Background Several small studies on patients with COVID-19 and haematological malignancies are available showing a high mortality in this population. The Italian Hematology Alliance on COVID-19 aimed to collect data from adult patients with haematological malignancies who required hospitalisation for COVID-19. Methods This multicentre, retrospective, cohort study included adult patients (aged ≥18 years) with diagnosis of a WHO-defined haematological malignancy admitted to 66 Italian hospitals between Feb 25 and May 18, 2020, with laboratory-confirmed and symptomatic COVID-19. Data cutoff for this analysis was June 22, 2020. The primary outcome was mortality and evaluation of potential predictive parameters of mortality. We calculated standardised mortality ratios between observed death in the study cohort and expected death by applying stratum-specific mortality rates of the Italian population with COVID-19 and an Italian cohort of 31 993 patients with haematological malignancies without COVID-19 (data up to March 1, 2019). Multivariable Cox proportional hazards model was used to identify factors associated with overall survival. This study is registered with ClinicalTrials.gov, NCT04352556, and the prospective part of the study is ongoing. Findings We enrolled 536 patients with a median follow-up of 20 days (IQR 10-34) at data cutoff, 85 (16%) of whom were managed as outpatients. 440 (98%) of 451 hospitalised patients completed their hospital course (were either discharged alive or died). 198 (37%) of 536 patients died. When compared with the general Italian population with COVID-19, the standardised mortality ratio was 2•04 (95% CI 1•77-2•34) in our whole study cohort and 3•72 (2•86-4•64) in individuals younger than 70 years. When compared with the non-COVID-19 cohort with haematological malignancies, the standardised mortality ratio was 41•3 (38•1-44•9). Older age (hazard ratio 1•03, 95% CI 1•01-1•05); progressive disease status (2•10, 1•41-3•12); diagnosis of acute myeloid leukaemia (3•49, 1•56-7•81), indolent non-Hodgin lymphoma (2•19, 1•07-4•48), aggressive non-Hodgkin lymphoma (2•56, 1•34-4•89), or plasma cell neoplasms (2•48, 1•31-4•69), and severe or critical COVID-19 (4•08, 2•73-6•09) were associated with worse overall survival. Interpretation This study adds to the evidence that patients with haematological malignancies have worse outcomes than both the general population with COVID-19 and patients with haematological malignancies without COVID-19. The high mortality among patients with haematological malignancies hospitalised with COVID-19 highlights the need for aggressive infection prevention strategies, at least until effective vaccination or treatment strategies are available. Funding Associazione italiana contro le leucemie, linfomi e mieloma-Varese Onlus.

Background Tocilizumab blocks pro-inflammatory activity of interleukin-6 (IL-6), involved in pathogenesis of pneumonia the most frequent cause of death in COVID-19 patients. Methods A multicenter, single-arm, hypothesis-driven trial was planned, according to a phase 2 design, to study the effect of tocilizumab on lethality rates at 14 and 30 days (co-primary endpoints, a priori expected rates being 20 and 35%, respectively). A further prospective cohort of patients, consecutively enrolled after the first cohort was accomplished, was used as a secondary validation dataset. The two cohorts were evaluated jointly in an exploratory multivariable logistic regression model to assess prognostic variables on survival. Results In the primary intention-to-treat (ITT) phase 2 population, 180/301 (59.8%) subjects received tocilizumab, and 67 deaths were observed overall. Lethality rates were equal to 18.4% (97.5% CI: 13.6–24.0, P = 0.52) and 22.4% (97.5% CI: 17.2–28.3, P < 0.001) at 14 and 30 days, respectively. Lethality rates were lower in the validation dataset, that included 920 patients. No signal of specific drug toxicity was reported. In the exploratory multivariable logistic regression analysis, older age and lower PaO2/FiO2 ratio negatively affected survival, while the concurrent use of steroids was associated with greater survival. A statistically significant interaction was found between tocilizumab and respiratory support, suggesting that tocilizumab might be more effective in patients not requiring mechanical respiratory support at baseline. Conclusions Tocilizumab reduced lethality rate at 30 days compared with null hypothesis, without significant toxicity. Possibly, this effect could be limited to patients not requiring mechanical respiratory support at baseline. Registration EudraCT (2020-001110-38); clinicaltrials.gov (NCT04317092).

SWA seems to provide accurate and reliable estimation of REE and useful information on TDEE also in cancer patients. Its use appears promising. Validation studies on larger samples and different cancer types should be considered.

COVID-19 is associated with high mortality in patients with haematological malignancies (HM) and rate of seroconversion is unknown. The ITA-HEMA-COV project (NCT04352556) investigated patterns of seroconversion for SARS-CoV-2 IgG in patients with HMs. A total of 237 patients, SARS-CoV-2 PCR-positive with at least one SARS-CoV-2 IgG test performed during their care, entered the analysis. Among these, 62 (26Á2%) had myeloid, 121 (51Á1%) lymphoid and 54 (22Á8%) plasma cell neoplasms. Overall, 69% of patients (164 of 237) had detectable IgG SARS-CoV-2 serum antibodies. Serologically negative patients (31%, 73 of 237) were evenly distributed across patients with myeloid, lymphoid and plasma cell neoplasms. In the multivariable logistic regression, chemoimmunotherapy [odds ratio (OR), 3Á42; 95% confidence interval (CI), 1Á04-11Á21; P = 0Á04] was associated with a lower rate of seroconversion. This effect did not decline after 180 days from treatment withdrawal (OR, 0Á35; 95% CI: 0Á11-1Á13; P = 0Á08). This study demonstrates a low rate of seroconversion in HM patients and indicates that treatment-mediated immune dysfunction is the main driver. As a consequence, we expect a low rate of seroconversion after vaccination and thus we suggest testing the efficacy of seroconversion in HM patients.

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Core-binding factor leukemia (CBFL) is a subgroup of acute myeloid leukemia (AML) characterized by genetic mutations involving the subunits of the core-binding factor (CBF). The leukemogenesis model for CBFL posits that one, or more, gene mutations inducing increased cell proliferation and/or inhibition of apoptosis cooperate with CBF mutations for leukemia development. One of the most common mutations associated with CBF mutations involves the KIT receptor. A high expression of KIT is a hallmark of a high proportion of CBFL. Previous studies indicate that microRNA (MIR) 222/221 targets the 3' untranslated region of the KIT messenger RNA and our observation that AML1 can bind the MIR-222/221 promoter, we hypothesized that MIR-222/221 represents the link between CBF and KIT. Here, we show that MIR-222/221 expression is upregulated after myeloid differentiation of normal bone marrow AC133(+) stem progenitor cells. CBFL blasts with either t(8;21) or inv(16) CBF rearrangements with high expression levels of KIT (CD117) display a significantly lower level of MIR-222/221 expression than non-CBFL blasts. Consistently, we found that the t(8;21) AML1-MTG8 fusion protein binds the MIR-222/221 promoter and induces transcriptional repression of a MIR-222/221-LUC reporter. Because of the highly conserved sequence homology, we demonstrated concomitant MIR-222/221 down-regulation and KIT up-regulation in the 32D/WT1 mouse cell model carrying the AML1-MTG16 fusion protein. This study provides the first hint that CBFL-associated fusion proteins may lead to up-regulation of the KIT receptor by down-regulating MIR-222/221, thus explaining the concomitant occurrence of CBF genetic rearrangements and overexpression of wild type or mutant KIT in AML.

Acute myeloid leukemia (AML) with deranged core‐binding factor beta (CBFβ) is usually associated with a favorable prognosis with 50–70% of patients cured using contemporary treatments. We analyzed the prognostic significance of clinical features on 58 patients with CBFβ‐AML aged ≤60 years. Increasing age was the only predictor for survival (P <0.001), with an optimal cut‐point at 43 years. White blood cells (WBCs) at diagnosis emerged as an independent risk factor for relapse incidence (P = 0.017), with 1.1% increase of hazard for each 1.0 × 109/L WBC increment. KIT mutations lacked prognostic value for survival and showed only a trend for relapse incidence (P = 0.069). Am. J. Hematol. 88:594–600, 2013. © 2013 Wiley Periodicals, Inc.

Acute myeloid leukemia (AML) is a genetically heterogeneous clonal disorder characterized by two molecularly distinct self-renewing leukemic stem cell (LSC) populations most closely related to normal progenitors and organized as a hierarchy. A requirement for WNT/β-catenin signaling in the pathogenesis of AML has recently been suggested by a mouse model. However, its relationship to a specific molecular function promoting retention of self-renewing leukemia-initiating cells (LICs) in human remains elusive. To identify transcriptional programs involved in the maintenance of a self-renewing state in LICs, we performed the expression profiling in normal (n = 10) and leukemic (n = 33) human long-term reconstituting AC133(+) cells, which represent an expanded cell population in most AML patients. This study reveals the ligand-dependent WNT pathway activation in AC133(bright) AML cells and shows a diffuse expression and release of WNT10B, a hematopoietic stem cell regenerative-associated molecule. The establishment of a primary AC133(+) AML cell culture (A46) demonstrated that leukemia cells synthesize and secrete WNT ligands, increasing the levels of dephosphorylated β-catenin in vivo. We tested the LSC functional activity in AC133(+) cells and found significant levels of engraftment upon transplantation of A46 cells into irradiated Rag2(-/-)γc(-/-) mice. Owing to the link between hematopoietic regeneration and developmental signaling, we transplanted A46 cells into developing zebrafish. This system revealed the formation of ectopic structures by activating dorsal organizer markers that act downstream of the WNT pathway. In conclusion, our findings suggest that AC133(bright) LSCs are promoted by misappropriating homeostatic WNT programs that control hematopoietic regeneration.