Current screening guidelines for malaria in new refugees include a combination of thick and thin film examination and immunochromatographic antigen test (ICT). However, as the prevalence of malaria ...in our population has decreased due to changing refugee demographics, we sought to determine if an ICT alone can reliably exclude malaria in our asymptomatic refugee population. A retrospective analysis was conducted of all investigations for malaria performed from 1 August 2011 to 31 July 2013, including thick and thin blood film examination, BinaxNOW ICT, and external morphological and polymerase chain reaction (PCR) validation where applicable. Malaria was diagnosed in 45 of 1248 (3.6%) patients investigated, all of whom were symptomatic and the majority (71.1%) returned travellers. All 599 asymptomatic refugees screened were negative. Overall, 42 of 45 malaria cases were detected by the ICT; sensitivity 93.3% (95% CI 80.7-98.3%) and negative predictive value (NPV) 99.8% (99.2-99.9%). All 21 cases of Plasmodium falciparum and 20 of 22 cases of Plasmodium vivax were detected, giving a sensitivity of 100% (80.8-100%) and 90.9% (69.4-98.4%) respectively. Too few cases of Plasmodium malariae and no cases of Plasmodium ovale or Plasmodium knowlesi were diagnosed for adequate assessment to be carried out. These data suggest that full malaria screening in all asymptomatic refugees with the combination of thick and thin blood films and rapid antigen test may not be warranted. Alternative screening approaches should be considered, including the use of ICT alone, or limiting screening of asymptomatic refugees to only those originating from countries with high incidence of malaria.
Background: Relapsed/refractory (R/R)acute leukemia withalterations in KMT2A (also called MLL1; 9-15% of adult AML, 10% of ALL) or NPM1 (30% of adult AML) are often associated with poor outcomes. ...Pre-clinical studies demonstrated the relevance of the menin-KMT2A protein-protein interaction in sustaining leukemic cells with KMT2A and NPM1 alterations (Kuhn 2016). JNJ-75276617 is a potent and selective inhibitor of the interaction between the scaffolding protein menin and the methyltransferase KMT2A with preclinical activity in KMT2A-rearranged or NPM1-mutated leukemic cell lines and primary leukemia patient samples in vitro and in vivo (Kwon 2022). We report initial data investigating JNJ-75276617 in adult participants (pts) with R/R acute leukemia harboring KMT2A alterations (rearrangements, amplifications, or partial tandem duplications) or NPM1 mutations. Methods: 75276617ALE1001 (NCT04811560) is an ongoing Phase 1, multicenter, open-label, dose-finding study. Pts in dose escalation receive JNJ-75276617 orally on a 28-day cycle. As of 8 April 2023, multiple dose levels ≥15 mg have been explored on either a daily or twice daily (BID) dosing schedule. AEs were graded by CTCAE v5.0. Responses were investigator-assessed per ELN2017. Preliminary safety, efficacy and PD data are reported herein, with a focused review of the efficacy in higher dose levels with ≥3 pts dosed. Results: Fifty-eight pts received JNJ-75276617. The median age was 63 (range: 19-83) years; 56 pts (97%) had R/R AML and 2 (3%) had R/R ALL. The median number of prior lines of treatment was 2 (range: 1-7), including 10 (17%) pts with a prior allogeneic stem cell transplant. A KMT2A or NPM1 alteration was present in 33 (57%) and 25 (43%) pts, respectively. Thirty (52%) pts experienced ≥1 treatment-related AE (TRAE); most commonly differentiation syndrome (DS) (8 14%). Grade ≥3 TRAEs were observed in 17 (29%) pts; those reported in ≥2 pts were neutropenia (6 10%), anemia and thrombocytopenia (4 7% each), DS (3 5%), and ALT and AST increase (2 3% each). Dose limiting toxicities (DLTs) were observed in 5 (9%) pts, with DS (2 3%) as the only DLT reported in ≥2 pts. In 26 (63%) of the 41 pts with disease evaluation data, there was a reduction in bone marrow (BM) disease burden ( Figure 1). Of these, a ≥50% decrease in BM blasts was observed in 16 (39%) pts. In the highest dose level with ≥3 pts (90 mg BID; n=8), the ORR (≥PR) was 50% (n=4), with all responders ongoing ( Figure 2). These responders (2 NPM1-, 2 KMT2A-altered) achieved CR (1 pt), CRh (1 pt), and CRi (2 pts). In a review of higher dose levels with ≥3 pts (≥45 mg BID; n=20), the ORR was 40% (n=8), with 7 responders ongoing ( Figure 2). These responders (5 NPM1-, 3 KMT2A-altered) achieved CR (3 pts), CRh (1 pt), CRi (3 pts), and PR (1 pt); median (range) time to first response (≥PR) 1.81 mos (1.0-3.3; n=8); time to CR, CRh, or CRi 1.77 mos (1.0-3.3; n=7); and time to CR 2.79 mos (1.8-2.9; n=3). Across all cohorts there were 12 responders, including 1 MRD negative CR. One responder discontinued treatment for allogeneic transplant; however, 8 responders continue on treatment, including 2 pts in cycle 9. Preliminary PD data from unfractionated BM and/or PBMCs in paired samples among responders (n=12) show biologic activity as indicated by reduction in expression (mean fold change from baseline calculated as on-tx-baseline/baseline range) of menin-KMT2A target genes ( MEIS1 -0.42 -1.0-9.0; HOXA9 -0.03 -1.0-21.7; FLT3 18.6 -1.0-425) and induction of genes associated with differentiation ( ITGAM 55.0 -0.93-1467; MNDA 5.9 -1.0-83.5). Compared to baseline, the percentage of KMT2A-altered cells or NPM1 variant allele frequency (VAF) was reduced in responders, with a decrease in KMT2A-altered cells by break-apart FISH probe from 59.2% at baseline to 8.1% post-treatment and in NPM1 VAF using a myeloid gene NGS panel from 13.1% at baseline to 2.8% post-treatment. Conclusions: Dose escalation in 75276617ALE1001 is ongoing with the RP2D(s) yet to be determined. Pts in dose expansion will receive JNJ-75276617 at the identified RP2D(s). Preliminary results of this FIH Phase 1 study demonstrate that JNJ-75276617 monotherapy has an acceptable safety profile, encouraging antileukemic activity, and emerging biologic activity consistent with the proposed mechanism of action in pts with R/R acute leukemia harboring KMT2A or NPM1 alterations.
The transcription factor IRF4 is essential for the survival of both normal plasma cells and the plasma cell malignancy multiple myeloma (MM). However the basis for this dependency remains uncertain, ...with the prevailing view that IRF4 loss in MM induces “death by a thousand cuts.”
Here we have explored the genetic basis for IRF4 addiction through CRISPR-Cas9 mediated deletion of IRF4 in three lenalidomide sensitive MM cells lines (MM1S, OPM2 and H929) and one resistant cell line (RPMI-8226). Loss of IRF4 resulted in marked loss of viability, irrespective of lenalidomide sensitivity, which was driven by two distinct mechanisms: 1) induction of apoptosis, which was rescued through prior deletion of apoptotic mediators BAX and BAK, and 2) proliferative arrest, which persisted despite rescue from apoptosis.
RNA-sequencing following IRF4 inactivation identified a core group of 86 genes whose dysregulation was shared across all 4 MM cell lines. We identified 31 common down-regulated genes (IRF4 activated), including several with previously described roles in survival (such as KLF2, TNFRSF17/BCMA and MYB). Furthermore, MYC, a previously identified target of IRF4 known to play an important role in MM pathogenesis and survival, was down-regulated in 3 of the 4 cell lines.
Most surprisingly, IRF4 inactivation resulted in 55 common up-regulated genes that included two BH3-only pro-apoptotic proteins, BMF and BCL2L11 (BIM). Up-regulation of BMF appeared more marked than BIM with an average fold change of 6.5x (range 2.7 - 10.3) vs 1.9x (range: 1.8 - 2.2) respectively. Remarkably, genetic ablation of BMF in the OPM2 cell line and BMF/BIM in the MM1S largely protected from the cell death observed following IRF4 inactivation, suggesting that IRF4 maintains MM survival through the transcriptional repression of BMF and BIM.
Our results confirm the vital role of IRF4 for MM proliferation and survival, and shed further light into its critical downstream transcriptional targets. Most interestingly, we have demonstrated that the ‘killer blow’ appears to be the concerted effect of the BH3-only pro-apoptotic proteins BMF and BIM.
Huang:Genentech: Patents & Royalties: DCSH is an employee of the Walter and Eliza Hall Institute which receives milestone and royalty payments related to venetoclax.
Introduction
Plasmablastic lymphoma (PBL) is a rare, aggressive large cell lymphoma, first described in 1997. PBL is strongly associated with immunodeficient states, such as HIV infection and solid ...organ transplantation, but up to one third of cases are reported to occur in immunocompetent patients. The pathogenesis of PBL is incompletely understood, though the oncogenic impact of EBV, in particular in the context of dysregulated immune surveillance, together with acquired abnormalities in the MYC pathway appear to play key roles in many cases. Plasma cell markers such as CD138 and CD38 are typically positive, as well as CD30 in a significant subset. Classical B cell markers such as CD20, CD19 and PAX5 are typically absent.
The literature on clinical outcomes in PBL is generally limited to small, single-centre case series. Reports describe an aggressive disease of poor prognosis, with median survival of 8 to 15 months, with one series reporting a longer median survival of 32 months.
Methods
We retrospectively identified patients diagnosed with PBL between 1999 and 2019 from 16 sites across Australia, the United Kingdom and Canada. Patients aged ≥18 years with confirmed tissue diagnosis of PBL at their local treating centre were included. Factors associated with overall survival (OS) were analysed using Cox regression, stratified by site to account for heterogeneity across sites. Risk time for mortality began on the date of diagnosis and ended on the date of death. Patients who were alive, lost to follow-up or transferred to another centre for care, were censored on the date of last follow-up. Risk factors analysed included age, year of diagnosis, HIV status, MYC rearrangement status, CD30 status, lactate dehydrogenase level, disease stage by Lugano consensus criteria, and bone marrow involvement.
Results
We identified 197 patients with PBL (Table 1). The median age at diagnosis was 55 years (range 18-95) and there was a male predominance (69%). 37% of patients were HIV positive, 56% were HIV negative and 7% were either not tested or had missing results. Other immunosuppressive risk factors included solid organ transplant, allogeneic stem cell transplant (SCT), and immunosuppressive medication. No immunodeficient state was detected in 44%. Fifty per cent of patients were stage IV at diagnosis. Fifty-four per cent were staged using PET/CT.
The median follow-up time from diagnosis was 1.36 years, with the longest follow up out to 18.4 years. There were 87 deaths (44%). For patients receiving first-line treatment with curative intent, the rate of complete remission was 57% (103 of 181 patients). Most patients (53%) received CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone)-based chemotherapy as first line, and 27% treatment of higher intensity than CHOP. Rituximab was administered to 20% and 10% were exposed to proteasome inhibitors as part of first line therapy. Five percent of patients underwent autologous SCT in first remission, and a further 5% after first relapse or later.
The median survival time was 4.8 years, with a 5-year OS of 49% and 10-year OS of 45% (figure 1). In multivariate analysis the only adverse factors associated with OS were bone marrow involvement and stage IV disease. Patients without bone marrow involvement at diagnosis had improved OS, compared to those who did (hazard ratio (HR) 0.36, 95%CI 0.18-0.72, p=0.004) (figure 2). There was an increasing trend for mortality with higher disease stages (p-trend=0.002). The median survival was 14.1 years for stage I, 10.7 years for stage II, 5.1 years for stage III and 1.2 years for stage IV. However, only stage IV disease was independently associated with inferior OS in multivariate analysis (HR 2.93, 95%CI 1.43-6.00, p=0.003) (figure 3). OS did not change depending upon year of diagnosis.
Conclusion
We report a multinational retrospective cohort of patients diagnosed with PBL and to our knowledge the largest single series of PBL to date. OS was longer than previously published data, particularly in patients with early-stage disease. However, patients with stage IV disease and baseline bone marrow involvement had inferior OS. HIV infection did not affect outcome. These findings suggest that baseline bone marrow biopsy and PET staging are useful prognostic tools. There is also an ongoing need for the evaluation of the predictive value of PET imaging and novel agents in PBL, especially in higher-risk disease.
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Di Ciaccio:Jansen: Honoraria, Other: travel and accomodation grant. Cwynarski:Takeda: Consultancy, Other: Conference/travel support; Roche: Consultancy, Other: Conference/travel support. Burton:Celgene: Honoraria; Leeds Teaching Hospitals NHS Trust: Current Employment; Takeda: Honoraria, Other: Travel Support; BMS: Honoraria; Roche: Honoraria, Other: Travel Support. Kuruvilla:Antengene: Honoraria; Janssen: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; AbbVie: Consultancy; AstraZeneca Pharmaceuticals LP: Honoraria, Research Funding; Merck: Consultancy, Honoraria; Celgene Corporation: Honoraria; Amgen: Honoraria; TG Therapeutics: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Bristol-Myers Squibb Company: Consultancy. McKay:Greater Glasgow and Clyde Health Board: Current Employment; Roche, Gilead, Takeda, Janssen: Other: For lectures etc; Roche: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees; Gilead: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; BeiGene: Membership on an entity’s Board of Directors or advisory committees; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; TAKEDA: Membership on an entity’s Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau. Linton:BeiGene: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Other: Conference/travel support; Roche: Consultancy, Speakers Bureau; Gilead: Membership on an entity’s Board of Directors or advisory committees; Karyopharm: Membership on an entity’s Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Patents & Royalties; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Hartley-Taylor: Honoraria; The Christie NHS Foundation Trust and The University of Manchester: Current Employment. Manos:Bristol-Myers Squibb: Other: Conference sponsorship. Hamad:Abbvie: Honoraria; Novartis: Honoraria.
The transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) have recently been found to be targeted for destruction by the immunomodulatory drugs (IMiDs). However, the role of Ikaros and Aiolos and ...why their loss leads to multiple myeloma (MM) cell death remains unclear. We have used CRISPR-Cas9 genome editing to delete IKZF1 and IKZF3 in human MM cell lines to gain further insight into their downstream gene regulatory networks.
Consistent with the action of the IMiDs, loss of either of these genes resulted in both a G1/S cell cycle arrest and induction of apoptosis. This was not dependent on the subsequent reduction of the IRF4-MYC “axis”, as neither IRF4 or MYC were consistently downregulated across all cell lines examined (despite cell death occurring) and overexpression of either factor failed to rescue for Ikaros loss. This led us to further investigate the transcriptional changes resulting from deletion of Ikaros, Aiolos or treatment with the IMiD lenalidomide using RNA-sequencing.
Supporting their central role in the action of the IMiDs, significant overlap was seen on loss of Ikaros, Aiolos, or lenalidomide treatment; with loss of Ikaros/Aiolos accounting for approximately 75% of differential gene expression following lenalidomide.
Importantly both Ikaros and Aiolos were found to repress the expression of interferon stimulated genes (ISGs) and their loss led to the activation of an interferon-like response, possibly contributing to cell death. In keeping with this, treatment with lenalidomide and low dose IFNb resulted in synergistic cell death. Furthermore, CD38 appeared to be both an ISG and repressed target of Ikaros/Aiolos through their interaction with the nucleosome remodelling and deacetylase complex, and its expression is increased at both mRNA and protein level on their loss. Given recent clinical studies have shown improved outcomes with combination treatment with lenalidomide and the anti-CD38 monoclonal antibody daratumumab, we wondered whether this represented a MM cell intrinsic mechanism explaining this synergy. Consistent with this hypothesis, loss of Ikaros, or treatment with lenalidomide or IFNb led to increased daratumumab induced NK cell mediated antibody-dependent cellular cytotoxicity.
These results give further insight into the mechanism of action of the IMiDs, and provide mechanistic rationale for combination with anti-CD38 monoclonal antibodies.
Fedele:Celgene: Other: Travel grant to attend ASH. Low:Merck: Honoraria.
Introduction
Current DLBCL prognostic scores are poor predictors of individual risk with 26% of “very good” and “good” risk patients having unfavourable outcomes. Hypercalcaemia has been associated ...with poor outcomes in several cancers including multiple myeloma, but is not included in current DLBCL prognostic scoring models.
Aim
To determine the prognostic significance of hypercalcaemia in newly diagnosed DLBCL and identify relationships between hypercalcaemia and other established prognostic variables including cell of origin, and the components of the revised international prognostic index (R-IPI including impaired performance status, older age, advanced stage, elevated lactate dehydrogenase, and extranodal involvement.
Methods
Retrospective cohort study at two academic healthcare networks in Melbourne, Australia. All patients with a newly diagnosed DLBCL by WHO 2008 criteria were eligible for inclusion.
Cases were identified from hospital lymphoma databases. Only cases with adequate clinical information including baseline characteristics, therapy received and outcomes were included. Cell of origin was determined by the modified Hans criteria. At Monash Health, patients were included from September 2002 until December 2015, and from Western Health, patients were included from January 2012 until December 2015. Hypercalcaemia was defined as a serum calcium >2.6mmol/L within 30 days prior to, or 15 days following the diagnosis of DLBCL. Serum calcium levels were corrected for hypoalbuminaemia if present. Immunohistochemical cell of origin was recorded using modified Hans criteria (Meyer et al. 2011). Survival correlates were estimated by Kaplan-Meier log rank method. Multivariable analysis was performed by Cox regression. Relationships between serum calcium and other covariates were examined by t test for continuous variables and χ2 for categorical variables.
This project was approved by the human research review boards at each institution.
Results
A total of 514 patients were identified as being eligible for inclusion, of which 41 (7.9%) were identified to have calcium >2.6mmol/L. No patients had an alternate endocrine cause of hypercalcaemia identified.
Patients with hypercalcaemia had higher median age (75.3 vs. 66.2 years, P <0.001), and higher proportion with poor R-IPI (80% vs. 46%, P <0.001), advanced stage (78.0% vs. 57.5%, P=0.010), elevated LDH (87.8% vs. 52.2%, P <0.001) and non-GCB cell of origin (53.3% vs. 36.6%, P=0.049).
Excluding patients treated with palliative intent, patients with hypercalcaemia had worse clinical outcomes with shorter median OS (3.3 vs. 8.8 years, P <0.001 HR 2.34, 95% CI 1.24 to 4.60, see figure 1) and median PFS (1.3yrs vs. 5.9 years, P <0.001, HR 2.25, 95%CI 1.27 to 4.00, see figure 2). The univariate adverse impact of hypercalcaemia on OS (HR 2.404, 95% CI: 1.519 to 3.803, P<0.001, see table 1) and PFS (HR 2.267, 95% CI: 1.504 to 3.419, P<0.001) remained independent of R-IPI on multivariate analysis (see table 2).
Conclusion
Hypercalcaemia is an independent adverse prognostic factor and should be considered for incorporation into future risk scores for DLBCL. The mechanisms of hypercalcaemia and its association with non-GCB type DLBCL warrants further investigation.
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Fedele:Celgene: Other: Travel grant to attend ASH. Low:Merck: Honoraria. Opat:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Research Funding; Mundipharma: Consultancy; Beigene: Research Funding.
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