For decades, intensive chemotherapy (IC) has been considered the best therapeutic option for treating acute myeloid leukemia (AML), with no curative option available for patients who are not eligible ...for IC or who have had failed IC. Over the last few years, several new drugs have enriched the therapeutic arsenal of AML treatment for both fit and unfit patients, raising new opportunities but also new challenges. These include the already approved venetoclax, the IDH1/2 inhibitors enasidenib and ivosidenib, gemtuzumab ozogamicin, the liposomal daunorubicin/cytarabine formulation CPX-351, and oral azacitidine. Venetoclax, an anti BCL2-inhibitor, in combination with hypomethylating agents (HMAs), has markedly improved the management of unfit and elderly patients from the perspective of improved quality of life and better survival. Venetoclax is currently under investigation in combination with other old and new drugs in early phase trials. Recently developed drugs with different mechanisms of action and new technologies that have already been investigated in other settings (BiTE and CAR-T cells) are currently being explored in AML, and ongoing trials should determine promising agents, more synergic combinations, and better treatment strategies. Access to new drugs and inclusion in clinical trials should be strongly encouraged to provide scientific evidence and to define the future standard of treatment in AML.
To respond to the legitimate questions raised by the application of invasive methods of monitoring and life-support techniques in cancer patients admitted in the ICU, the European Lung Cancer Working ...Party and the Groupe de Recherche Respiratoire en Réanimation Onco-Hématologique, set up a consensus conference. The methodology involved a systematic literature review, experts’ opinion and a final consensus conference about nine predefined questions
1. Which triage criteria, in terms of complications and considering the underlying neoplastic disease and possible therapeutic limitations, should be used to guide admission of cancer patient to intensive care units?
2. Which ventilatory support High Flow Oxygenation, Non-invasive Ventilation (NIV), Invasive Mechanical Ventilation (IMV), Extra-Corporeal Membrane Oxygenation (ECMO) should be used, for which complications and in which environment?
3. Which support should be used for extra-renal purification, in which conditions and environment?
4. Which haemodynamic support should be used, for which complications, and in which environment?
5. Which benefit of cardiopulmonary resuscitation in cancer patients and for which complications?
6. Which intensive monitoring in the context of oncologic treatment (surgery, anti-cancer treatment …)?
7. What specific considerations should be taken into account in the intensive care unit?
8. Based on which criteria, in terms of benefit and complications and taking into account the neoplastic disease, patients hospitalized in an intensive care unit (or equivalent) should receive cellular elements derived from the blood (red blood cells, white blood cells and platelets)?
9. Which training is required for critical care doctors in charge of cancer patients?
Despite severe immunosuppression due to conditioning chemotherapy for acute myeloid leukemia, COVID‐19 did not lead to clinical deterioration or death, thus raising the question of the impact of ...immunosuppressive treatment on clinical course evolution.
Leucocyte kinetics and PCR results in our patients during hospitalization for conditioning chemotherapy for allogeneic hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia (AML).
The treatment of high-risk classic Hodgkin lymphoma (cHL) patients remains challenging, especially after autologous stem cell transplant (ASCT) failure. Moreover, the outcome of chemorefractory ...patients is still poor.
The development of novel targeted therapies has changed the therapeutic options for high-risk patients. To improve outcome, treatment algorithms should integrate up-front, newly established prognostic markers. Tandem ASCT instead of single ASCT has been proposed as an option to improve outcome for high-risk patients. Availability of less toxic reduced intensity conditioning regimens and recent development in haploidentical transplantation have widened applicability and improved outcomes of allo-hematopoietic cell transplantation. Their exact role in cHL is still controversial and there is no consensus on the optimal transplantation strategy. In this context, results of tandem ASCT should also be compared with those of the autologous/reduced intensity conditioning-allo tandem approach. In this review, we discuss how transplantation strategies (auto and allo) can fit into the salvage treatment plan for patients with relapsed/refractory cHL, taking into account the new drugs available and integrating modern risk assessment.
We speculated that improvements could be achieved by transplanting patients in earlier phases of their disease, if necessary after 'bridging' using the new drugs, and we propose an algorithm integrating the different treatment options.
Chronic myeloid leukemia is a clonal multilineage myeloproliferative disease of stem cell origin characterized by the presence of the Bcr/Abl oncoprotein, a constitutively active tyrosine kinase. In ...previous studies, we have provided evidence that Bcr/Abl overexpression in leukemic cells increased their susceptibility to NK-mediated lysis by different mechanisms. In the present study, using UT-7/9 cells, a high level Bcr/Abl transfectant of UT-7 cells, we show that the treatment of Bcr/Abl target by imatinib mesylate (IM), a specific Abl tyrosine kinase inhibitor, hampers the formation of the NK/target immunological synapse. The main effect of IM involves an induction of surface GM1 ganglioside on Bcr/Abl transfectants that prevents the redistribution of MHC-related Ag molecules in lipid rafts upon interaction with NK cells. IM also affects cell surface glycosylation of targets, as assessed by binding of specific lectins resulting in the subsequent modulation of their binding to lectin type NK receptor, particularly NKG2D. In addition, we demonstrate that the tyrosine kinase activity repression results in a decrease of MHC-related Ags-A/B and UL-16-binding protein expression on Bcr/Abl transfectants UT-7/9. We show that NKG2D controls the NK-mediated lysis of UT-7/9 cells, and IM treatment inhibits this activating pathway. Taken together, our results show that the high expression of Bcr/Abl in leukemic cells controls the expression of NKG2D receptor ligands and membrane GM1 via a tyrosine kinase-dependent mechanism and that the modulation of these molecules by IM interferes with NK cell recognition and cytolysis of the transfectants.
Hepatosplenic lymphoma (HSTCL) is a rare T-cell malignancy occurring in young males, associated with immune deficiency in 20% of the cases which, despite aggressive treatments, has a poor survival. ...Specific recommendations for first-line treatment remain debatable.
Published data covering case reports or series of HSTCL concur that allogeneic stem cell transplant should be proposed as a consolidation after response to chemotherapy in all patients eligible for transplant. In the light of two recent clinical examples, we also confirm that specific chemotherapy and a first-line consolidation with allogeneic transplantation when a donor is available to represent a treatment of choice these rare and distinctive lymphomas. Recent molecular studies are summarized in this review and suggest potential targets for new therapeutic strategies.
Major progresses have been achieved in improving the outcome of HSTCL l patients using intensive chemotherapy and allogeneic transplantation.
Abstract
Background
Herpes simplex virus 1 can cause severe infections in individuals who are immunocompromised. In these patients, emergence of drug resistance mutations causes difficulties in ...infection management.
Methods
Seventeen herpes simplex virus 1 isolates were obtained from orofacial/anogenital lesions in a patient with leaky severe combined immunodeficiency over 7 years, before and after stem cell transplantation. Spatial/temporal evolution of drug resistance was characterized genotypically—with Sanger and next-generation sequencing of viral thymidine kinase (TK) and DNA polymerase (DP)—and phenotypically. CRISPR/Cas9 was used to introduce the novel DP Q727R mutation, and dual infection-competition assays were performed to assess viral fitness.
Results
Isolates had identical genetic backgrounds, suggesting that orofacial/anogenital infections derived from the same virus lineage. Eleven isolates proved heterogeneous TK virus populations by next-generation sequencing, undetectable by Sanger sequencing. Thirteen isolates were acyclovir resistant due to TK mutations, and the Q727R isolate additionally exhibited foscarnet/adefovir resistance. Recombinant Q727R mutant virus showed multidrug resistance and increased fitness under antiviral pressure.
Conclusions
Long-term follow-up of a patient with severe combined immunodeficiency revealed virus evolution and frequent reactivation of wild-type and TK mutant strains, mostly as heterogeneous populations. The DP Q727R resistance phenotype was confirmed with CRISPR/Cas9, a useful tool to validate novel drug resistance mutations.
Long-term follow-up of a patient with immunodeficiency was conducted before and after stem cell transplantation, and it revealed herpes simplex virus 1 evolution and frequent reactivation of wild-type and mutant virus strains. The multidrug resistance phenotype of the novel Q727R DNA polymerase mutation was confirmed by gene editing.
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