Myelodysplastic syndromes are clonal disorders with morphological dysplasia, a variable degree of cytopenia and a risk of transformation to acute myeloid leukemia. Prognosis is very variable and is ...defined by blast count, cytopenia, cytogenetics and more recently by somatic mutations, with IPSS or revised IPSS score being the most widely used to assess disease risk. HSCT remains the only curative treatment to date, with high-risk patients obtaining the biggest benefit. However, NRM should be carefully assessed before indicating the transplant in this usually old population, where organ toxicity and comorbid conditions are to be considered. Multi-domain assessment tools, such as CGA (comprehensive geriatric assessment) and EBMT score, are useful in this context and might guide physician decisions regarding the transplant. Indeed, with the development of reduced intensity conditioning regimens, the number of patient candidates for an HSCT has increased. Regarding pre-transplant treatment, patients with a blast excess > 10% might be treated with HMAs or chemotherapy, although there are no randomized trials confirming the benefit of this approach, even when achieving a complete response. Concerning donor choice, matched sibling donors continue to be the first option, although matched unrelated donors, and more recently haploidentical donors, have proven to be valid options and should be offered in the absence of a related donor. Relapse remains the main cause of transplantation failure. MRD assessment and pre-emptive or prophylactic use of HMA or other targeted inhibitors with or without DLI are accepted strategies to reduce relapse risk, but the prognosis in this context remains dismal, and is the subject for several ongoing clinical protocols.
Artificial intelligence (AI) can unveil novel personalized treatments based on drug screening and whole-exome sequencing experiments (WES). However, the concept of “black box” in AI limits the ...potential of this approach to be translated into the clinical practice. In contrast, explainable AI (XAI) focuses on making AI results understandable to humans. Here, we present a novel XAI method -called multi-dimensional module optimization (MOM)- that associates drug screening with genetic events, while guaranteeing that predictions are interpretable and robust. We applied MOM to an acute myeloid leukemia (AML) cohort of 319
ex-vivo
tumor samples with 122 screened drugs and WES. MOM returned a therapeutic strategy based on the
FLT3
,
CBFβ-MYH11
, and
NRAS
status, which predicted AML patient response to Quizartinib, Trametinib, Selumetinib, and Crizotinib. We successfully validated the results in three different large-scale screening experiments. We believe that XAI will help healthcare providers and drug regulators better understand AI medical decisions.
Acute myeloid leukemia is a heterogeneous disease defined by a large spectrum of genetic aberrations that are potential therapeutic targets. New targeted therapies have changed the landscape for a ...disease with poor outcomes. They are more effective than standard chemotherapy with a good safety profile. For “fit patients” in first-line, the combination of gemtuzumab ozogamicin or midostaurin with intensive chemotherapy or Vyxeos is now considered the “standard of care” for selected patients. On the other hand, for “unfit patients”, azacitidine-venetoclax has been consolidated as a frontline treatment, while other combinations with magrolimab or ivosidenib are in development. Nevertheless, global survival results, especially in relapsed or refractory patients, remain unfavorable. New immunotherapies or targeted therapies, such as Menin inhibitors or sabatolimab, represent an opportunity in this situation. Future directions will probably come from combinations of different targeted therapies (“triplets”) and maintenance strategies guided by measurable residual disease.
Despite the potential of CAR-T therapies for hematological malignancies, their efficacy in patients with relapse and refractory Acute Myeloid Leukemia has been limited. The aim of our study has been ...to develop and manufacture a CAR-T cell product that addresses some of the current limitations. We initially compared the phenotype of T cells from AML patients and healthy young and elderly controls. This analysis showed that T cells from AML patients displayed a predominantly effector phenotype, with increased expression of activation (CD69 and HLA-DR) and exhaustion markers (PD1 and LAG3), in contrast to the enriched memory phenotype observed in healthy donors. This differentiated and more exhausted phenotype was also observed, and corroborated by transcriptomic analyses, in CAR-T cells from AML patients engineered with an optimized CAR construct targeting CD33, resulting in a decreased
in vivo
antitumoral efficacy evaluated in xenograft AML models. To overcome some of these limitations we have combined CRISPR-based genome editing technologies with virus-free gene-transfer strategies using
Sleeping Beauty
transposons, to generate CAR-T cells depleted of HLA-I and TCR complexes (HLA-I
KO
/TCR
KO
CAR-T cells) for allogeneic approaches. Our optimized protocol allows one-step generation of edited CAR-T cells that show a similar phenotypic profile to non-edited CAR-T cells, with equivalent
in vitro
and
in vivo
antitumoral efficacy. Moreover, genomic analysis of edited CAR-T cells revealed a safe integration profile of the vector, with no preferences for specific genomic regions, with highly specific editing of the HLA-I and TCR, without significant off-target sites. Finally, the production of edited CAR-T cells at a larger scale allowed the generation and selection of enough HLA-I
KO
/TCR
KO
CAR-T cells that would be compatible with clinical applications. In summary, our results demonstrate that CAR-T cells from AML patients, although functional, present phenotypic and functional features that could compromise their antitumoral efficacy, compared to CAR-T cells from healthy donors. The combination of CRISPR technologies with transposon-based delivery strategies allows the generation of HLA-I
KO
/TCR
KO
CAR-T cells, compatible with allogeneic approaches, that would represent a promising option for AML treatment.
Acute myeloid leukemia (AML) in the elderly remains a clinical challenge, with a five-year overall survival rate below 10%. The current ELN 2017 genetic risk classification considers cytogenetic and ...mutational characteristics to stratify fit AML patients into different prognostic groups. However, this classification is not validated for elderly patients treated with a non-intensive approach, and its performance may be suboptimal in this context. Indeed, the transcriptomic landscape of AML in the elderly has been less explored and it might help stratify this group of patients. In the current study, we analyzed the transcriptome of 224 AML patients > 65 years-old at diagnosis treated in the Spanish PETHEMA-FLUGAZA clinical trial in order to identify new prognostic biomarkers in this population. We identified a specific transcriptomic signature for high-risk patients with mutated
or complex karyotype, revealing that low expression of
gene with high expression of
gene identifies a subset of high-risk AML patients surviving more than 12 months. This result was further validated in the BEAT AML cohort. This unique signature highlights the potential of transcriptomics to identify prognostic biomarkers in in elderly AML.
Background. To study the feasibility of a response-guided therapy for chronic hepatitis C virus (HCV) infection in patients coinfected with human immunodeficiency virus (HIV) in a tertiary care ...hospital. Methods. Treatment duration was individualized on the basis of week 4 and week 12 virologic response. Sixty patients were enrolled and received pegylated interferon alfa-2b (1.5 μg/kg per week) plus weight-based ribavirin (800–1400 mg/day). Patients who achieved a rapid virologic response, defined as viral load <50 IU/mL at treatment week 4, completed 24 weeks of therapy. Patients who did not achieve a rapid virologic response were reassessed at treatment week 12. Patients with a complete early virologic response, defined as an HCV RNA level <600 IU/mL, were treated for 48 weeks. Patients with a partial response, defined as a decrease in the viral load ⩾2 log>10 and an HCV RNA level ⩾600 IU/mL, who attained an undetectable viral load at week 24 were treated for 60 weeks. The primary efficacy end point was sustained virologic response, defined as HCV RNA <50 IU/mL, 24 weeks after the end of treatment. Results. Overall, 33 (55%) of 60 patients achieved a sustained virologic response: 11 (44%) of 25 patients with HCV genotype 1, 3 (27%) of 11 patients with genotype 4, and 19 (79%) of 24 patients with genotype 3. One-third of patients showed a rapid virologic response. Of patients with genotype 1, there was a rapid virologic response in 4 (16%) of 25; with genotype 4, in 1 (9%) of 11; and with genotype 3, in 14 (58%) of 24. Of the 19 patients with a rapid virologic response, 17 (89.5%) eradicated the virus after 24 weeks of therapy. The rate of sustained virologic response was significantly higher among patients with genotype 3 and low pretreatment HCV RNA levels. A high relapse rate (46%) after 48 weeks of therapy occurred among patients infected with genotypes 1 or 4 who first achieved undetectable viral load at treatment week 12. Conclusion. A response-guide therapy is feasible and may be useful to optimize the individual outcome of HCV treatment in patients coinfected with HIV.
Latent parasitic infections can reactivate because of immunosuppression. We conducted a prospective observational study of all human immunodeficiency virus (HIV)-infected immigrants who visited the ...Infectious Diseases Department of the Hospital Universitari Vall d'Hebron, Barcelona, Spain, during June 2010-May 2011. Screening of the most prevalent tropical diseases (intestinal parasitosis, Chagas disease, leishmaniasis, malaria, schistosomiasis, and strongyloidiasis) was performed according to geographic origin. A total of 190 patients were included: 141 (74.2%) from Latin America, 41 (21.6%) from sub-Saharan Africa, and 8 (4.2%) from northern Africa. Overall, 36.8% (70 of 190) of the patients had at least one positive result for any parasitic disease: 5 patients with positive Trypanosoma cruzi serology, 11 patients with positive Schistosoma mansoni serology, 35 patients with positive Strongyloides stercoralis serology, 7 patients with positive Leishmania infantum serology, intestinal parasitosis were detected in 37 patients, malaria was diagnosed in one symptomatic patient. We propose a screening and management strategy of latent parasitic infections in immigrant patients infected with HIV.
Boosted darunavir (DRV/r) plus etravirine (ETR), in DUET trials, and raltegravir, in BENCHMRK trials, showed high rates of virologic response in patients with multidrug-resistant HIV-1 infection, ...particularly when associated with two more fully active antiretroviral drugs. No data from clinical trials, about this combination, are available.
Thirty-two consecutive heavily pretreated patients with multidrug-resistant HIV-1 infection who started a new salvage regimen with RAL (400 mg twice daily), ETR (200 mg twice daily), and DRV/r (600/100 mg twice daily) were studied. Clinical evaluation and immunologic, virologic, and biochemical parameters were collected at baseline and at Weeks 4, 12, and 24.
Median baseline characteristics were age 44 years, 13 years on antiretroviral therapy, nine prior highly active antiretroviral therapy regimens, 261 CD4 cells/mL, and HIV-1 RNA 4.2 log10 copies/mL. Sixteen (50%) and 14 (44%) patients were enfuvirtide- and tipranavir-experienced, respectively. Three-class resistance mutations were present in all patients. Three patients (9%) had isolates with three ETR resistance mutations. All patients were DRV-naïve with a median of one DRV resistance mutation. At Weeks 4, 12, and 24, respectively, 63%, 81%, and 94% of patients achieved HIV1-RNA less than 50 copies/mL. Median CD4 cell count increased 30, 73, and 103 cells/mL at Weeks 4, 12, and 24, respectively. No patient had adverse events leading to discontinuation of the regimen.
The combination of raltegravir, ETR, and DRV/r was a highly effective and well-tolerated antiretroviral salvage regimen in patients infected with multidrug-resistant HIV-1.
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