Tandem versus single haematopoietic stem cell transplant and BV maintenance in relapsed/refractory Hodgkin lymphoma: A matched cohort analysis from the LYSA.

Autologous hematopoietic stem cell transplant (ASCT) is the standard curative treatment for patients with high-risk relapsed/refractory Hodgkin lymphoma (R/R HL). The AETHERA study showed survival gain with Brentuximab Vedotin (BV) maintenance after ASCT in BV-naive patients, which was recently confirmed in the retrospective AMAHRELIS cohort, including a majority of BV-exposed patients. However, this approach has not been compared to intensive tandem auto/auto or auto/allo transplant strategies, which were used before BV approval. Here, we matched BV maintenance (AMAHRELIS) and tandem SCT (HR2009) cohorts, and observed that BV maintenance was associated with better survival outcome in patients with HR R/R HL.

Dihydroartemisinin-induced ferroptosis in acute myeloid leukemia: links to iron metabolism and metallothionein.

Artemisinin is an anti-malarial drug that has shown anticancer properties. Recently, ferroptosis was reported to be induced by dihydroartemisinin (DHA) and linked to iron increase. In the current study, we determined the effect of DHA in leukemic cell lines on ferroptosis induction and iron metabolism and the cytoprotective effect triggered in leukemic cells. We found that treatment of DHA induces early ferroptosis by promoting ferritinophagy and subsequent iron increase. Furthermore, our study demonstrated that DHA activated zinc metabolism signaling, especially the upregulation of metallothionein (MT). Supportingly, we showed that inhibition MT2A and MT1M isoforms enhanced DHA-induced ferroptosis. Finally, we demonstrated that DHA-induced ferroptosis alters glutathione pool, which is highly dependent on MTs-driven antioxidant response. Taken together, our study indicated that DHA activates ferritinophagy and subsequent ferroptosis in AML and that MTs are involved in glutathione regenerating and antioxidant response.

A meropenem pharmacokinetics model in patients with haematological malignancies.

BACKGROUND: Optimal dosing of antibiotics is critical in immunocompromised patients suspected to have an infection. Data on pharmacokinetics (PK) of meropenem in patients with haematological malignancies are scarce. OBJECTIVES: To optimize dosing regimens, we aimed to develop a PK population model for meropenem in this population. METHODS: Patients aged ≥18 years, hospitalized in the haematology department of our 1500 bed university hospital for a malignant haematological disease and who had received at least one dose of meropenem were eligible. Meropenem was quantified by HPLC. PK were described using a non-linear mixed-effect model and external validation performed on a distinct database. Monte Carlo simulations estimated the PTA, depending on renal function, duration of infusion and MIC. Target for free trough concentration was set at >4× MIC. RESULTS: Overall, 88 patients (181 samples) were included, 66 patients (75%) were in aplasia and median Modification of Diet in Renal Disease (MDRD) CLCR was 117 mL/min/1.73 m2 (range: 35-359). Initial meropenem dosing regimen ranged from 1 g q8h to 2 g q8h over 30 to 60 min. A one-compartment model with first-order elimination adequately described the data. Only MDRD CLCR was found to be significantly associated with CL. Only continuous infusion achieved a PTA of 100% whatever the MIC and MDRD CLCR. Short duration of infusion (<60 min) failed to reach an acceptable PTA, except for bacteria with MIC < 0.25 mg/L in patients with MDRD CLCR below 90 mL/min/1.73 m2. CONCLUSIONS: In patients with malignant haematological diseases, meropenem should be administered at high dose (6 g/day) and on continuous infusion to reach acceptable trough concentrations.

Radiotherapy in combination with nivolumab for relapsed/refractory classical Hodgkin lymphoma: About two cases.

Hodgkin lymphoma is a highly curable malignancy involving lymph nodes and the lymphatic system. Even at late stage disease, about 70% of patients will be cured with standard first line therapy. For patients who experience relapse or refractory classical Hodgkin lymphoma, the standard treatment option is high-dose chemotherapy followed by autologous stem cell rescue or transplant. However about 50% of patients will have recurrence after high-dose chemotherapy followed by autologous stem cell rescue or transplantation and have worse prognosis with median overall survival of 32% at 5 years. The anti-PD1 checkpoints inhibitors pembrolizumab and nivolumab have remarkably improved outcomes of patients with relapse of refractory classical Hodgkin lymphoma after high-dose chemotherapy followed by autologous stem cell rescue or transplantation. On the other hand, radiotherapy is an entire component of salvage therapy and its efficacy is now well established in term of local disease control in sites of relapsed or refractory Hodkin lymphoma. Defining the optimal modality and timing of radiotherapy as these new agents arrive is a challenge. An interesting approach is the combination of radiotherapy with checkpoint inhibitor and the possibility of stopping the treatment when complete response is achieved. We add to the literature two new cases of combination of radiotherapy with immunotherapy in patients who relapsed after high-dose chemotherapy followed by autologous stem cell rescue or transplantation and consolidation with brentuximab vedotin, resulting in excellent outcomes.

Radiotherapy of relapse-refractory follicular lymphoma.

PURPOSE: To assess the efficacy of treatment and outcomes of patients with relapsed or refractory follicular lymphoma treated with external beam irradiation. PATIENTS AND METHODS: Fifteen patients who received external beam radiotherapy for relapsed or refractory follicular lymphoma were studied. The median age was 68.3 years (range: 37.9-87.08 years) with four men and 11 women. Seven patients had early stage (I or II); eight advanced stage (III or IV). Median FLIPI score was 2. Two patients had high tumour bulk disease. Six patients had extranodal invasion, with five patients having bone marrow invasion. RESULTS: The median time of follow-up after relapse or first-line treatment in case of refractory disease was 61.9 months (range: 9.1-119.7 months). Complete response after external beam radiotherapy was seen in 11 cases (73%) and partial response in two (13%), with a median dose of 30Gy (range: 2-40Gy) and median number of fractions of 15 (range: 2-20). Eight patients (53%) relapsed after external beam radiation therapy in a median of 20.2 months, mostly out of irradiated volumes. Most patients (66%) had a disease control after one or two courses of external beam radiation therapy. At last follow-up, 86% of patients were in remission including those with salvage chemotherapy. The toxicity profile was favourable with toxicity higher than grade 1. In univariate analysis, a Follicular Lymphoma International Prognostic Index (FLIPI) score above 2 was the only predicting factor for non-control disease. CONCLUSION: For relapsed and refractory follicular lymphoma, external beam radiotherapy should be considered as an effective modality when integrated in a multimodality approach. Randomised studies are warranted to validate this strategy.

RSK2 is a new Pim2 target with pro-survival functions in FLT3-ITD-positive acute myeloid leukemia.

Acute myeloid leukemia (AML) with the FLT3 internal tandem duplication (FLT3-ITD AML) accounts for 20-30% of AML cases. This subtype usually responds poorly to conventional therapies, and might become resistant to FLT3 tyrosine kinase inhibitors (TKIs) due to molecular bypass mechanisms. New therapeutic strategies focusing on resistance mechanisms are therefore urgently needed. Pim kinases are FLT3-ITD oncogenic targets that have been implicated in FLT3 TKI resistance. However, their precise biological function downstream of FLT3-ITD requires further investigation. We performed high-throughput transcriptomic and proteomic analyses in Pim2-depleted FLT3-ITD AML cells and found that Pim2 predominantly controlled apoptosis through Bax expression and mitochondria disruption. We identified ribosomal protein S6 kinase A3 (RSK2), a 90 kDa serine/threonine kinase involved in the mitogen-activated protein kinase cascade encoded by the RPS6KA3 gene, as a novel Pim2 target. Ectopic expression of an RPS6KA3 allele rescued the viability of Pim2-depleted cells, supporting the involvement of RSK2 in AML cell survival downstream of Pim2. Finally, we showed that RPS6KA3 knockdown reduced the propagation of human AML cells in vivo in mice. Our results point to RSK2 as a novel Pim2 target with translational therapeutic potential in FLT3-ITD AML.

High mTORC1 activity drives glycolysis addiction and sensitivity to G6PD inhibition in acute myeloid leukemia cells.

Alterations in metabolic activities are cancer hallmarks that offer a wide range of new therapeutic opportunities. Here we decipher the interplay between mTORC1 activity and glucose metabolism in acute myeloid leukemia (AML). We show that mTORC1 signaling that is constantly overactivated in AML cells promotes glycolysis and leads to glucose addiction. The level of mTORC1 activity determines the sensitivity of AML cells to glycolysis inhibition as switch-off mTORC1 activity leads to glucose-independent cell survival that is sustained by an increase in mitochondrial oxidative phosphorylation. Metabolic analysis identified the pentose phosphate pathway (PPP) as an important pro-survival pathway for glucose metabolism in AML cells with high mTORC1 activity and provided a clear rational for targeting glucose-6-phosphate dehydrogenase (G6PD) in AML. Indeed, our analysis of the cancer genome atlas AML database pinpointed G6PD as a new biomarker in AML, as its overexpression correlated with an adverse prognosis in this cohort. Targeting the PPP using the G6PD inhibitor 6-aminonicotinamide induces in vitro and in vivo cytotoxicity against AML cells and synergistically sensitizes leukemic cells to chemotherapy. Our results demonstrate that high mTORC1 activity creates a specific vulnerability to G6PD inhibition that may work as a new AML therapy.

A phase Ib GOELAMS study of the mTOR inhibitor RAD001 in association with chemotherapy for AML patients in first relapse.

The mTORC1 signaling pathway is constitutively activated in almost all acute myelogenous leukemia (AML) patients. We conducted a phase Ib trial combining RAD001 (everolimus), an allosteric inhibitor of mTORC1, and conventional chemotherapy, in AML patients under 65 years of age at first relapse (clinical trial NCT 01074086). Increasing doses of RAD001 from 10-70 mg were administrated orally on days 1 and 7 (d1 and d7) of a 3+7 daunorubicin+cytarabine conventional induction chemotherapy regimen. Twenty-eight patients were enrolled in this trial. The treatment was well tolerated with <10% toxicity, mainly involving the gastrointestinal tract and lungs. In this phase Ib trial, the RAD001 maximum tolerated dose was not reached at 70 mg. Sixty-eight percent of patients achieved CR, of which 14 received a double induction. Eight subsequently were intensified with allogeneic-stem cell transplant. Strong plasma inhibition of P-p70S6K was observed after RAD001 administration, still detectable at d7 (d7)at the 70 mg dosage. CR rates in patients with RAD001 areas under or above the curve median were 53% versus 85%. A 70 mg dose of RAD001 at d1 and d7 of an induction chemotherapy regimen for AML has acceptable toxicity and may improve treatment.

The cap-translation inhibitor 4EGI-1 induces apoptosis in multiple myeloma through Noxa induction.

BACKGROUND: Cancer cells are frequently addicted to deregulated oncogenic protein translation. The small molecule 4EG-I selectively inhibits the cap-dependent translation of mRNAs. As multiple myeloma is an incurable disease that requires new therapeutic approaches, we investigated whether targeting the translation initiation pathway could be a target for myeloma therapy. METHODS: Six myeloma cell lines and primary samples were included in this study. The 4EGI-1 effect was determined by AnnexinV staining and caspase activation. Modification of Bcl-2 protein expression was analysed, and the significance of modified proteins was analysed by knock-down experiments. RESULTS: We demonstrated that 4EGI-1 impaired the assembly of the eIF4F complex and decreased the expression of the eIF4E-regulated proteins in myeloma cells. Furthermore, we showed that 4EGI-1 induced strong apoptosis in five out of six myeloma cell lines. Apoptosis is associated with the activation of the intrinsic mitochondrial pathway. The 4EGI-1 triggered Noxa induction only in cells undergoing apoptosis through endoplasmic reticulum (ER) stress. Furthermore, Noxa silencing prevented myeloma cells from 4EGI-1-induced apoptosis. Finally, Noxa induction led to a disruption of Mcl-1/Bim complexes in parallel to the generation of 'Mcl-1-free Noxa'. CONCLUSION: Our results suggested that the use of inhibitors that directly target the translation initiation complex eIF4F could represent a potential novel approach for multiple myeloma therapy.

The dual mTORC1 and mTORC2 inhibitor AZD8055 has anti-tumor activity in acute myeloid leukemia.

The serine/threonine kinase mammalian target of rapamycin (mTOR) is crucial for cell growth and proliferation, and is constitutively activated in primary acute myeloid leukemia (AML) cells, therefore representing a major target for drug development in this disease. We show here that the specific mTOR kinase inhibitor AZD8055 blocked mTORC1 and mTORC2 signaling in AML. Particularly, AZD8055 fully inhibited multisite eIF4E-binding protein 1 phosphorylation, subsequently blocking protein translation, which was in contrast to the effects of rapamycin. In addition, the mTORC1-dependent PI3K/Akt feedback activation was fully abrogated in AZD8055-treated AML cells. Significantly, AZD8055 decreased AML blast cell proliferation and cell cycle progression, reduced the clonogenic growth of leukemic progenitors and induced caspase-dependent apoptosis in leukemic cells but not in normal immature CD34+ cells. Interestingly, AZD8055 strongly induced autophagy, which may be either protective or cell death inducing, depending on concentration. Finally, AZD8055 markedly increased the survival of AML transplanted mice through a significant reduction of tumor growth, without apparent toxicity. Our current results strongly suggest that AZD8055 should be tested in AML patients in clinical trials.

Perspectives on inhibiting mTOR as a future treatment strategy for hematological malignancies.

Mammalian target of rapamycin (mTOR) is a protein kinase implicated in the regulation of various cellular processes, including those required for tumor development, such as the initiation of mRNA translation, cell-cycle progression and cellular proliferation. In a wide range of hematological malignancies, the mTORC1 signaling pathway has been found to be deregulated and has been designed as a major target for tumor therapy. Given that pre-clinical studies have clearly established the therapeutic value of mTORC1 inhibition, numerous clinical trials of rapamycin and its derivates (rapalogs) are ongoing for treatment of these diseases. At this time, although disease stabilization and tumor regression have been observed, objective responses in some tumor types have been modest. Nevertheless, some of the mechanisms underlying cancer-cell resistance to rapamycin have now been described, thereby leading to the development of new strategy to efficiently target mTOR signaling in these diseases. In this review, we discuss the rationale for using mTOR inhibitors as novel therapies for a variety of hematological, malignancies with a focus on promising new perspectives for these approaches.

PI-103, a dual inhibitor of Class IA phosphatidylinositide 3-kinase and mTOR, has antileukemic activity in AML.

The phosphatidylinositol 3-kinase (PI3K)/Akt and mammalian target of rapamycin complex 1 (mTORC1) signaling pathways are frequently activated in acute myelogenous leukemia (AML). mTORC1 inhibition with RAD001 induces PI3K/Akt activation and both pathways are activated independently, providing a rationale for dual inhibition of both pathways. PI-103 is a new potent PI3K/Akt and mTOR inhibitor. In human leukemic cell lines and in primary blast cells from AML patients, PI-103 inhibited constitutive and growth factor-induced PI3K/Akt and mTORC1 activation. PI-103 was essentially cytostatic for cell lines and induced cell cycle arrest in the G1 phase. In blast cells, PI-103 inhibited leukemic proliferation, the clonogenicity of leukemic progenitors and induced mitochondrial apoptosis, especially in the compartment containing leukemic stem cells. In contrast, apoptosis was not induced with RAD001 and IC87114 association, which specifically inhibits mTORC1 and p110delta activity, respectively. PI-103 had additive proapoptotic effects with etoposide in blast cells and in immature leukemic cells. Interestingly, PI-103 did not induce apoptosis in normal CD34(+) cells and had moderate effects on their clonogenic and proliferative properties. Here, we demonstrate that multitargeted therapy against PI3K/Akt and mTOR with PI-103 may be of therapeutic value in AML.