Abstract: Immunocompromised patients are at high risk of invasive fungal infections (IFI), in particular those with haematological malignancies undergoing remission-induction chemotherapy for acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) and recipients of allogeneic haematopoietic stem cell transplants (HSCT). Despite the development of new treatment options in the past decades, IFI remains a concern due to substantial morbidity and mortality in these patient populations. In addition, the increasing use of new immune modulating drugs in cancer therapy has opened an entirely new spectrum of at risk periods. Since the last edition of antifungal prophylaxis recommendations of the German Society for Haematology and Medical Oncology in 2014, seven clinical trials regarding antifungal prophylaxis in patients with haematological malignancies have been published, comprising 1227 patients. This update assesses the impact of this additional evidence and effective revisions. Our key recommendations are the following: prophylaxis should be performed with posaconazole delayed release tablets during remission induction chemotherapy for AML and MDS (AI). Posaconazole iv can be used when the oral route is contraindicated or not feasible. Intravenous liposomal amphotericin B did not significantly decrease IFI rates in acute lymphoblastic leukaemia (ALL) patients during induction chemotherapy, and there is poor evidence to recommend it for prophylaxis in these patients (CI). Despite substantial risk of IFI, we cannot provide a stronger recommendation for these patients. There is poor evidence regarding voriconazole prophylaxis in patients with neutropenia (CII). Therapeutic drug monitoring TDM should be performed within 2 to 5 days of initiating voriconazole prophylaxis and should be repeated in case of suspicious adverse events or of dose changes of interacting drugs (BIItu). General TDM during posaconazole prophylaxis is not recommended (CIItu), but may be helpful in cases of clinical failure such as breakthrough IFI for verification of compliance or absorption.

Abstract: Dear Editor, Extranodal natural killer (NK)/T cell lymphoma is an aggressive malignancy. Effective regimens for this lymphoma contain L-asparaginase. For patients failing L-asparaginase-containing regimens, there are no useful conventional salvage approaches [1]. We recently reported that blockade of programmed cell death protein 1 (PD1) on effector T cells with the anti-PD1 antibody pembrolizumab was highly efficacious in NK/T cell lymphoma failing L-asparaginase [2]. Anti-PD1 antibodies are off-label non-reimbursed drugs for NK/T cell lymphomas. Not every patient can afford pembrolizumab. Since employing PD1 blockade as an option for NK/T cell lymphomas failing L-asparaginase, we have with informed consent treated three patients who could only afford another anti-PD1 antibody nivolumab, which if given at 40 mg (the smallest vial available) every 2 weeks (Q2W) was much cheaper than pembrolizumab. Patient 1 was a 59-year-old man with stage IV disease involving the nasal cavity, right testis and bone marrow (Table 1). Initial treatment with an L-asparaginase-containing regimen for three cycles resulted in complete response (CR), as assessed by 18F-fluorodeoxyglucose (FDG) positron emission tomography computed tomography (PET/CT). However, he presented with fever, facial skin infiltration, pancytopenia, and ataxia after the fourth course. Magnetic resonance imaging (MRI) showed lymphomatous infiltration of the cerebellum and dorsal midbrain (Fig. 1a). Biopsy of bone marrow and skin confirmed lymphoma relapse. Cerebrospinal fluid also showed lymphoma cells. Nivolumab was started. Shortly after the first dose, his mental state worsened and bilateral vocal cord palsy developed, requiring emergency tracheostomy. Interestingly, the facial skin lesion then totally regressed. MRI brain repeated 10 days after the second dose of nivolumab showed stable disease (Fig. 1a). However, his genera l physique deter iorated and he died from Stenotrophomonas maltophilia chest infection. Patient 2 was a 43-year-old man with stage II disease involving the nasopharynx and cervical lymph nodes, who achieved CR with SMILE (Table 1) and sandwiched radiotherapy (50 Gy). He presented 3.5 years later with gastrointestinal bleeding. CT scan showed a distal jejunal lesion with adjacent lymphadenopathy. Histology of the resected tumor confirmed lymphomatous recurrence. PET/CT scan showed residual FDG-avid foci after the operation (Fig. 1b). Nivolumab was started. PET/CT scan after four doses of nivolumab showed no FDG-avid lesions (Fig. 1b). He has since received five additional doses, and is asymptomatic. Patient 3 was an 80-year-old woman with stage IV disease and widespread cutaneous infiltration. After six courses of an L-asparaginase-containing regimen (Table 1), CR was achieved. The lymphoma relapsed 3 months later, and there was a delay before the patient sought treatment. She was admitted in a moribund state. PET/CT scan showed hypermetabolic hepatosplenomegaly, generalized lymphadenopathy, and extensive skin lesions (Fig. 1c). Nivolumab was given. Approximately a week afterwards, there was fever associated with a mild hyperbilirubinemia, hypofibrinogenemia, and increased D-dimer; which could be consistent with grade I cytokine release syndrome (CRS) [3]. These problems subsided with * Yok-Lam Kwong ylkwong@hkucc.hku.hk

Abstract: Infections by multidrug-resistant (MDR) bacteria are a worrisome phenomenon in hematological patients. Data on the incidence of MDR colonization and related bloodstream infections (BSIs) in haematological patients are scarce. A multicentric prospective observational study was planned in 18 haematological institutions during a 6-month period. All patients showing MDR rectal colonization as well as occurrence of BSI at admission were recorded. One-hundred forty-four patients with MDR colonization were observed (6.5% of 2226 admissions). Extended spectrum beta-lactamase (ESBL)-producing (ESBL-P) enterobacteria were observed in 64/144 patients, carbapenem-resistant (CR) Gram-negative bacteria in 85/144 and vancomycin-resistant enterococci (VREs) in 9/144. Overall, 37 MDR-colonized patients (25.7%) developed at least one BSI; 23 of them (62.2%, 16% of the whole series) developed BSI by the same pathogen (MDRrel BSI), with a rate of 15.6% (10/64) for ESBL-P enterobacteria, 14.1% (12/85) for CR Gram-negative bacteria and 11.1% (1/9) for VRE. In 20/23 cases, MDRrel BSI occurred during neutropenia. After a median follow-up of 80 days, 18 patients died (12.5%). The 3-month overall survival was significantly lower for patients colonized with CR Gram-negative bacteria (83.6%) and VRE (77.8%) in comparison with those colonized with ESBL-P enterobacteria (96.8%). CR-rel BSI and the presence of a urinary catheter were independent predictors of mortality. MDR rectal colonization occurs in 6.5% of haematological inpatients and predicts a 16% probability of MDRrel BSI, particularly during neutropenia, as well as a higher probability of unfavourable outcomes in CR-rel BSIs. Tailored empiric antibiotic treatment should be decided on the basis of colonization.

Abstract: The treatment approaches for Waldenstrom macroglobulinemia (WM) are largely based upon information from single-arm phase II trials, without comparative data. We compared the efficacy of two commonly used regimens in routine practice (bendamustine-rituximab (BR) and dexamethasone, rituximab plus cyclophosphamide (DRC)) and evaluated their activity with respect to the patients’ MYD88L265P mutation status. Of 160 consecutive patients, 60 received BR (43 with relapsed/refractory WM) and 100 received DRC (50 had relapsed/refractory WM). In the treatment-naive setting, overall response rate (ORR) was 93% with BR versus 96% with DRC (p = 0.55). Two-year progression-free survival (PFS) with BR and DRC was 88 and 61%, respectively (p = 0.07). In salvage setting, ORR was 95% with BR versus 87% with DRC, p = 0.45; median PFS with BR was 58 versus 32 months with DRC (2-year PFS was 66 versus 53%; p = 0.08). Median disease-specific survival was not reached with BR versus 166 months with DRC (p = 0.51). The time-to-event endpoints and depth of response were independent of the MYD88 mutation status. Grade ≥ 3 adverse events of both regimens were comparable. A trend for longer PFS was observed with BR although the regimens have comparable toxicities. The activity of BR and DRC appears to be unaffected by patients’ MYD88 mutation status.

Abstract: This consensus statement is directed to intensivists, hematologists, and oncologists caring for critically ill cancer patients and focuses on the management of these patients.

Abstract: Autoimmune disorders (ADs) are encountered in 10 to 20% of patients with myelodysplastic syndromes (MDS). Available data suggest that ADs concern more often younger patients with higher risk IPSS. MDS subtypes associated with ADs are mainly MDS with single lineage dysplasia (MDS-SLD) and MDS with excess blasts (MDS-EB). Various types of ADs have been described in association with MDS, ranging from limited clinical manifestations to systemic diseases affecting multiple organs. Defined clinical entities as vasculitis, connective tissue diseases, inflammatory arthritis, and neutrophilic diseases are frequently reported; however, unclassified or isolated organ impairment can be seen. In general, ADs do not seem to confer worse survival, although certain ADs may be associated with adverse outcomes (i.e., vasculitis) or progression of MDS (Sweet syndrome). While steroids and immunosuppressive treatment (IST) remain the backbone of first-line treatment, increasing evidence suggests that MDS-specific therapy as hypomethylating agents, based on their immunomodulatory effect, may be effective in treating these complications and for sparing steroids.

Abstract: Follicular Lymphoma (FL) is the second most common type of non-Hodgkin lymphoma and is considered to be the prototype of indolent lymphomas. Histologic transformation into an aggressive lymphoma, which is expected to occur at a rate of 2 to 3% each year, is associated with rapid progression, treatment resistance, and poor prognosis. Recent modifications to the physiopathologic mechanism of transformed follicular lymphoma (t-FL) have been proposed, including genetic and epigenetic mechanisms as well as a role for the microenvironment. Although t-FL is considered a devastating complication, as it is associated with treatment-refractory disease and a dismal outcome, recent data in the rituximab era have suggested that not only is the prognosis less severe than reported in the previous literature but the risk of transformation is also lower. Thus, this study aimed to review the most recent research on t-FL in an attempt to better understand the clinical meaning of transformation from FL to diffuse large B cell lymphoma (DLBCL) and the impact of current treatment strategies on the curability of this intriguing subentity of lymphoma.

Abstract: Allogeneic hematopoietic stem cell transplantation is an established consolidation therapy for patients with acute myeloid leukemia. However, relapse after transplantation remains a major clinical problem resulting in poor prognosis. Thus, detection of measurable (“minimal”) residual disease to identify patients at high risk of relapse is essential. A feasible method to determine measurable residual disease may be digital droplet PCR (ddPCR) that allows absolute quantification with high sensitivity and specificity without the necessity of standard curves. Using ddPCR, we analyzed pre-transplant peripheral blood and bone marrow of 51 NPM1-mutated acute myeloid leukemia patients transplanted in complete remission or complete remission with incomplete recovery. Mutated NPM1 measurable residual disease-positive patients had higher cumulative incidence of relapse (P < 0.001) and shorter overall survival (P = 0.014). Restricting the analyses to patients receiving non-myeloablative conditioning, mutated NPM1 measurable residual disease positivity is associated with higher cumulative incidence of relapse (P < 0.001) and shorter overall survival (P = 0.006). Positive mutated NPM1 measurable residual disease status determined by ddPCR before allogeneic stem cell transplantation is associated with worse prognosis independent of other known prognostic markers—also for those receiving non-myeloablative conditioning. In the future, mutated NPM1 measurable residual disease status determined by ddPCR might guide treatment and improve patients’ outcomes.

Abstract: The geriatric nutritional risk index (GNRI) is a simple and well-established nutritional assessment tool that is a significant prognostic factor for various cancers. However, the role of the GNRI in predicting clinical outcomes of diffuse large B cell lymphoma (DLBCL) patients has not been investigated. To address this issue, we retrospectively analyzed a total of 476 patients with newly diagnosed de novo DLBCL. We defined the best cutoff value of the GNRI as 96.8 using a receiver operating characteristic curve. Patients with a GNRI < 96.8 had significantly lower overall survival (OS) and progression-free survival (PFS) than those with a GNRI ≥ 96.8 (5-year OS, 61.2 vs. 84.4%, P < 0.001; 5-year PFS, 53.7 vs. 75.8%, P < 0.001). Multivariate analysis showed that performance status, Ann Arbor stage, serum lactate dehydrogenase, and GNRI were independent prognostic factors for OS. Among patients with high-intermediate and high-risk by National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI), the 5-year OS was significantly lower in patients with a GNRI < 96.8 than in those with a GNRI ≥ 96.8 (high-intermediate risk, 59.5 vs. 75.2%, P = 0.006; high risk, 37.4 vs. 64.9%, P = 0.033). In the present study, we demonstrated that the GNRI was an independent prognostic factor in DLBCL patients. The GNRI could identify a population of poor-risk patients among those with high-intermediate and high-risk by NCCN-IPI.

Abstract: Recent reports identify NLR (the ratio between absolute neutrophils counts, ANC, and absolute lymphocyte count, ALC), as predictor of progression-free survival (PFS) and overall survival (OS) in cancer patients. We retrospectively tested NLR and LMR (the ratio between absolute lymphocyte and monocyte counts) in newly diagnosed Hodgkin lymphoma (HL) patients treated upfront with a PET-2 risk-adapted strategy. NLR and LMR were calculated using records obtained from the complete blood count (CBC) from 180 newly diagnosed HL patients. PFS was evaluated accordingly to Kaplan-Meier method. Higher NLR was associated to advanced stage, increased absolute counts of neutrophils and reduced count of lymphocytes, and markers of systemic inflammation. After a median follow-up of 68 months, PFS at 60 months was 86.6% versus 70.1%, respectively, in patients with NLR ≥ 6 or NLR < 6. Predictors of PFS at 60 months were PET-2 scan (p < 0.0001), NLR ≥ 6.0 (p = 0.02), LMR < 2 (p = 0.048), and ANC (p = 0.0059) in univariate analysis, but only PET-2 was an independent predictor of PFS in multivariate analysis. Advanced-stage patients (N = 119) were treated according to a PET-2 risk-adapted protocol, with an early switch to BEACOPP regimen in case of PET-2 positivity. Despite this strategy, patients with positive PET-2 still had an inferior outcome, with PFS at 60 months of 84.7% versus 40.1% (negative and positive PET-2 patients, respectively, p < 0.0001). Independent predictors of PFS by multivariate analysis were PET-2 status and to a lesser extend NLR in advanced stage, while LMR maintained its significance in early stage. By focusing on PET-2 negative patients, we found that patients with NLR ≥ 6.0 or LMR < 2 had an inferior outcome compared to patients with both ratios above the cutoff (78.7 versus 91.9 months, p = 0.01). We confirm NLR as predictor of PFS in HL patients independently from stage at diagnosis. Integration of PET-2 scan, NLR and LMR can result in a meaningful prognostic system that needs to be further validated in prospective series including patients treated upfront with PET-2 adapted-risk therapy.

Abstract: RESPONSE-2 is a phase 3 study comparing the efficacy and safety of ruxolitinib with the best available therapy (BAT) in hydroxyurea-resistant/hydroxyurea-intolerant polycythemia vera (PV) patients without palpable splenomegaly. This analysis evaluated the durability of the efficacy and safety of ruxolitinib after patients completed the visit at week 80 or discontinued the study. Endpoints included proportion of patients achieving hematocrit control (< 45%), proportion of patients achieving complete hematologic remission (CHR) at week 28, and the durability of hematocrit control and CHR. At the time of analysis, 93% (69/74) of patients randomized to ruxolitinib were receiving ruxolitinib; while in the BAT arm, 77% (58/75) of patients crossed over to ruxolitinib after week 28. No patient remained on BAT by week 80. Among patients who achieved a hematocrit response at week 28, the probability of maintaining response up to week 80 was 78% in the ruxolitinib arm. At week 80, durable CHR was achieved in 18 patients (24%) in the ruxolitinib arm versus 2 patients (3%) in the BAT arm. The safety profile of ruxolitinib was consistent with previous reports. These data support that ruxolitinib treatment should be considered also as a standard of care for hydroxyurea-resistant/hydroxyurea-intolerant PV patients without palpable splenomegaly.

Abstract: CD19 chimeric antigen receptor (CAR) T cell therapy has shown impressive results in treating acute lymphoblastic leukemia (B-ALL), chronic lymphoblastic leukemia (B-CLL), and B-cell non-Hodgkin lymphoma (B-NHL) over the past few years. Meanwhile, the cytokine release syndrome (CRS), which could be moderate or even life-threatening, has emerged as the most significant adverse effect in the clinical course of this novel targeting immunotherapy. In this systematic review, we analyzed the incidence of severe CRS in 19 clinical trials selected from studies published between 2010 and 2017. The pooled severe CRS proportion was 29.3% (95% confidence interval [CI] 12.3-49.1%) in B-ALL, 38.8% (95%CI 12.9-67.6%) in B-CLL, and 19.8% (95%CI 4.2-40.8%) in B-NHL. In the univariate meta regression analysis, the proliferation of CD19-CAR-T cell in vivo was correlated with the severe CRS. Specifically, total infusion cell dose contributed to the severe CRS occurring in B-ALL patients but not in B-CLL or B-NHL patients. Tumor burden was strongly associated with the severity of CRS in B-ALL. Besides, post-HSCT CD19 CAR-T cell infusion represented lower severe CRS incidence. Further investigations into the risk factors of CRS in B-CLL and B-NHL are needed.

Abstract: Composition of the gut microbiota seems to influence early complications of allogeneic hematopoietic cell transplantation (HCT) such as bacterial infections and acute graft-versus-host disease (GVHD). In this study, we assessed the impact of colonization with multidrug-resistant bacteria (MDRB) prior to HCT and the use of antibiotics against anaerobic bacteria on the outcomes of HCT. We retrospectively analyzed the data of 120 patients who underwent HCT for hematologic disorders between 2012 and 2014. Fifty-one (42.5%) patients were colonized with MDRB and 39 (32.5%) had infections caused by MDRB. Prior colonization was significantly correlated with MDRB infections (P 40 years (P = 0.002). Colonization had a negative impact on overall survival (OS) after HCT (64 vs. 47% at 24 months; P = 0.034) and infection-associated mortality (P < 0.001). Use of metronidazole was correlated with an increased incidence of acute GVHD (P < 0.001) and lower OS (P = 0.002). Patients colonized with MDRB are more susceptible to life-threatening infections. Colonization with virulent flora is the most probable source of neutropenic infection; therefore, information about prior positive colonization should be crucial for the selection of empiric antibiotic therapy. The use of metronidazole, affecting the biodiversity of the intestinal microbiome, seems to have a significant impact on OS and acute GVHD.

Abstract: Tumor cells can evade immune surveillance through overexpressing the ligands of checkpoint receptors on tumor cells or adjacent cells, leading T cells to anergy or exhaustion. Growing evidence of the interaction between tumor cells and microenvironment promoted the emergence of immune-checkpoint blockade. By targeting programmed cell death-1 (PD-1) pathway, cytotoxic activity of T cell is enhanced significantly and tumor cell lysis is induced subsequently. Currently, various antibodies against PD-1 and programmed death-ligand 1 (PD-L1) are under clinical studies in lymphomas. In this review, we outline the rationale for investigation of PD-1-PD-L1 immune-checkpoint blockade in lymphomas and discuss their prospect of applications in clinical treatment.

Abstract: The Japan Adult Leukemia Study Group (JALSG) Ph+ALL202 study reported a high complete remission (CR) rate for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) patients treated with imatinib-combined chemotherapy. However, the long-term treatment efficacy remains uncertain. Here, we report a final analysis of the JALSG Ph+ALL202 study. The outcomes were compared with those of the JALSG ALL93 and ALL97 studies, which were conducted in the pre-imatinib era. Ninety-nine newly diagnosed Ph+ALL patients were enrolled in Ph+ALL202 (median age, 45 years; median follow-up, 4.5 years). CR was achieved in 96/99 (97%) patients. Fifty-nine of these 96 patients (61%) underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) in their first CR (CR1). The 5-year overall and disease-free survival (DFS) rates were 50 and 43%, respectively, which were significantly higher compared to those in the pre-imatinib era (15 and 19%, respectively). Multivariate analysis revealed that imatinib administration, allo-HSCT in CR1, and a white blood cell count < 30 × 109/L were favorable independent prognostic factors for long-term DFS. Improved odds of receiving allo-HSCT and a lower relapse rate leaded to good long-term outcomes. The 3-year DFS tended to be higher in PCR-negative than that in PCR-positive patients (29 vs. 14%) in the non-HSCT patients, and this tendency was also seen in the allo-HSCT patients (59 vs. 50%). The higher rate of CR upon imatinib use may have contributed to these improvements.

Abstract: Maintenance therapy after autologous stem cell transplantation (ASCT) is recommended for use in multiple myeloma (MM); however, more data are needed on its impact on health-related quality of life (HRQoL) Presented here is an analysis of HRQoL in a Connect MM registry cohort of patients who received ASCT ± maintenance therapy The Connect MM Registry is one of the earliest and largest, active, observational, prospective US registry of patients with symptomatic newly diagnosed MM Patients completed the Functional Assessment of Cancer Therapy-MM (FACT-MM) version 4, EuroQol-5D (EQ-5D) questionnaire, and Brief Pain Inventory (BPI) at study entry and quarterly thereafter until death or study discontinuation Patients in three groups were analyzed: any maintenance therapy (n = 244), lenalidomide-only maintenance therapy (n = 169), and no maintenance therapy (n = 137); any maintenance and lenalidomide-only maintenance groups were not mutually exclusive There were no significant differences in change from pre-ASCT baseline between any maintenance (P = 060) and lenalidomide-only maintenance (P = 072) versus no maintenance for the FACT-MM total score There were also no significant differences in change from pre-ASCT baseline between any maintenance and lenalidomide-only maintenance versus no maintenance for EQ-5D overall index, BPI, FACT-MM Trial Outcomes Index, and myeloma subscale scores In all three groups, FACT-MM, EQ-5D Index, and BPI scores improved after ASCT; FACT-MM and BPI scores deteriorated at disease progression These data suggest that post-ASCT any maintenance or lenalidomide-only maintenance does not negatively impact patients’ HRQoL Additional research is needed to verify these findings

Abstract: To conduct a systematic review of the literature reporting efficacy and safety of recombinant factor VIIa (rFVIIa) for the treatment of bleeding in acquired haemophilia and, if data permitted, undertake a meta-analysis of the current evidence. MEDLINE®, Embase®, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched for all studies on rFVIIa treatment in acquired haemophilia. Heterogeneity of included studies was measured using the inconsistency index (I2). Of the 2353 publications screened, 290 potentially relevant references were identified: 12 studies published in 32 publications met inclusion criteria. In total, 1244 patients and 1714 bleeds were included (671 patients received rFVIIa treatment for 1063 bleeds). In seven of 12 studies, the initial dose of Recombinant FVIIa was 90 ± 10 μg/kg. Recombinant FVIIa was used as first-line therapy in the majority of cases. Median number of doses administered ranged from 10 to 28. Between 68 and 74% of bleeds were spontaneous, whereas 4–50% were traumatic. Thirty-nine to 90% of bleeds were severe. Haemostatic effectiveness was > 90% in 5/6 studies for both patient and bleed level. Recombinant FVIIa had a favourable safety profile with low risk of general adverse events and thromboembolic-associated events. The heterogeneity of the studies and data precluded a meta-analysis. Recombinant FVIIa demonstrated effectiveness for the treatment of bleeds and had a good safety profile. It is apparent from these data that there is a need for more standardised measures of clinical effectiveness in acquired haemophilia to enable comparison and pooling of results in the future.

Abstract: JAK2V617F monitoring and NGS of non-driver genes was performed in 100 patients with polycythemia vera (PV) or essential thrombocythemia (ET) with long molecular follow-up. Patients who did not progress to myelofibrosis (MF) or acute myeloid leukemia (AML) after more than 10 years (n = 50) showed a low frequency of mutations at first sample (18%) and an incidence rate of 1.7 new mutations × 100 person-years. Mutations were detected at first sample in 83% of PV/ET patients who later progressed to AML (n = 12) with these patients having a rate of 25.6 mutations × 100 person-years. Presence of mutations at diagnosis was the unique risk factor for acquiring a new genetic event (HR 2.7, 95% CI 1.1–6.8, p = 0.03) after correction for age, PV diagnosis, and total duration of hydroxyurea (HU) exposure. Patients with additional mutation at first sample showed a higher probability of developing cytopenia under HU therapy and a higher risk of AML (HR 12.2, 95% CI 2.6–57.1, p = 0.001) with mutations in ASXL1 (p < 0.0001), TP53 (p = 0.01), SRSF2 (p < 0.0001), IDH1/2 (p < 0.0001), and RUNX1 (p < 0.0001) being associated with a higher probability of AML. Myelofibrotic transformation was more frequent in patients with additional mutations, especially in SF3B1 (p = 0.02) and IDH1/2 (p < 0.0001) although a persistently high or a progressive increase of the JAK2V617F allele burden while receiving cytoreduction was the strongest predictor of MF transformation (HR 10.8, 95% CI 2.4–49.1, p = 0.002). In conclusion, NGS may be useful to identify a minority of PV and ET patients with high genetic instability and increased risk of AML transformation.

Abstract: Chronic lymphocytic leukemia (CLL) has a highly variable clinical course. About 2–10% of CLL patients develop aggressive histological transformation, most commonly to diffuse large B cell lymphoma (DLBCL), historically called Richter transformation (RT). Clinical features suggestive of RT include elevated LDH and non-specific symptoms such as fever, weight loss, and lymphadenopathy. 18-fluorodeoxyglucose (18-FDG) uptake is increased on PET scan (standardized uptake value max most commonly ≥ 10). PET/CT study can identify optimal site for excisional biopsy, which is the gold standard for RT diagnosis, as well as aid in disease staging and prognostication. In addition to clinical prognostic features such lactate dehydrogenase level, platelet count, and performance status, important predictors of poor outcome in RT are TP53 disruption and clonal relationship of DLBCL to underlying CLL. Chemoimmunotherapy constitutes the standard treatment for RT, followed by stem cell transplant (SCT) in eligible patients. However, the majority of patients do not proceed to allogeneic SCT, either due to inadequate disease control with initial therapy, poor performance status, or lack of donor availability. Overall outcome is dismal. Some novel agents under investigation, particularly PD-1 inhibitors, are showing clinical activity in Phase I and II trials. An ongoing incidence of RT has been noted in studies of previously treated patients receiving targeted therapies such as ibrutinib and venetoclax; the frequency of RT in patients initially treated with novel agents rather than chemoimmunotherapy will be important to determine with longer follow-up. This review focuses on the development, clinicopathologic features, and treatment of RT in the context of novel therapies.

Abstract: To characterize the clinical features, associated disorders, and treatment of necrobiotic xanthogranuloma (NXG), a rare non-Langerhans cell histiocytosis, we conducted a retrospective review of pathologically confirmed NXG at Mayo Clinic Arizona from 1987 to June 2017. Data on clinical findings, laboratory findings, associated disorders, therapy, and response to therapy were extracted. Nineteen patients were identified. Mean age was 54 years (range, 17–84) with equal gender distribution. Median follow-up was 5.5 years (range, 1–18). Most patients had a detectable monoclonal protein (84%), and IgG kappa constituted 58%. The most common cutaneous lesions involved the periorbital region (53%). The majority of patients had extracutaneous manifestations, most commonly affecting the liver (32%) and the sinuses (21%). Hematologic malignancies were diagnosed in 26% of patients and included Hodgkin lymphoma, chronic lymphocytic leukemia (CLL), smoldering myeloma, and multiple myeloma. The most common treatment was chlorambucil with or without systemic corticosteroids. Response was seen in most patients (95%), and most patients received 1–3 lines of therapy (74%). NXG is a reactive histiocytic disorder that commonly involves multiple organ systems and requires a high degree of clinical suspicion for accurate diagnosis. Treatment decisions should be based on coexisting conditions and pattern of disease involvement.

Abstract: Cancer patients frequently suffer from gastrointestinal complications. In this manuscript, we update our 2013 guideline on the diagnosis and management of gastrointestinal complications in adult cancer patients by the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO). An expert group was put together by the AGIHO to update the existing guideline. For each sub-topic, a literature search was performed in PubMed, Medline, and Cochrane databases, and strengths of recommendation and the quality of the published evidence for major therapeutic strategies were categorized using the 2015 European Society for Clinical Microbiology and Infectious Diseases (ESCMID) criteria. Final recommendations were approved by the AGIHO plenary conference. Recommendations were made with respect to non-infectious and infectious gastrointestinal complications. Strengths of recommendation and levels of evidence are presented. A multidisciplinary approach to the diagnosis and management of gastrointestinal complications in cancer patients is mandatory. Evidence-based recommendations are provided in this updated guideline.

Abstract: Infections and especially blood stream infections (BSI) with gram-negative bacteria (GNB) represent a major threat for patients with hematological diseases undergoing chemotherapy and mainly contribute to morbidity and mortality. In this retrospective single-center study, we analyzed the impact of BSI with different gram-negative multidrug-resistant bacteria (MDRGN) compared to BSI with antibiotic susceptible gram-negative bacteria. Data of 109 patients with hematological malignancies and GNB BSI were analyzed with overall survival (OS) 30 days after BSI being the primary endpoint. BSI with non-fermentative gram-negative bacteria were found in 26.6% of all patients and 73.4% suffered from a BSI with an Enterobacteriaceae. Thirty-two of 109 patients suffered from BSI with MDRGN. Characteristics of MDRGN and non-MDRGN BSI patients did not differ besides the fact that significantly more patients received an immunosuppressive therapy in the MDRGN BSI group. OS (30 days after BSI) of patients with MDRGN BSI was significantly lower (85.6 vs. 55.9%; p < 0.001) compared to patients with non-MDRGN BSI. Patients with MDRGN BSI with non-fermentative pathogens had a worse OS after 30 days compared to MDRGN BSI with Enterobacteriaceae and the same holds true for non-MDRGN BSI. In multivariate analysis of MDRGN BSI, non-fermenters and ICU admission were independently associated with increased 30-day mortality. Our data demonstrate the negative impact of non-fermentative gram-negative pathogens causing BSI compared to Enterobacteriaceae in hematological patients and thereby underlining the heterogeneity of gram-negative BSI.

Abstract: The International Myeloma Working Group has proposed the Revised International Staging System (R-ISS) for risk stratification of multiple myeloma (MM) patients. There are a limited number of studies that have validated this risk model in the autologous stem cell transplant (ASCT) setting. In this retrospective study, we evaluated the applicability and value for predicting survival of the R-ISS model in 134 MM patients treated with new agents and ASCT at the Mayo Clinic in Arizona and the University Hospital of Salamanca in Spain. The patients were reclassified at diagnosis according to the R-ISS: 44 patients (33%) had stage I, 75 (56%) had stage II, and 15 (11%) had stage III. After a median follow-up of 60 months, R-ISS assessed at diagnosis was an independent predictor for overall survival (OS) after ASCT, with median OS not reached, 111 and 37 months for R-ISS I, II and III, respectively (P < 0.001). We also found that patients belonging to R-ISS II and having high-risk chromosomal abnormalities (CA) had a significant shorter median OS than those with R-ISS II without CA: 70 vs. 111 months, respectively. Therefore, this study lends further support for the R-ISS as a reliable prognostic tool for estimating survival in transplant myeloma patients and suggests the importance of high-risk CA in the R-ISS II group.

Abstract: Scarce information is available on the use of ponatinib as second-line treatment in chronic phase chronic myeloid leukemia (CP-CML) patients resistant and/or intolerant to prior tyrosine kinase inhibitor (TKI) therapy. We collected data from 29 CML patients, with a median age of 54 years (range 32–72). Eleven patients had received dasatinib, 15 patients received nilotinib, and 3 patients received imatinib as first-line treatment. Forty-five percent of patients started ponatinib for secondary resistance, 38% for primary resistance, 7% for severe intolerance associated to a molecular warning, 7% due to the presence of a T315I mutation, and 3% for severe intolerance. Ponatinib was started at a dose of 45 mg in 60% of patients, 30 mg in 38%, and 15 mg in 2% of patients. Overall, at a median follow-up of 12 months, 85% of treated patients improved the level of response as compared to baseline, with 10 patients achieving a deep molecular response (MR4-4.5). No thrombotic events were recorded. The dose was reduced during treatment in 2 patients due to intolerance and in 8 patients in order to reduce the cardiovascular risk. Ponatinib seems a valid second-line treatment option for chronic phase CML, in particular for patients who failed a front-line second-generation TKI due to BCR-ABL-independent mechanisms of resistance.

Abstract: Due to fewer cancer services in rural locations, rural survivors may have unique unmet needs compared to urban survivors. This study compared among rural and urban haematological cancer survivors the most common "high/very high" unmet supportive care needs and the unmet need scores for five domains (information, financial concerns, access and continuity of care, relationships and emotional health). Survivors' socio-demographics, rurality, cancer history and psychological factors associated with each unmet need domain were also explored. A total of 1511 haematological cancer survivors were recruited from five Australian state cancer registries and 1417 (1145 urban, 272 rural) allowed extraction of their residential postcode from registry records. A questionnaire that contained the Survivor Unmet Needs Survey was mailed to survivors. Dealing with feeling tired was the most common "high/very high" unmet need for rural (15.2%) and urban (15.5%) survivors. The emotional health domain had the highest mean unmet need score for rural and urban survivors. Rurality was associated with a decreased unmet emotional health domain score whereas travelling for more than 1 h to treatment was associated with increased unmet financial concerns and unmet access and continuity of care. Depression, anxiety and stress were associated with increased unmet need scores for all five domains. Unmet need domain scores generally did not differ by rurality. Travelling for more than 1 h to treatment was associated with increased unmet need scores on two domains. Telemedicine and increased financial assistance with travel and accommodation may help those travelling long distances for treatment.

Abstract: Little is known about the outcomes of Philadelphia-negative myeloproliferative neoplasms (MPNs) in adolescents and young adults (AYA). We reviewed all patients with essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF) treated at our institution from 1988 to 2016 who were aged 16 to 39 years (AYA) and described their outcomes in comparison to older MPN population. Of 2206 patients, 185 (8.3%) were identified as AYA: 105 (57%) ET, 43 (23%) PV, and 37 (20%) MF. The median age was 33 years [range, 16–39], and median follow-up time 3 years [range, 0.04–25]. JAK2 allele burdens were significantly lower among AYA JAK2V617F-mutated patients in both PV (p = 0.001) and MF (p = 0.005). Seven percent of MPN AYA patients were diagnosed with a thrombotic event at, or prior to, diagnosis. Over the short median follow-up, 4 thrombotic (PV = 1, MF = 3) and 3 leukemia (ET = 2, MF = 1) events occurred. In multivariate analysis, AYA did not predict for thrombotic or transformational events across three cohorts. In the MF cohort, there was a reduced frequency of negative prognostic variables of anemia (p = 0.011) and leukocytosis (p = 0.048) in AYA when compared with non-AYA. Overall survival was significantly superior in the AYA cohorts in all three MPN groups, namely MF (p < 0.001), PV (p < 0.001), and ET (p = 0.002). Our findings suggest that MPN AYA patients exhibit an indolent clinical phenotype characterized by favorable survival outcomes.

Abstract: We retrospectively analyzed a large study to investigate the association of hepatitis B virus (HBV) with aggressive B cell non-Hodgkin's lymphoma (aggressive B-NHL) in China, where HBV is endemic. HBV was present in 39 aggressive B-NHL patients (10.46%), 13 indolent B-NHL patients (5.09%), 12 multiple myeloma (MM) patients (3.67%), and 5 solitary plasmacytoma (SP) patients (6.67%). HBV infection was significantly associated with increased risks for aggressive B-NHL (P < 0.01). HBV seems to have a very important role in the pathogenesis of aggressive B-NHL in China.

Abstract: The name of Pau Montesinos was inadvertently presented as Pau Montesinos Fernandez in the original article.The original version of this article was revised: The name of Pau Montesinos was inadvertently presented as Pau Montesinos Fernandez.

Abstract: Burkitt lymphoma is an aggressive B cell malignancy accounting for 1–2% of all adult lymphomas. Treatment with dose-intensive, multi-agent chemotherapy is effective but associated with considerable toxicity. In this observational study, we compared real-world efficacy, toxicity, and costs of four frequently employed treatment strategies for Burkitt lymphoma: the Lymphome Malins B (LMB), the Berlin-Frankfurt-Munster (BFM), the HOVON, and the CODOX-M/IVAC regimens. We collected data from 147 adult patients treated in eight referral centers. Following central pathology assessment, 105 of these cases were accepted as Burkitt lymphoma, resulting in the following treatment groups: LMB 36 patients, BFM 19 patients, HOVON 29 patients, and CODOX-M/IVAC 21 patients (median age 39 years, range 14–74; mean duration of follow-up 47 months). There was no significant difference between age, sex ratio, disease stage, or percentage HIV-positive patients between the treatment groups. Five-year progression-free survival (69%, p = 0.966) and 5-year overall survival (69%, p = 0.981) were comparable for all treatment groups. Treatment-related toxicity was also comparable with only hepatotoxicity seen more frequently in the CODOX/M-IVAC group (p = 0.004). Costs were determined by the number of rituximab gifts and the number of inpatients days. Overall, CODOX-M/IVAC had the most beneficial profile with regards to costs, treatment duration, and percentage of patients completing planned treatment. We conclude that the four treatment protocols for Burkitt lymphoma yield nearly identical results with regards to efficacy and safety but differ in treatment duration and costs. These differences may help guide future choice of treatment.