Switzerland, representing 50% of alloHSCT activity within the participating countries in 2018. RESULTS: All centers reported having nutritional guidelines for patients undergoing alloHSCT, whereby 86% (n = 24) provided a low-microbial diet during the neutropenic phase. The criteria to start parenteral nutrition (PN) directly after alloHSCT seemed to be consistent, 75% (n = 21) of the corresponding centers started PN if the oral nutritional intake or the bodyweight dropped below a certain limit. In the setting of intestinal graft-versus-host disease (GvHD) the current practice appeared to be more heterogenous. About 64% (n = 18) of the centers followed a special diet, added food stepwise modulated by GvHD symptoms, while only four centers regularly stopped oral intake completely (intestinal GvHD grade >1). Half of the centers (54%, n = 15) applied a lactose-free diet, followed by 43% (n = 12) which provided fat- and 18% (n = 5) gluten-free food in patients with intestinal GvHD. Supplementation of micronutrients in acute intestinal GvHD patients was performed by 54% (n = 15) of the centers, whereas vitamin D (89%, n = 25) and vitamin B12 (68%, n = 19) was added regularly independently of the presence of GvHD. Only 5 (18%) participating centers ever observed a food-associated infection during hospitalization, whereas food-associated infections were reported to occur more often in the outpatient setting (64%, n = 18). CONCLUSION: The survey documented a general consensus about the need for nutritional guidelines for patients undergoing alloHSCT. However, the nutritional treatment in clinical practice (i.e. lactose-, gluten- or fat-free in intestinal GvHD) as well as the use of food supplements was very heterogeneous. In line with current general recommendations the centers seemed to focus on safe food handling practice rather than providing a strict neutropenic diet. More high-quality data are required to provide evidence-based nutrition to patients during and after alloHSCT.

The IPSS-R has prognostic impact in untreated patients with MDS del(5q).

The IPSS-R proved to be a powerful tool for the assessment of prognosis in MDS patients. We aimed at a validation of the IPSS-R for patients with MDS harboring deletion (5q) isolated or accompanied by additional aberrations. The study was based on 444 MDS patients from MDS centers in Europe. 67% of the patients were female, median age was 69 years. 43.5% had MDS del(5q), 5.9% were diagnosed with RCUD, 2.0% RARS, 18.4% RCMD, 14.6% RAEB-I and 15.5% RAEB-II. According to the IPSS-R, there were 9.9% very low, 39.6% low, 16.6% intermediate, 12.8% high, 20.9% very high risk patients. For very low risk patients survival was 7.5 years, low 9.0 years, intermediate 6.5 years, high 1.5 years and very high 0.7 years (p < 0.001). For low and intermediate risk, the probability of AML evolution was significantly different (p = 0.03) as well as for high versus very high risk groups (p = 0.002). The IPSS-R proved to be an appropriate prognostic tool for MDS with del(5q).

Characterization of the novel HLA-B*49:39 allele identified in a German leukaemia patient.

HLA-B*49:39 allele is characterised by 1 amino acid substitution in the alpha 1 domain.

Acute myeloid leukemia derived from lympho-myeloid clonal hematopoiesis.

We studied acute myeloid leukemia (AML) patients with lympho-myeloid clonal hematopoiesis (LM-CH), defined by the presence of DNA methyltransferase 3A (DNMT3A) mutations in both the myeloid and lymphoid T-cell compartment. Diagnostic, complete remission (CR) and relapse samples were sequenced for 34 leukemia-related genes in 171 DNMT3A mutated adult AML patients. AML with LM-CH was found in 40 patients (23%) and was associated with clonal hematopoiesis of indeterminate potential years before AML, older age, secondary AML and more frequent MDS-type co-mutations (TET2, RUNX1 and EZH2). In 82% of AML patients with LM-CH, the preleukemic clone was refractory to chemotherapy and was the founding clone for relapse. Both LM-CH and non-LM-CH MRD-positive AML patients who achieved CR had a high risk of relapse after 10 years (75% and 75%, respectively) compared with patients without clonal hematopoiesis in CR with negative MRD (27% relapse rate). Long-term survival of patients with LM-CH was only seen after allogeneic hematopoietic stem cell transplantation (HSCT). We define AML patients with LM-CH as a distinct high-risk group of AML patients that can be identified at diagnosis through mutation analysis in T cells and should be considered for HSCT.

Efficacy and safety of deferasirox in non-thalassemic patients with elevated ferritin levels after allogeneic hematopoietic stem cell transplantation.

Elevated serum ferritin contributes to treatment-related morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). The multicenter DE02 trial assessed the safety, efficacy and impact of deferasirox on iron homeostasis after allogeneic HSCT. Deferasirox was administered at a starting dose of 10 mg/kg per day to 76 recipients of allogeneic HSCT, with subsequent dose adjustments based on efficacy and safety. Deferasirox was initiated at a median of 168 days after HSCT, with 84% of patients still on immunosuppression. Baseline serum ferritin declined from 2045 to 957 ng/mL. Deferasirox induced a negative iron balance in 84% of patients. Hemoglobin increased in the first 3 months, and trough serum cyclosporine levels were stable. Median exposure was 330 days, with a median compliance rate of >80%. The most common investigator-reported drug-related adverse events (AEs) were increased blood creatinine (26.5%), nausea (9.0%) and abdominal discomfort (8.3%). Fifty-four (71.1%) patients experienced drug-related AEs, which occasionally resulted in discontinuation (gastrointestinal (n=6), skin (n=3), elevated transaminases (n=1) and creatinine (n=1)). The incidence of AEs appeared to be dose related, with 7.5 mg/kg per day being the best-tolerated dose. Low-dose deferasirox is an effective chelation therapy after allogeneic HSCT, with a manageable safety profile, even in patients receiving cyclosporine.

Clofarabine salvage therapy before allogeneic hematopoietic stem cell transplantation in patients with relapsed or refractory AML: results of the BRIDGE trial.

In patients with relapsed or refractory (r/r) acute myeloid leukemia (AML), long-term disease control can only be achieved by allogeneic hematopoietic stem cell transplantation (HSCT). We studied the safety and efficacy of clofarabine-based salvage therapy. The study was designed as phase II, multicenter, intent-to-transplant (ITT) study. A total of 84 patients with r/r AML were enrolled. All patients received at least one cycle of CLARA (clofarabine 30 mg/m(2) and cytarabine 1 g/m(2), days 1-5). Chemo-responsive patients with a donor received HSCT in aplasia after first CLARA. Generally, HSCT was performed as soon as possible. The conditioning regimen consisted of clofarabine (4 × 30 mg/m(2)) and melphalan (140 mg/m(2)). The median patient age was 61 years (range 40-75). On day 15 after start of CLARA, 26% of patients were in a morphologically leukemia-free state and 79% exposed a reduction in bone marrow blasts. Overall, 67% of the patients received HSCT within the trial. The primary end point, defined as complete remission after HSCT, was achieved by 60% of the patients. According to the ITT, overall survival at 2 years was 43% (95% confidence interval (CI), 32-54%). The 2-year disease-free survival for transplanted patients was 52% (95% CI, 40-69%). Clofarabine-based salvage therapy combined with allogeneic HSCT in aplasia shows promising results in patients with r/r AML.

Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey.

Despite major improvements in allogeneic hematopoietic cell transplantation over the past decades, corticosteroid-refractory (SR) acute (a) and chronic (c) graft-versus-host disease (GVHD) cause high mortality. Preclinical evidence indicates the potent anti-inflammatory properties of the JAK1/2 inhibitor ruxolitinib. In this retrospective survey, 19 stem cell transplant centers in Europe and the United States reported outcome data from 95 patients who had received ruxolitinib as salvage therapy for SR-GVHD. Patients were classified as having SR-aGVHD (n=54, all grades III or IV) or SR-cGVHD (n=41, all moderate or severe). The median number of previous GVHD-therapies was 3 for both SR-aGVHD (1-7) and SR-cGVHD (1-10). The overall response rate was 81.5% (44/54) in SR-aGVHD including 25 complete responses (46.3%), while for SR-cGVHD the ORR was 85.4% (35/41). Of those patients responding to ruxolitinib, the rate of GVHD-relapse was 6.8% (3/44) and 5.7% (2/35) for SR-aGVHD and SR-cGVHD, respectively. The 6-month-survival was 79% (67.3-90.7%, 95% confidence interval (CI)) and 97.4% (92.3-100%, 95% CI) for SR-aGVHD and SR-cGVHD, respectively. Cytopenia and cytomegalovirus-reactivation were observed during ruxolitinib treatment in both SR-aGVHD (30/54, 55.6% and 18/54, 33.3%) and SR-cGVHD (7/41, 17.1% and 6/41, 14.6%) patients. Ruxolitinib may constitute a promising new treatment option for SR-aGVHD and SR-cGVHD that should be validated in a prospective trial.

Antagonism between granulocytic maturation and deacetylase inhibitor-induced apoptosis in acute promyelocytic leukaemia cells.

BACKGROUND: Transcriptional repression is a key mechanism driving leukaemogenesis. In acute promyelocytic leukaemia (APL), the fusion protein promyelocytic leukaemia-retinoic acid receptor-α fusion (PML-RARα) recruits transcriptional repressors to myeloid differentiation genes. All-trans-retinoic acid (ATRA) induces the proteasomal degradation of PML-RARα and granulocytic differentiation. Histone deacetylases (HDACs) fall into four classes (I-IV) and contribute to the transcription block caused by PML-RARα. METHODS: Immunoblot, flow cytometry, and May-Grünwald-Giemsa staining were used to analyze differentiation and induction of apoptosis. RESULTS: A PML-RARα- and ATRA-dependent differentiation programme induces granulocytic maturation associated with an accumulation of the myeloid transcription factor CCAAT/enhancer binding protein (C/EBP)ɛ and of the surface protein CD11b. While this process protects APL cells from inhibitors of class I HDAC activity, inhibition of all Zinc-dependent HDACs (classes I, II, and IV) with the pan-HDACi (histone deacetylase inhibitor(s)) LBH589 induces apoptosis of immature and differentiated APL cells. LBH589 can eliminate C/EBPɛ and the mitochondrial apoptosis regulator B-cell lymphoma (BCL)-xL in immature and differentiated NB4 cells. Thus, BCL-xL and C/EBPɛ are newly identified molecular markers for the efficacy of HDACi against APL cells. CONCLUSIONS: Our results could explain the therapeutic limitations occurring with ATRA and class I HDACi combinations. Pro-apoptotic effects caused by pan-HDAC inhibition are not blunted by ATRA-induced differentiation and may provide a clinically interesting alternative.

Successful systemic high-dose ribavirin treatment of respiratory syncytial virus-induced infections occurring pre-engraftment in allogeneic hematopoietic stem cell transplant recipients.

INTRODUCTION: Respiratory syncytial virus (RSV) is a frequent cause of respiratory tract infectious disease (RTID) in allogeneic hematopoietic stem cell transplant (HSCT) recipients associated with a high mortality once infection has progressed from upper RTID (URTID) to lower RTID (URTID). Aerosolized ribavirin (RBV) is considered a cornerstone of treatment, but is expensive and has toxic side effects on patients and staff. In this study, RSV infection was detected by polymerase chain reaction (PCR) from routinely collected throat swabs in HSCT patients. Infected individuals were treated according to an institutional protocol using intravenous (IV) RBV for patients with LRTID and oral ribavirin for URTID. RESULTS: RSV infection was diagnosed in 10 patients (median age 60 years) a median of 15 days after allogeneic HSCT for high-risk acute myeloid leukemia. Five patients with LRTID received IV RBV within 7 days after HSCT, and 5 with URTID were treated with oral RBV 12-40 days after HSCT. One patient died of septic shock associated with Pseudomonas aeruginosa-induced pneumonia 28 days after HSCT in prolonged neutropenia. All patients became RSV PCR negative on throat swabs within a median of 22 days from start of RBV. Despite severe lymphopenia, no patient treated for URTID progressed to LRTID. Neutrophil recovery was delayed in 3 patients. CONCLUSIONS: We show that IV and oral RBV were efficacious in preventing progression and reducing mortality of RSV infection in this small series of allogeneic HSCT recipients. Randomized studies are not to be expected for this condition and therefore reporting case series could help in determining optimal RSV treatment.

Leucodepletion for hyperleucocytosis--first report on a novel technology featuring electronic interphase management.

BACKGROUND AND OBJECTIVES: Therapeutic leucodepletion plays an established role in the initial treatment of patients with acute myeloid leukaemia (AML) and possibly other leukaemias presenting with leucostasis. Recently, a new leucodepletion technology, Spectra Optia IDL, has become available that differs from its predecessor, COBE Spectra MNC, by a variety of electronic supports, including by electronic adjustment of buffy coat positioning at the collection port. Given the paucity of patients in need of leucodepletions and marked differences in clinical presentation as well as blast properties (e.g. size, density), formal clinical trials comparing leucodepletion technologies have never been executed. MATERIALS AND METHODS: Here, we present aggregate data from eight leucodepletions performed in AML patients with clinical signs of leucostasis between 11/2011 and 07/2012 with the new device and compare the apheresis outcomes with those from fifteen leucodepletions performed with the old technology between 06/2010 and 10/2011. RESULTS: Patients did not differ with respect to epidemiological data. Pre-apheresis leucocyte count (WBC) was significantly higher in Spectra Optia IDL patients. Tolerability was excellent with both devices. Basic apheresis denominators such as duration, processed volume, inlet pump rate, ACD-A consumption and product volume were very similar. A negative correlation between pre-apheresis WBC and collection efficiency was noted. Mean collection efficiency for leucocytes with Spectra Optia IDL (47·3%) was similar to that with COBE Spectra MNC (50·5%). Platelet attrition was similar with both devices, approximately 30%. CONCLUSION: The novel, electronically guided leukapheresis system is suitable for leucodepletion.

Azacitidine and donor lymphocyte infusions as first salvage therapy for relapse of AML or MDS after allogeneic stem cell transplantation.

The combination of azacitidine and donor lymphocyte infusions (DLI) as first salvage therapy for relapse after allogeneic transplantation (allo-HSCT) was studied in 30 patients with acute myeloid leukemia (AML; n=28) or myelodysplastic syndromes (MDS; n=2) within a prospective single-arm multicenter phase-II trial. Treatment schedule contained up to eight cycles azacitidine (100 mg/m(2)/day, days 1-5, every 28 days) followed by DLI (from 1-5 × 10(6) to 1-5 × 10(8) CD3(+)cells/kg) after every second azacitidine cycle. A median of three courses azacitidine (range 1-8) were administered, and 22 patients (73%) received DLI. Overall response rate was 30%, including seven complete remissions (CRs, 23%) and two partial remissions (7%). Five patients remain in CR for a median of 777 days (range 461-888). Patients with MDS or AML with myelodysplasia-related changes were more likely to respond (P=0.011), and a lower blast count (P=0.039) as well as high-risk cytogenetics (P=0.035) correlated with the likelihood to achieve CR. Incidence of acute and chronic graft-versus-host disease was 37% and 17%, respectively. Neutropenia and thrombocytopenia grade III/IV occurred during 65% and 63% of treatment cycles, while infections were the most common grade III/IV non-hematological toxicity. Azacitidine and DLI as salvage therapy is safe, induces long-term remissions and may become an alternative for patients with AML or MDS relapsing after allo-HSCT.

SIAH proteins: critical roles in leukemogenesis.

The delicate balance between the synthesis and the degradation of proteins ensures cellular homeostasis. Proteases act in an irreversible manner and therefore have to be strictly regulated. The ubiquitin-proteasome system (UPS) is a major pathway for the proteolytic degradation of cellular proteins. As dysregulation of the UPS is observed in most cancers including leukemia, the UPS is a valid target for therapeutic intervention strategies. Ubiquitin-ligases selectively bind substrates to target them for poly-ubiquitinylation and proteasomal degradation. Therefore, pharmacological modulation of these proteins could allow a specific level of control. Increasing evidence accumulates that ubiquitin-ligases termed mammalian seven in absentia homologs (SIAHs) are not only critical for the pathogenesis of solid tumors but also for leukemogenesis. However, the relevance and therapeutic potential of SIAH-dependent processes has not been fully elucidated. Here, we summarize functions of SIAH ubiquitin-ligases in leukemias, how they select leukemia-relevant substrates for proteasomal degradation, and how the expression and activity of SIAH1 and SIAH2 can be modulated in vivo. We also discuss that epigenetic drugs belonging to the group of histone deacetylase inhibitors induce SIAH-dependent proteasomal degradation to accelerate the turnover of leukemogenic proteins. In addition, our review highlights potential areas for future research on SIAH proteins.