1,210 results on '"Martinelli, Giovanni"'
Search Results
2. Diagnosis, prognostic factors, and assessment of ALL in adults: 2024 ELN recommendations from a European expert panel
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Gökbuget, Nicola, Boissel, Nicolas, Chiaretti, Sabina, Dombret, Hervé, Doubek, Michael, Fielding, Adele, Foà, Robin, Giebel, Sebastian, Hoelzer, Dieter, Hunault, Mathilde, Marks, David I., Martinelli, Giovanni, Ottmann, Oliver, Rijneveld, Anita, Rousselot, Philippe, Ribera, Josep, and Bassan, Renato
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[Display omitted]
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- 2024
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3. 10-day decitabine versus 3 + 7 chemotherapy followed by allografting in older patients with acute myeloid leukaemia: an open-label, randomised, controlled, phase 3 trial
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Lübbert, Michael, Wijermans, Pierre W, Kicinski, Michal, Chantepie, Sylvain, Van der Velden, Walter J F M, Noppeney, Richard, Griškevičius, Laimonas, Neubauer, Andreas, Crysandt, Martina, Vrhovac, Radovan, Luppi, Mario, Fuhrmann, Stephan, Audisio, Ernesta, Candoni, Anna, Legrand, Olivier, Foà, Robin, Gaidano, Gianluca, van Lammeren-Venema, Danielle, Posthuma, Eduardus F M, Hoogendoorn, Mels, Giraut, Anne, Stevens-Kroef, Marian, Jansen, Joop H, de Graaf, Aniek O, Efficace, Fabio, Ammatuna, Emanuele, Vilque, Jean-Pierre, Wäsch, Ralph, Becker, Heiko, Blijlevens, Nicole, Dührsen, Ulrich, Baron, Frédéric, Suciu, Stefan, Amadori, Sergio, Venditti, Adriano, Huls, Gerwin, Finke, Jürgen, Schaap, Nicolaas Petrus Michael, Zucenka, Andrius, Metzelder, Stephan, Jost, Edgar, Perić, Zinaida, Forghieri, Fabio, Allione, Bernadino, Martelli, Maurizio, Iori, Anna Paola, Wittnebel, Sebastian, Mengarelli, Andrea, Imovilli, Annalisa, Olivieri, Attilio, De Prijck, Bernard José Marie, van der Poel, Marjolein W.M., Junghanß, Christian, Salih, Helmut Rainer, Tafuri, Agostino, Guimarães, José Eduardo, Musso, Maurizio, De Fabritiis, Paolo, Chevallier, Patrice, Selleslag, Dominik Luc, Cascavilla, Nicola, Berneman, Zwi, Jaspers, Aurélie, Zuffa, Eliana, Vanstraelen, Gaëtan, Visani, Giuseppe, Cuijpers, Maria Louisa Henriëtte, De Becker, Ann, Mianulli, Anna Maria, Hackanson, Björn, Mihaylov, Georgi Georgiev, Martinelli, Giovanni, Paolini, Stefania, Zinzani, Pier Luigi, Henkes, Martin, Al-Ali, Haifa Kathrin, La Rosée, Paul, Chierichini, Anna, Cudillo, Laura, Specchia, Giorgina, Šimec, Njetočka Gredelj, Capalbo, Silvana Franca, Spinosa, Giuseppina, Molica, Stefano, and de Jonge-Peeters, Susan Dorothé
- Abstract
Many older patients with acute myeloid leukaemia die or cannot undergo allogeneic haematopoietic stem-cell transplantation (HSCT) due to toxicity caused by intensive chemotherapy. We hypothesised that replacing intensive chemotherapy with decitabine monotherapy could improve outcomes.
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- 2023
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4. Cusatuzumab plus azacitidine in newly diagnosed acute myeloid leukaemia ineligible for intensive chemotherapy (CULMINATE): part one of a randomised, phase 2, dose optimisation study
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Pabst, Thomas, Papayannidis, Cristina, Demirkan, Fatih, Doronin, Vadim, Fogliatto, Laura M, Guttke, Christina, Gyan, Emmanuel, Hamad, Nada, Herrera, Pilar, Hultberg, Anna, Jacobs, Julie, Johnson, Amy J, Langlois, Angélique, Ma, Xuewen, Martinelli, Giovanni, Arnan, Montserrat, Müller, Rouven, Nottage, Kerri, Ofran, Yishai, Özcan, Muhit, Samoilova, Olga, Tolbert, Jaszianne A, Trudel, Géralyn C, Xiu, Liang, Vey, Norbert, and Wei, Andrew H
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Cusatuzumab, a high-affinity anti-CD70 antibody, has shown preliminary activity as a treatment for acute myeloid leukaemia when combined with azacitidine. We aimed to determine the optimum dose for future trials of cusatuzumab in combination with azacitidine in patients with previously untreated acute myeloid leukaemia who are not eligible for intensive chemotherapy.
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- 2023
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5. Pegaspargase-modified risk-oriented program for adult acute lymphoblastic leukemia: results of the GIMEMA LAL1913 trial
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Bassan, Renato, Chiaretti, Sabina, Della Starza, Irene, Spinelli, Orietta, Santoro, Alessandra, Paoloni, Francesca, Messina, Monica, Elia, Loredana, De Propris, Maria Stefania, Scattolin, Anna Maria, Audisio, Ernesta, Marbello, Laura, Borlenghi, Erika, Zappasodi, Patrizia, Mauro, Elisa, Martinelli, Giovanni, Mattei, Daniele, Fracchiolla, Nicola, Bocchia, Monica, De Fabritiis, Paolo, Bonifacio, Massimiliano, Candoni, Anna, Cassibba, Vincenzo, Di Bartolomeo, Paolo, Latte, Giancarlo, Trappolini, Silvia, Guarini, Anna, Vitale, Antonella, Fazi, Paola, Piciocchi, Alfonso, Rambaldi, Alessandro, and Foà, Robin
- Abstract
•An improved pegaspargase-modified MRD and risk-oriented regimen was prospectively tested in adults aged 18-65 years with Ph–ALL/LL.•Three-year survival rates were >60% with HCT or chemotherapy, further improved by MRD negativity and age ≤40 years.
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- 2023
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6. MEK1/2 regulate normal BCR and ABL1 tumor-suppressor functions to dictate ATO response in TKI-resistant Ph+ leukemia
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Mazzera, Laura, Abeltino, Manuela, Lombardi, Guerino, Cantoni, Anna Maria, Jottini, Stefano, Corradi, Attilio, Ricca, Micaela, Rossetti, Elena, Armando, Federico, Peli, Angelo, Ferrari, Anna, Martinelli, Giovanni, Scupoli, Maria Teresa, Visco, Carlo, Bonifacio, Massimiliano, Ripamonti, Alessia, Gambacorti-Passerini, Carlo, Bonati, Antonio, Perris, Roberto, and Lunghi, Paolo
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Resistance to tyrosine kinase inhibitors (TKIs) remains a clinical challenge in Ph-positive variants of chronic myeloid leukemia. We provide mechanistic insights into a previously undisclosed MEK1/2/BCR::ABL1/BCR/ABL1-driven signaling loop that may determine the efficacy of arsenic trioxide (ATO) in TKI-resistant leukemic patients. We find that activated MEK1/2 assemble into a pentameric complex with BCR::ABL1, BCR and ABL1 to induce phosphorylation of BCR and BCR::ABL1 at Tyr360 and Tyr177, and ABL1, at Thr735 and Tyr412 residues thus provoking loss of BCR’s tumor-suppression functions, enhanced oncogenic activity of BCR::ABL1, cytoplasmic retention of ABL1 and consequently drug resistance. Coherently, pharmacological blockade of MEK1/2 induces dissociation of the pentameric MEK1/2/BCR::ABL1/BCR/ABL1 complex and causes a concurrent BCRY360/Y177, BCR::ABL1Y360/Y177and cytoplasmic ABL1Y412/T735dephosphorylation thereby provoking the rescue of the BCR’s anti-oncogenic activities, nuclear accumulation of ABL1 with tumor-suppressive functions and consequently, growth inhibition of the leukemic cells and an ATO sensitization via BCR-MYC and ABL1-p73 signaling axes activation. Additionally, the allosteric activation of nuclear ABL1 was consistently found to enhance the anti-leukemic effects of the MEK1/2 inhibitor Mirdametinib, which when combined with ATO, significantly prolonged the survival of mice bearing BCR::ABL1-T315I-induced leukemia. These findings highlight the therapeutic potential of MEK1/2-inhibitors/ATO combination for the treatment of TKI-resistant leukemia.
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- 2023
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7. Venetoclax and idasanutlin in relapsed/refractory AML: a nonrandomized, open-label phase 1b trial
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Daver, Naval G., Dail, Monique, Garcia, Jacqueline S., Jonas, Brian A., Yee, Karen W. L., Kelly, Kevin R., Vey, Norbert, Assouline, Sarit, Roboz, Gail J., Paolini, Stefania, Pollyea, Daniel A., Tafuri, Agostino, Brandwein, Joseph M., Pigneux, Arnaud, Powell, Bayard L., Fenaux, Pierre, Olin, Rebecca L., Visani, Giuseppe, Martinelli, Giovanni, Onishi, Maika, Wang, Jue, Huang, Weize, Green, Cherie, Ott, Marion G., Hong, Wan-Jen, Konopleva, Marina Y., and Andreeff, Michael
- Abstract
This phase 1b trial (NCT02670044) evaluated venetoclax-idasanutlin in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) ineligible for cytotoxic chemotherapy. Two-dimensional dose escalation (DE, n = 50) was performed for venetoclax daily with idasanutlin on days 1 to 5 in 28-day cycles, followed by dosing schedule optimization (n = 6) to evaluate reduced venetoclax schedules (21-/14-day dosing). Common adverse events (occurring in ≥40% of patients) included diarrhea (87.3% of patients), nausea (74.5%), vomiting (52.7%), hypokalemia (50.9%), and febrile neutropenia (45.5%). During DE, across all doses, composite complete remission (CRc; CR + CR with incomplete blood count recovery + CR with incomplete platelet count recovery) rate was 26.0% and morphologic leukemia-free state (MLFS) rate was 12%. For anticipated recommended phase 2 doses (venetoclax 600 mg + idasanutlin 150 mg; venetoclax 600 mg + idasanutlin 200 mg), the combined CRc rate was 34.3% and the MLFS rate was 14.3%. Pretreatment IDH1/2 and RUNX1 mutations were associated with higher CRc rates (50.0% and 45.0%, respectively). CRc rate in patients with TP53 mutations was 20.0%, with responses noted among those with co-occurring IDH and RUNX1 mutations. In 12 out of 36 evaluable patients, 25 emergent TP53 mutations were observed; 22 were present at baseline with low TP53 variant allele frequency (median 0.0095% [range, 0.0006-0.4]). Venetoclax-idasanutlin showed manageable safety and encouraging efficacy in unfit patients with R/R AML. IDH1/2 and RUNX1 mutations were associated with venetoclax-idasanutlin sensitivity, even in some patients with co-occurring TP53 mutations; most emergent TP53 clones were preexisting. Our findings will aid ongoing/future trials of BCL-2/MDM2 inhibitor combinations. This trial was registered at www.clinicaltrials.gov as #NCT02670044.
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- 2023
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8. Biological therapy in elderly patients with acute myeloid leukemia
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Ciotti, Giulia, Marconi, Giovanni, Sperotto, Alessandra, Giannini, Maria B, Gottardi, Michele, and Martinelli, Giovanni
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ABSTRACTIntroductionThe introduction of target molecules and immunological therapies is changing the treatment landscape of acute myeloid leukemia (AML).Areas coveredWe recapitulate the biological therapies that can be employed in the treatment of elderly patients with AML. Alongside small molecules inhibitors that target specific gene mutations, antibodies, tumor microenvironment modulators, and cellular therapies are being developed for the cure of the disease. Here, we report the biological activities, the efficacy and toxicities of humanized antibodies and antibody-drug conjugates that targets surface antigens as CD33 (gemtuzumab ozogamicine) or CD123 (pivekimab sunirine). We further explore mechanisms and effectiveness of medications that modify the microenvironment, such as glasdegib, or that harness the immune system against leukemia, such as CD47 antibody magrolimab, PD1/PDL1 inhibitors pembrolizumab and nivolumab, TIM3 inhibitor sabatolimab, T-cell and NK-cell engagers. Cellular therapies are considered, even if a large trial is still pending for the feasibility of the approach. In this scenario, a brief overview of the mechanism of action of target agents is provided, particularly with respect to their biological mechanisms.Expert opinionOverall, this therapeutic armamentarium will constitute the basis for multimodal and personalized combinations that, in the idea of precision medicine, will enormously benefit elderly AML patients.
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- 2023
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9. Effects of yoga practice on physiological distress, fatigue and QOL in patients affected by breast cancer undergoing adjuvant radiotherapy
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Micheletti, Simona, Serra, Patrizia, Tesei, Anna, Azzali, Irene, Arienti, Chiara, Ancarani, Valentina, Corelli, Stefania, Romeo, Antonino, and Martinelli, Giovanni
- Abstract
In this study we want to evaluate the efficacy of yoga practice on dysfunctional stress, inflammation and QOL in breast cancer patients undergoing adjuvant radiotherapy.
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- 2022
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10. Broad Activity for the Pivekimab Sunirine (PVEK, IMGN632), Azacitidine, and Venetoclax Triplet in High-Risk Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML)
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Daver, Naval, Montesinos, Pau, Aribi, Ahmed, Marconi, Giovanni, Altman, Jessica K., Wang, Eunice S., Roboz, Gail J., Burke, Patrick W., Gaidano, Gianluca, Walter, Roland B., Thomas, Xavier, Jeyakumar, Deepa, DeAngelo, Daniel J., Erba, Harry P., Todisco, Elisabetta, Begna, Kebede H., Advani, Anjali, Gastaud, Lauris, De La Fuente, Adolfo, Curti, Antonio, Mendez, Lourdes M., Vyas, Paresh, Boissel, Nicolas, Vey, Norbert, Recher, Christian, Longval, Thomas, Platzbecker, Uwe, Kapp-Schwoerer, Silke, Schliemann, Christoph, Konopleva, Marina, Torres, Laura, Sallman, David A., Marcucci, Guido, Pemmaraju, Naveen, Martinelli, Giovanni, Kantarjian, Hagop, Sloss, Callum M, Malcolm, Kara E, Zweidler-McKay, Patrick A, and Sweet, Kendra
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- 2022
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11. Broad Activity for the Pivekimab Sunirine (PVEK, IMGN632), Azacitidine, and Venetoclax Triplet in High-Risk Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML)
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Daver, Naval, Montesinos, Pau, Aribi, Ahmed, Marconi, Giovanni, Altman, Jessica K., Wang, Eunice S., Roboz, Gail J., Burke, Patrick W., Gaidano, Gianluca, Walter, Roland B., Thomas, Xavier, Jeyakumar, Deepa, DeAngelo, Daniel J., Erba, Harry P., Todisco, Elisabetta, Begna, Kebede H., Advani, Anjali, Gastaud, Lauris, De La Fuente, Adolfo, Curti, Antonio, Mendez, Lourdes M., Vyas, Paresh, Boissel, Nicolas, Vey, Norbert, Recher, Christian, Longval, Thomas, Platzbecker, Uwe, Kapp-Schwoerer, Silke, Schliemann, Christoph, Konopleva, Marina, Torres, Laura, Sallman, David A., Marcucci, Guido, Pemmaraju, Naveen, Martinelli, Giovanni, Kantarjian, Hagop, Sloss, Callum M, Malcolm, Kara E, Zweidler-McKay, Patrick A, and Sweet, Kendra
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- 2022
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12. Idasanutlin plus cytarabine in relapsed or refractory acute myeloid leukemia: results of the MIRROS trial
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Konopleva, Marina Y., Röllig, Christoph, Cavenagh, Jamie, Deeren, Dries, Girshova, Larisa, Krauter, Jürgen, Martinelli, Giovanni, Montesinos, Pau, Schäfer, Jonas A., Ottmann, Oliver, Petrini, Mario, Pigneux, Arnaud, Rambaldi, Alessandro, Recher, Christian, Rodriguez-Veiga, Rebeca, Taussig, David, Vey, Norbert, Yoon, Sung-Soo, Ott, Marion, Muehlbauer, Susanne, Beckermann, Benjamin M., Catalani, Olivier, Genevray, Magali, Mundt, Kirsten, Jamois, Candice, Fenaux, Pierre, and Wei, Andrew H.
- Abstract
The phase 3 MIRROS (MDM2 antagonist Idasanutlin in Relapsed or Refractory acute myeloid leukemia [AML] for Overall Survival) trial (NCT02545283) evaluated the efficacy and safety of the small-molecule MDM2 antagonist idasanutlin plus cytarabine in patients with relapsed/refractory (R/R) AML. Adults (n = 447) with R/R AML whose disease relapsed or was refractory after ≤2 prior induction regimens as initial treatment or following salvage chemotherapy regimen, with Eastern Cooperative Oncology Group performance status ≤2 were enrolled regardless of TP53 mutation status and randomly assigned 2:1 to idasanutlin 300 mg or placebo orally twice daily plus cytarabine 1 g/m2 IV on days 1 to 5 of 28-day cycles. At primary analysis (cutoff, November 2019), 436 patients were enrolled, including 355 in the TP53 wild-type intention-to-treat (TP53WT-ITT) population. The primary endpoint, overall survival in the TP53WT-ITT population, was not met (median, 8.3 vs 9.1 months with idasanutlin-cytarabine vs placebo-cytarabine; stratified hazard ratio [HR], 1.08; 95% confidence interval [CI], 0.81-1.45; P = .58). The complete remission (CR) rate, a key secondary endpoint, was 20.3% vs 17.1% (odds ratio [OR], 1.23; 95% CI, 0.70-2.18). The overall response rate (ORR) was 38.8% vs 22.0% (OR, 2.25; 95% CI, 1.36-3.72). Common any-grade adverse events (≥10% incidence in any arm) were diarrhea (87.0% vs 32.9%), febrile neutropenia (52.8% vs 49.3%), and nausea (52.5% vs 31.5%). In summary, despite improved ORR, adding idasanutlin to cytarabine did not improve overall survival or CR rates in patients with R/R AML.
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- 2022
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13. Lineage-specific mechanisms and drivers of breast cancer chemoresistance revealed by 3D biomimetic culture.
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Liverani, Chiara, De Vita, Alessandro, Spadazzi, Chiara, Miserocchi, Giacomo, Cocchi, Claudia, Bongiovanni, Alberto, De Lucia, Anna, La Manna, Federico, Fabbri, Francesco, Tebaldi, Michela, Amadori, Dino, Tasciotti, Ennio, Martinelli, Giovanni, Mercatali, Laura, and Ibrahim, Toni
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To improve the success rate of current preclinical drug trials, there is a growing need for more complex and relevant models that can help predict clinical resistance to anticancer agents. Here, we present a three-dimensional (3D) technology, based on biomimetic collagen scaffolds, that enables the modeling of the tumor hypoxic state and the prediction of in vivo chemotherapy responses in terms of efficacy, molecular alterations, and emergence of resistance mechanisms. The human breast cancer cell lines MDA-MB-231 (triple negative) and MCF-7 (luminal A) were treated with scaling doses of doxorubicin in monolayer cultures, 3D collagen scaffolds, or orthotopically transplanted murine models. Lineage-specific resistance mechanisms were revealed by the 3D tumor model. Reduced drug uptake, increased drug efflux, and drug lysosomal confinement were observed in triple-negative MDA-MB-231 cells. In luminal A MCF-7 cells, the selection of a drug-resistant subline from parental cells with deregulation of p53 pathways occurred. These cells were demonstrated to be insensitive to DNA damage. Transcriptome analysis was carried out to identify differentially expressed genes (DEGs) in treated cells. DEG evaluation in breast cancer patients demonstrated their potential role as predictive biomarkers. High expression of the transporter associated with antigen processing 1 (TAP1) and the tumor protein p53-inducible protein 3 (TP53I3) was associated with shorter relapse in patients affected by ER+ breast tumor. Likewise, the same clinical outcome was associated with high expression of the lysosomal-associated membrane protein 1 LAMP1 in triple-negative breast cancer. Hypoxia inhibition by resveratrol treatment was found to partially re-sensitize cells to doxorubicin treatment. Our model might improve preclinical in vitro analysis for the translation of anticancer compounds as it provides: (a) more accurate data on drug efficacy and (b) enhanced understanding of resistance mechanisms and molecular drivers. [ABSTRACT FROM AUTHOR]
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- 2022
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14. Follow-up of patients with R/R FLT3-mutation–positive AML treated with gilteritinib in the phase 3 ADMIRAL trial
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Perl, Alexander E., Larson, Richard A., Podoltsev, Nikolai A., Strickland, Stephen, Wang, Eunice S., Atallah, Ehab, Schiller, Gary J., Martinelli, Giovanni, Neubauer, Andreas, Sierra, Jorge, Montesinos, Pau, Récher, Christian, Yoon, Sung-Soo, Hosono, Naoko, Onozawa, Masahiro, Chiba, Shigeru, Kim, Hee-Je, Hasabou, Nahla, Lu, Qiaoyang, Tiu, Ramon, and Levis, Mark J.
- Abstract
The phase 3 ADMIRAL (NCT02421939; Study ID: 2215-CL-0301) trial showed superior overall survival in patients with relapsed/refractory FLT3-mutation–positive acute myeloid leukemia (AML) randomized 2:1 to receive the oral FMS-like tyrosine kinase 3 inhibitor gilteritinib vs those randomized to receive salvage chemotherapy (SC). Here we provide a follow-up of the ADMIRAL trial 2 years after the primary analysis to clarify the long-term treatment effects and safety of gilteritinib in these patients with AML. At the time of this analysis, the median survival follow-up was 37.1 months, with deaths in 203 of 247 and 97 of 124 patients in the gilteritinib and SC arms, respectively; 16 gilteritinib-treated patients remained on treatment. The median overall survival for the gilteritinib and SC arms was 9.3 and 5.6 months, respectively (hazard ratio, 0.665; 95% confidence interval [CI], 0.518, 0.853; two-sided P = .0013); 2-year estimated survival rates were 20.6% (95% CI, 15.8, 26.0) and 14.2% (95% CI, 8.3, 21.6). The gilteritinib-arm 2-year cumulative incidence of relapse after composite complete remission was 75.7%, with few relapses occurring after 18 months. Overall, 49 of 247 patients in the gilteritinib arm and 14 of 124 patients in the SC arm were alive for ≥2 years. Twenty-six gilteritinib-treated patients remained alive for ≥2 years without relapse; 18 of these patients underwent transplantation (hematopoietic stem cell transplantation [HSCT]) and 16 restarted gilteritinib as post-HSCT maintenance therapy. The most common adverse events of interest during years 1 and 2 of gilteritinib therapy were increased liver transaminase levels; adverse event incidence decreased in year 2. Thus, continued and post-HSCT gilteritinib maintenance treatment sustained remission with a stable safety profile. These findings confirm that prolonged gilteritinib therapy is safe and is associated with superior survival vs SC. This trial was registered at www.clinicaltrials.gov as #NCT02421939.
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- 2022
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15. Follow-up of patients with R/R FLT3-mutation–positive AML treated with gilteritinib in the phase 3 ADMIRAL trial
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Perl, Alexander E., Larson, Richard A., Podoltsev, Nikolai A., Strickland, Stephen, Wang, Eunice S., Atallah, Ehab, Schiller, Gary J., Martinelli, Giovanni, Neubauer, Andreas, Sierra, Jorge, Montesinos, Pau, Récher, Christian, Yoon, Sung-Soo, Hosono, Naoko, Onozawa, Masahiro, Chiba, Shigeru, Kim, Hee-Je, Hasabou, Nahla, Lu, Qiaoyang, Tiu, Ramon, and Levis, Mark J.
- Abstract
The phase 3 ADMIRAL (NCT02421939; Study ID: 2215-CL-0301) trial showed superior overall survival in patients with relapsed/refractory FLT3-mutation–positive acute myeloid leukemia (AML) randomized 2:1 to receive the oral FMS-like tyrosine kinase 3 inhibitor gilteritinib vs those randomized to receive salvage chemotherapy (SC). Here we provide a follow-up of the ADMIRAL trial 2 years after the primary analysis to clarify the long-term treatment effects and safety of gilteritinib in these patients with AML. At the time of this analysis, the median survival follow-up was 37.1 months, with deaths in 203 of 247 and 97 of 124 patients in the gilteritinib and SC arms, respectively; 16 gilteritinib-treated patients remained on treatment. The median overall survival for the gilteritinib and SC arms was 9.3 and 5.6 months, respectively (hazard ratio, 0.665; 95% confidence interval [CI], 0.518, 0.853; two-sided P= .0013); 2-year estimated survival rates were 20.6% (95% CI, 15.8, 26.0) and 14.2% (95% CI, 8.3, 21.6). The gilteritinib-arm 2-year cumulative incidence of relapse after composite complete remission was 75.7%, with few relapses occurring after 18 months. Overall, 49 of 247 patients in the gilteritinib arm and 14 of 124 patients in the SC arm were alive for ≥2 years. Twenty-six gilteritinib-treated patients remained alive for ≥2 years without relapse; 18 of these patients underwent transplantation (hematopoietic stem cell transplantation [HSCT]) and 16 restarted gilteritinib as post-HSCT maintenance therapy. The most common adverse events of interest during years 1 and 2 of gilteritinib therapy were increased liver transaminase levels; adverse event incidence decreased in year 2. Thus, continued and post-HSCT gilteritinib maintenance treatment sustained remission with a stable safety profile. These findings confirm that prolonged gilteritinib therapy is safe and is associated with superior survival vs SC. This trial was registered at www.clinicaltrials.govas #NCT02421939.
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- 2022
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16. ELN2017 risk stratification improves outcome prediction when applied to the prospective GIMEMA AML1310 protocol
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Buccisano, Francesco, Palmieri, Raffaele, Piciocchi, Alfonso, Arena, Valentina, Candoni, Anna, Melillo, Lorella, Calafiore, Valeria, Cairoli, Roberto, de Fabritiis, Paolo, Storti, Gabriella, Salutari, Prassede, Lanza, Francesco, Martinelli, Giovanni, Luppi, Mario, Capria, Saveria, Maurillo, Luca, Del Principe, Maria Ilaria, Paterno, Giovangiacinto, Irno Consalvo, Maria Antonietta, Ottone, Tiziana, Lavorgna, Serena, Voso, Maria Teresa, Fazi, Paola, Vignetti, Marco, Arcese, William, and Venditti, Adriano
- Abstract
The 2017 version of the European LeukemiaNet (ELN) recommendations, by integrating cytogenetics and mutational status of specific genes, divides patients with acute myeloid leukemia into 3 prognostically distinct risk categories: favorable (ELN2017-FR), intermediate (ELN2017-IR), and adverse (ELN2017-AR). We performed a post hoc analysis of the GIMEMA (Gruppo Italiano Malattie EMatologiche dell’Adulto) AML1310 trial to investigate the applicability of the ELN2017 risk stratification to our study population. In this trial, after induction and consolidation, patients in complete remission were to receive an autologous stem cell transplant (auto-SCT) if categorized as favorable risk or an allogeneic stem cell transplant (allo-SCT) if adverse risk. Intermediate-risk patients were to receive auto-SCT or allo-SCT based on the postconsolidation levels of measurable residual disease as measured by using flow cytometry. Risk categorization was originally conducted according to the 2009 National Comprehensive Cancer Network recommendations. Among 500 patients, 445 (89%) were reclassified according to the ELN2017 criteria: ELN2017-FR, 186 (41.8%) of 455; ELN2017-IR, 179 (40.2%) of 445; and ELN2017-AR, 80 (18%) of 455. In 55 patients (11%), ELN2017 was not applicable. Two-year overall survival (OS) was 68.8%, 51.3%, 45.8%, and 42.8% for the ELN2017-FR, ELN2017-IR, ELN2017-not classifiable, and ELN2017-AR groups, respectively (P < .001). When comparing the 2 different transplant strategies in each ELN2017 risk category, a significant benefit of auto-SCT over allo-SCT was observed among ELN2017-FR patients (2-year OS of 83.3% vs 66.7%; P = .0421). The 2 transplant procedures performed almost equally in the ELN2017-IR group (2-year OS of 73.9% vs 70.8%; P = .5552). This post hoc analysis of the GIMEMA AML1310 trial confirms that the ELN2017 classification is able to accurately discriminate patients with different outcomes and who may benefit from different transplant strategies. This trial was registered as EudraCT number 2010-023809-36 and at www.clinicaltrials.gov as #NCT01452646.
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- 2022
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17. INCB84344-201: Ponatinib and steroids in frontline therapy for unfit patients with Ph+ acute lymphoblastic leukemia
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Martinelli, Giovanni, Papayannidis, Cristina, Piciocchi, Alfonso, Robustelli, Valentina, Soverini, Simona, Terragna, Carolina, Marconi, Giovanni, Lemoli, Roberto M., Guolo, Fabio, Fornaro, Antonella, Lunghi, Monia, de Fabritiis, Paolo, Candoni, Anna, Selleri, Carmine, Simonetti, Federico, Bocchia, Monica, Vitale, Antonella, Frison, Luca, Tedeschi, Alessandra, Cuneo, Antonio, Bonifacio, Massimiliano, Martelli, Maria Paola, D’Ardia, Stefano, Trappolini, Silvia, Tosi, Patrizia, Galieni, Piero, Fabbiano, Francesco, Abbenante, Maria Chiara, Granier, Muriel, Zhu, Zhaoyin, Wang, Mingyue, Sartor, Chiara, Paolini, Stefania, Cavo, Michele, Foà, Robin, Fazi, Paola, Vignetti, Marco, and Baccarani, Michele
- Abstract
Tyrosine kinase inhibitors have improved survival for patients with Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL). However, prognosis for old or unfit patients remains poor. In the INCB84344-201 (formerly GIMEMA LAL 1811) prospective, multicenter, phase 2 trial, we tested the efficacy and safety of ponatinib plus prednisone in newly diagnosed patients with Ph+ ALL ≥60 years, or unfit for intensive chemotherapy and stem cell transplantation. Forty-four patients received oral ponatinib 45 mg/d for 48 weeks (core phase), with prednisone tapered to 60 mg/m2/d from days-14-29. Prophylactic intrathecal chemotherapy was administered monthly. Median age was 66.5 years (range, 26-85). The primary endpoint (complete hematologic response [CHR] at 24 weeks) was reached in 38/44 patients (86.4%); complete molecular response (CMR) in 18/44 patients (40.9%) at 24 weeks. 61.4% of patients completed the core phase. As of 24 April 2020, median event-free survival was 14.31 months (95% CI 9.30-22.31). Median overall survival and duration of CHR were not reached; median duration of CMR was 11.6 months. Most common treatment-emergent adverse events (TEAEs) were rash (36.4%), asthenia (22.7%), alanine transaminase increase (15.9%), erythema (15.9%), and γ-glutamyltransferase increase (15.9%). Cardiac and vascular TEAEs occurred in 29.5% (grade ≥3, 18.2%) and 27.3% (grade ≥3, 15.9%), respectively. Dose reductions, interruptions, and discontinuations due to TEAEs occurred in 43.2%, 43.2%, and 27.3% of patients, respectively; 5 patients had fatal TEAEs. Ponatinib and prednisone showed efficacy in unfit patients with Ph+ ALL; however, a lower ponatinib dose may be more appropriate in this population. This trial was registered at www.clinicaltrials.gov as #NCT01641107.
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- 2022
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18. INCB84344-201: Ponatinib and steroids in frontline therapy for unfit patients with Ph+acute lymphoblastic leukemia
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Martinelli, Giovanni, Papayannidis, Cristina, Piciocchi, Alfonso, Robustelli, Valentina, Soverini, Simona, Terragna, Carolina, Marconi, Giovanni, Lemoli, Roberto M., Guolo, Fabio, Fornaro, Antonella, Lunghi, Monia, de Fabritiis, Paolo, Candoni, Anna, Selleri, Carmine, Simonetti, Federico, Bocchia, Monica, Vitale, Antonella, Frison, Luca, Tedeschi, Alessandra, Cuneo, Antonio, Bonifacio, Massimiliano, Martelli, Maria Paola, D'Ardia, Stefano, Trappolini, Silvia, Tosi, Patrizia, Galieni, Piero, Fabbiano, Francesco, Abbenante, Maria Chiara, Granier, Muriel, Zhu, Zhaoyin, Wang, Mingyue, Sartor, Chiara, Paolini, Stefania, Cavo, Michele, Foà, Robin, Fazi, Paola, Vignetti, Marco, and Baccarani, Michele
- Abstract
Tyrosine kinase inhibitors have improved survival for patients with Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL). However, prognosis for old or unfit patients remains poor. In the INCB84344-201 (formerly GIMEMA LAL 1811) prospective, multicenter, phase 2 trial, we tested the efficacy and safety of ponatinib plus prednisone in newly diagnosed patients with Ph+ALL ≥60 years, or unfit for intensive chemotherapy and stem cell transplantation. Forty-four patients received oral ponatinib 45 mg/d for 48 weeks (core phase), with prednisone tapered to 60 mg/m2/d from days-14-29. Prophylactic intrathecal chemotherapy was administered monthly. Median age was 66.5 years (range, 26-85). The primary endpoint (complete hematologic response [CHR] at 24 weeks) was reached in 38/44 patients (86.4%); complete molecular response (CMR) in 18/44 patients (40.9%) at 24 weeks. 61.4% of patients completed the core phase. As of 24 April 2020, median event-free survival was 14.31 months (95% CI 9.30-22.31). Median overall survival and duration of CHR were not reached; median duration of CMR was 11.6 months. Most common treatment-emergent adverse events (TEAEs) were rash (36.4%), asthenia (22.7%), alanine transaminase increase (15.9%), erythema (15.9%), and γ-glutamyltransferase increase (15.9%). Cardiac and vascular TEAEs occurred in 29.5% (grade ≥3, 18.2%) and 27.3% (grade ≥3, 15.9%), respectively. Dose reductions, interruptions, and discontinuations due to TEAEs occurred in 43.2%, 43.2%, and 27.3% of patients, respectively; 5 patients had fatal TEAEs. Ponatinib and prednisone showed efficacy in unfit patients with Ph+ALL; however, a lower ponatinib dose may be more appropriate in this population. This trial was registered at www.clinicaltrials.govas #NCT01641107.
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- 2022
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19. Gimema ALL2418: Interim Analysis of a Phase Iia Study of Feasibility and Effectiveness of Inotuzumab Ozogamicin in Adult Patients with B-Cell Acute Lymphoblastic Leukemia with Positive Minimal Residual Disease before Any Hematopoietic Stem Cell Transplantation
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Marconi, Giovanni, Piciocchi, Alfonso, Chiaretti, Sabina, Papayannidis, Cristina, Lunghi, Monia, Salutari, Prassede, Zappasodi, Patrizia, Rambaldi, Alessandro, Olivieri, Attilio, Cavallari, Maurizio, Soddu, Stefano, Fracchiolla, Nicola S, Gigli, Federica, Cattaneo, Chiara, Mattei, Daniele Giovanni, Candoni, Anna, Grillo, Giovanni, Abbenante, Maria Chiara, Audisio, Ernesta, Bonifacio, Massimiliano, Lico, Albana, Lemoli, Roberto Massimo, De Fabritiis, Paolo, Ferrara, Felicetto, Marino, Martina Rachele, Messina, Monica, Ferrari, Anna, Robustelli, Valentina, Nanni, Jacopo, Della Starza, Irene, Simonetti, Giorgia, De Propris, Maria Stefania, Bochicchio, Maria Teresa, Vignetti, Marco, Fazi, Paola, and Martinelli, Giovanni
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- 2022
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20. Safety and Tolerability of AZD0466 As Monotherapy for Patients with Advanced Hematological Malignancies. Preliminary Results from an Ongoing Phase I/II Trial
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Arslan, Shukaib, Fleming, Shaun, Jain, Nitin, Martinelli, Giovanni, Stein, Anthony S., Blachly, James S., Bajel, Ashish, Curti, Antonio, Marconi, Giovanni, Fabbri, Giulia, Marmor, Yotvat, Sharma, Shringi, Elgeioushi, Nairouz, Couto-Francisco, Natalia, Saeh, Jamal, Tibes, Raoul, Cader, Fathima Zumla, and Konopleva, Marina
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- 2022
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21. Safety and Tolerability of AZD0466 As Monotherapy for Patients with Advanced Hematological Malignancies. Preliminary Results from an Ongoing Phase I/II Trial
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Arslan, Shukaib, Fleming, Shaun, Jain, Nitin, Martinelli, Giovanni, Stein, Anthony S., Blachly, James S., Bajel, Ashish, Curti, Antonio, Marconi, Giovanni, Fabbri, Giulia, Marmor, Yotvat, Sharma, Shringi, Elgeioushi, Nairouz, Couto-Francisco, Natalia, Saeh, Jamal, Tibes, Raoul, Cader, Fathima Zumla, and Konopleva, Marina
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- 2022
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22. Gimema AML1718 Part 1: Planned Interim Analysis of a Safety Run-in and Phase 2 Open-Label Study of Venetoclax, Fludarabine, Idarubicin and Cytarabine (V-FLAI) in the Induction Therapy of Non Low-Risk Acute Myeloid Leukemia
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Marconi, Giovanni, Piciocchi, Alfonso, Audisio, Ernesta, Priolo, Giorgio, Papayannidis, Cristina, Martelli, Maurizio, Paoloni, Francesca, Lemoli, Roberto Massimo, Bocchia, Monica, Lanza, Francesco, Lico, Albana, Ciceri, Fabio, Della Porta, Matteo G., Frigeni, Marco, Giaccone, Luisa, Beltrami, Germana, Borlenghi, Erika, Di Chio, Maria Chiara, Selleri, Carmine, Crea, Enrico, Urbino, Irene, Sartor, Chiara, Minotti, Clara, Guolo, Fabio, La Sala, Edoardo, Nanni, Jacopo, Simonetti, Giorgia, Bochicchio, Maria Teresa, Saglio, Giuseppe, Venditti, Adriano, Vignetti, Marco, Fazi, Paola, and Martinelli, Giovanni
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- 2022
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23. Gimema AML1718 Part 1: Planned Interim Analysis of a Safety Run-in and Phase 2 Open-Label Study of Venetoclax, Fludarabine, Idarubicin and Cytarabine (V-FLAI) in the Induction Therapy of Non Low-Risk Acute Myeloid Leukemia
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Marconi, Giovanni, Piciocchi, Alfonso, Audisio, Ernesta, Priolo, Giorgio, Papayannidis, Cristina, Martelli, Maurizio, Paoloni, Francesca, Lemoli, Roberto Massimo, Bocchia, Monica, Lanza, Francesco, Lico, Albana, Ciceri, Fabio, Della Porta, Matteo G., Frigeni, Marco, Giaccone, Luisa, Beltrami, Germana, Borlenghi, Erika, Di Chio, Maria Chiara, Selleri, Carmine, Crea, Enrico, Urbino, Irene, Sartor, Chiara, Minotti, Clara, Guolo, Fabio, La Sala, Edoardo, Nanni, Jacopo, Simonetti, Giorgia, Bochicchio, Maria Teresa, Saglio, Giuseppe, Venditti, Adriano, Vignetti, Marco, Fazi, Paola, and Martinelli, Giovanni
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- 2022
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24. Gimema ALL2418: Interim Analysis of a Phase Iia Study of Feasibility and Effectiveness of Inotuzumab Ozogamicin in Adult Patients with B-Cell Acute Lymphoblastic Leukemia with Positive Minimal Residual Disease before Any Hematopoietic Stem Cell Transplantation
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Marconi, Giovanni, Piciocchi, Alfonso, Chiaretti, Sabina, Papayannidis, Cristina, Lunghi, Monia, Salutari, Prassede, Zappasodi, Patrizia, Rambaldi, Alessandro, Olivieri, Attilio, Cavallari, Maurizio, Soddu, Stefano, Fracchiolla, Nicola S, Gigli, Federica, Cattaneo, Chiara, Mattei, Daniele Giovanni, Candoni, Anna, Grillo, Giovanni, Abbenante, Maria Chiara, Audisio, Ernesta, Bonifacio, Massimiliano, Lico, Albana, Lemoli, Roberto Massimo, De Fabritiis, Paolo, Ferrara, Felicetto, Marino, Martina Rachele, Messina, Monica, Ferrari, Anna, Robustelli, Valentina, Nanni, Jacopo, Della Starza, Irene, Simonetti, Giorgia, De Propris, Maria Stefania, Bochicchio, Maria Teresa, Vignetti, Marco, Fazi, Paola, and Martinelli, Giovanni
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- 2022
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25. Integrated genomic-metabolic classification of acute myeloid leukemia defines a subgroup with NPM1and cohesin/DNA damage mutations
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Simonetti, Giorgia, Mengucci, Carlo, Padella, Antonella, Fonzi, Eugenio, Picone, Gianfranco, Delpino, Claudio, Nanni, Jacopo, De Tommaso, Rossella, Franchini, Eugenia, Papayannidis, Cristina, Marconi, Giovanni, Pazzaglia, Martina, Perricone, Margherita, Scarpi, Emanuela, Fontana, Maria Chiara, Bruno, Samantha, Tebaldi, Michela, Ferrari, Anna, Bochicchio, Maria Teresa, Ghelli Luserna Di Rorà, Andrea, Ghetti, Martina, Napolitano, Roberta, Astolfi, Annalisa, Baldazzi, Carmen, Guadagnuolo, Viviana, Ottaviani, Emanuela, Iacobucci, Ilaria, Cavo, Michele, Castellani, Gastone, Haferlach, Torsten, Remondini, Daniel, Capozzi, Francesco, and Martinelli, Giovanni
- Abstract
Although targeting of cell metabolism is a promising therapeutic strategy in acute myeloid leukemia (AML), metabolic dependencies are largely unexplored. We aimed to classify AML patients based on their metabolic landscape and map connections between metabolic and genomic profiles. Combined serum and urine metabolomics improved AML characterization compared with individual biofluid analysis. At intracellular level, AML displayed dysregulated amino acid, nucleotide, lipid, and bioenergetic metabolism. The integration of intracellular and biofluid metabolomics provided a map of alterations in the metabolism of polyamine, purine, keton bodies and polyunsaturated fatty acids and tricarboxylic acid cycle. The intracellular metabolome distinguished three AML clusters, correlating with distinct genomic profiles: NPM1-mutated(mut), chromatin/spliceosome-mut and TP53-mut/aneuploid AML that were confirmed by biofluid analysis. Interestingly, integrated genomic-metabolic profiles defined two subgroups of NPM1-mut AML. One was enriched for mutations in cohesin/DNA damage-related genes (NPM1/cohesin-mut AML) and showed increased serum choline + trimethylamine-N-oxide and leucine, higher mutation load, transcriptomic signatures of reduced inflammatory status and better ex-vivo response to EGFR and MET inhibition. The transcriptional differences of enzyme-encoding genes between NPM1/cohesin-mut and NPM1-mut allowed in silico modeling of intracellular metabolic perturbations. This approach predicted alterations in NAD and purine metabolism in NPM1/cohesin-mut AML that suggest potential vulnerabilities, worthy of being therapeutically explored.
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- 2021
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26. Mutant Isocitrate Dehydrogenase 1 Inhibitor Ivosidenib in Combination With Azacitidine for Newly Diagnosed Acute Myeloid Leukemia.
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DiNardo, Courtney D., Stein, Anthony S., Stein, Eytan M., Fathi, Amir T., Frankfurt, Olga, Schuh, Andre C., Döhner, Hartmut, Martinelli, Giovanni, Patel, Prapti A., Raffoux, Emmanuel, Tan, Peter, Zeidan, Amer M., de Botton, Stéphane, Kantarjian, Hagop M., Stone, Richard M., Frattini, Mark G., Lersch, Frederik, Gong, Jing, Gianolio, Diego A., and Zhang, Vickie
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- 2021
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27. The safety profile of FLT3 inhibitors in the treatment of newly diagnosed or relapsed/refractory acute myeloid leukemia
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Marconi, Giovanni, Giannini, Maria Benedetta, Bagnato, Gianmarco, Simonetti, Giorgia, Cerchione, Claudio, Mosquera Orgueira, Adrián, Musuraca, Gerardo, and Martinelli, Giovanni
- Abstract
ABSTRACTIntroductionFLT3 inhibitors are important drugs in the therapy of FLT3 positive acute myeloid leukemia (AML). Midostaurin was registered in combination with chemotherapy to treat newly diagnosed AML. Gilteritinib and quizartinib demonstrate effectiveness in a randomized trial in relapsed/refractory AML. Several promising FLT3 inhibitors are being evaluated in clinical research.Areas coveredThis review will report the safety of FLT3 inhibitors that are registered for acute myeloid leukemia induction and rescue therapy.Expert opinionIn the near future, it is possible that all the FLT3 positive non M3-AML patients will receive a FLT3 inhibitor. Therapy adherence and strategies to mitigate adverse events must be pursued. The treatment with FLT3 inhibitors may be optimized in terms of toxicities with a rational evaluation of antifungal prophylaxis and concomitant therapy, cardiology monitoring, and keeping in mind rare adverse events. Future studies on unfit patients, special populations, and maintenance settings are warranted, together with post-market studies and real-life experiences. Whenever new FLT3 inhibitors will come to the clinic, we could face a scenario in which profound knowledge of effectiveness, toxicities, and off-target effects will be relevant to choose the best drug for each patient.
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- 2021
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28. BCR-ABL1 compound mutants: prevalence, spectrum and correlation with tyrosine kinase inhibitor resistance in a consecutive series of Philadelphia chromosome-positive leukemia patients analyzed by NGS
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Soverini, Simona, Martelli, Margherita, Bavaro, Luana, De Benedittis, Caterina, Sica, Simona, Sorà, Federica, Iurlo, Alessandra, Bonifacio, Massimiliano, Pregno, Patrizia, Galimberti, Sara, Lunghi, Francesca, Albano, Francesco, D’Adda, Mariella, Crugnola, Monica, Capodanno, Isabella, Castagnetti, Fausto, Gugliotta, Gabriele, Papayannidis, Cristina, Rosti, Gianantonio, Percesepe, Antonio, Mignone, Flavio, Baccarani, Michele, Martinelli, Giovanni, and Cavo, Michele
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- 2021
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29. Clinical Outcomes in Patients with FLT3-ITD-Mutated Relapsed/Refractory Acute Myelogenous Leukemia Undergoing Hematopoietic Stem Cell Transplantation after Quizartinib or Salvage Chemotherapy in the QuANTUM-R Trial
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Ganguly, Siddhartha, Cortes, Jorge E., Krämer, Alwin, Levis, Mark J., Martinelli, Giovanni, Perl, Alexander E., Russell, Nigel H., Arunachalam, Meena, Santos, Cedric Dos, Gammon, Guy, Lesegretain, Arnaud, Mires, Derek E., Pham, Hoang, Wang, Yibin, and Khaled, Samer K.
- Abstract
•Quizartinib enabled more patients to undergo hematopoietic stem cell transplantation (HSCT) versus chemotherapy.•Continuation of quizartinib after HSCT was tolerable, with no new safety signals.•Quizartinib before and after HSCT may confer clinical benefits in relapsed/refractory FLT3-ITD acute myelogenous leukemia.
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- 2024
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30. Management of ALL in adults: 2024 ELN recommendations from a European expert panel
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Gökbuget, Nicola, Boissel, Nicolas, Chiaretti, Sabina, Dombret, Herve, Doubek, Michael, Fielding, Adele, Foa, Robin, Giebel, Sebastian, Hoelzer, Dieter, Hunault, Mathilde, Marks, David I., Martinelli, Giovanni, Ottmann, Oliver, Rijneveld, Anita, Rousselot, Philippe, Ribera, Josep, and Bassan, Renato
- Abstract
[Display omitted]
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- 2024
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31. Clinical Outcomes in Patients with FLT3-ITD-Mutated Relapsed/Refractory Acute Myelogenous Leukemia Undergoing Hematopoietic Stem Cell Transplantation after Quizartinib or Salvage Chemotherapy in the QuANTUM-R Trial
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Ganguly, Siddhartha, Cortes, Jorge E., Krämer, Alwin, Levis, Mark J., Martinelli, Giovanni, Perl, Alexander E., Russell, Nigel H., Arunachalam, Meena, Santos, Cedric Dos, Gammon, Guy, Lesegretain, Arnaud, Mires, Derek E., Pham, Hoang, Wang, Yibin, and Khaled, Samer K.
- Abstract
•Quizartinib enabled more patients to undergo hematopoietic stem cell transplantation (HSCT) versus chemotherapy.•Continuation of quizartinib after HSCT was tolerable, with no new safety signals.•Quizartinib before and after HSCT may confer clinical benefits in relapsed/refractory FLT3-ITD acute myelogenous leukemia.
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- 2021
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32. MDM2 inhibition: an important step forward in cancer therapy
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Konopleva, Marina, Martinelli, Giovanni, Daver, Naval, Papayannidis, Cristina, Wei, Andrew, Higgins, Brian, Ott, Marion, Mascarenhas, John, and Andreeff, Michael
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Targeting the interaction between tumor suppressor p53 and the E3 ligase MDM2 represents an attractive treatment approach for cancers with wild-type or functional TP53. Indeed, several small molecules have been developed and evaluated in various malignancies. We provide an overview of MDM2 inhibitors under preclinical and clinical investigation, with a focus on molecules with ongoing clinical trials, as indicated by ClinicalTrials.gov. Because preclinical and clinical exploration of combination strategies is underway, data supporting these combinations are also described. We identified the following molecules for inclusion in this review: RG7112 (RO5045337), idasanutlin (RG7388), AMG-232 (KRT-232), APG-115, BI-907828, CGM097, siremadlin (HDM201), and milademetan (DS-3032b). Information about each MDM2 inhibitor was collected from major congress records and PubMed using the following search terms: each molecule name, “MDM2”and “HDM2.” Only congress records were limited by date (January 1, 2012–March 6, 2020). Special attention was given to available data in hematologic malignancies; however, available safety data in any indication are reported. Overall, targeting MDM2 is a promising treatment strategy, as evidenced by the increasing number of MDM2 inhibitors entering the clinic. Additional clinical investigation is needed to further elucidate the role of MDM2 inhibitors in the treatment of human cancers.
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- 2020
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33. SAKK38/07 study: integration of baseline metabolic heterogeneity and metabolic tumor volume in DLBCL prognostic model
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Ceriani, Luca, Gritti, Giuseppe, Cascione, Luciano, Pirosa, Maria Cristina, Polino, Angela, Ruberto, Teresa, Stathis, Anastasios, Bruno, Andrea, Moccia, Alden A., Giovanella, Luca, Hayoz, Stefanie, Schär, Sämi, Dirnhofer, Stefan, Rambaldi, Alessandro, Martinelli, Giovanni, Mamot, Christoph, and Zucca, Emanuele
- Abstract
Several functional parameters from baseline (18)F-fluorodeoxyglucose positron emission tomography (PET)/computed tomography have been proposed as promising biomarkers of treatment efficacy in diffuse large B-cell lymphoma (DLBCL). We tested their ability to predict outcome in 2 cohorts of DLBCL patients receiving conventional immunochemotherapy (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone [R-CHOP] regimen), either every 14 (R-CHOP14) or 21 days (R-CHOP21). Baseline PET analysis was performed in 141 patients with DLBCL treated with R-CHOP14 in the prospective SAKK38/07 study (NCT00544219) of the Swiss Group for Clinical Cancer Research (testing set). Reproducibility was examined in a validation set of 113 patients treated with R-CHOP21. In the SAKK38/07 cohort, progression-free survival (PFS) at 5 years was 83% for patients with low metabolic tumor volume (MTV) and 59% for those with high MTV (hazard ratio [HR], 3.4; 95% confidence interval [CI], 1.6-7.0; P= .0005), whereas overall survival (OS) was 91% and 64%, respectively (HR, 4.4; 95% CI, 1.9-10; P= .0001). MTV was the most powerful predictor of outcome also in the validation set. Elevated metabolic heterogeneity (MH) significantly predicted poorer outcomes in the subgroups of patients with elevated MTV. A model integrating MTV and MH identified high-risk patients with shorter PFS (testing set: HR, 5.6; 95% CI, 1.8-17; P< .0001; validation set: HR, 5.6; 95% CI, 1.7-18; P= .0002) and shorter OS (testing set: HR, 9.5; 95% CI, 1.7-52; P< .0001; validation set: HR, 7.6; 95% CI, 2.0-28; P= .0003). This finding was confirmed by an unsupervised regression tree analysis indicating that prognostic models based on MTV and MH may allow early identification of refractory patients who might benefit from treatment intensification. This trial was registered at www.clinicaltrials.govas #NCT00544219.
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- 2020
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34. SAKK38/07 study: integration of baseline metabolic heterogeneity and metabolic tumor volume in DLBCL prognostic model
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Ceriani, Luca, Gritti, Giuseppe, Cascione, Luciano, Pirosa, Maria Cristina, Polino, Angela, Ruberto, Teresa, Stathis, Anastasios, Bruno, Andrea, Moccia, Alden A., Giovanella, Luca, Hayoz, Stefanie, Schär, Sämi, Dirnhofer, Stefan, Rambaldi, Alessandro, Martinelli, Giovanni, Mamot, Christoph, and Zucca, Emanuele
- Abstract
Several functional parameters from baseline (18)F-fluorodeoxyglucose positron emission tomography (PET)/computed tomography have been proposed as promising biomarkers of treatment efficacy in diffuse large B-cell lymphoma (DLBCL). We tested their ability to predict outcome in 2 cohorts of DLBCL patients receiving conventional immunochemotherapy (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone [R-CHOP] regimen), either every 14 (R-CHOP14) or 21 days (R-CHOP21). Baseline PET analysis was performed in 141 patients with DLBCL treated with R-CHOP14 in the prospective SAKK38/07 study (NCT00544219) of the Swiss Group for Clinical Cancer Research (testing set). Reproducibility was examined in a validation set of 113 patients treated with R-CHOP21. In the SAKK38/07 cohort, progression-free survival (PFS) at 5 years was 83% for patients with low metabolic tumor volume (MTV) and 59% for those with high MTV (hazard ratio [HR], 3.4; 95% confidence interval [CI], 1.6-7.0; P = .0005), whereas overall survival (OS) was 91% and 64%, respectively (HR, 4.4; 95% CI, 1.9-10; P = .0001). MTV was the most powerful predictor of outcome also in the validation set. Elevated metabolic heterogeneity (MH) significantly predicted poorer outcomes in the subgroups of patients with elevated MTV. A model integrating MTV and MH identified high-risk patients with shorter PFS (testing set: HR, 5.6; 95% CI, 1.8-17; P < .0001; validation set: HR, 5.6; 95% CI, 1.7-18; P = .0002) and shorter OS (testing set: HR, 9.5; 95% CI, 1.7-52; P < .0001; validation set: HR, 7.6; 95% CI, 2.0-28; P = .0003). This finding was confirmed by an unsupervised regression tree analysis indicating that prognostic models based on MTV and MH may allow early identification of refractory patients who might benefit from treatment intensification. This trial was registered at www.clinicaltrials.gov as #NCT00544219.
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- 2020
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35. Prospective assessment of NGS-detectable mutations in CML patients with nonoptimal response: the NEXT-in-CML study
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Soverini, Simona, Bavaro, Luana, De Benedittis, Caterina, Martelli, Margherita, Iurlo, Alessandra, Orofino, Nicola, Sica, Simona, Sorà, Federica, Lunghi, Francesca, Ciceri, Fabio, Galimberti, Sara, Baratè, Claudia, Bonifacio, Massimiliano, Scaffidi, Luigi, Castagnetti, Fausto, Gugliotta, Gabriele, Albano, Francesco, Russo Rossi, Antonella Vita, Stagno, Fabio, di Raimondo, Francesco, D'Adda, Mariella, di Bona, Eros, Abruzzese, Elisabetta, Binotto, Gianni, Sancetta, Rosaria, Salvucci, Marzia, Capodanno, Isabella, Girasoli, Mariella, Coluzzi, Sabrina, Attolico, Immacolata, Musolino, Caterina, Calistri, Elisabetta, Annunziata, Mario, Bocchia, Monica, Stella, Stefania, Serra, Anna, Errichiello, Santa, Saglio, Giuseppe, Pane, Fabrizio, Vigneri, Paolo, Mignone, Flavio, Laginestra, Maria Antonella, Pileri, Stefano Aldo, Percesepe, Antonio, Tenti, Elena, Rosti, Gianantonio, Baccarani, Michele, Cavo, Michele, and Martinelli, Giovanni
- Abstract
In chronic myeloid leukemia (CML) patients, tyrosine kinase inhibitors (TKIs) may select for drug-resistant BCR-ABL1 kinase domain (KD) mutants. Although Sanger sequencing (SS) is considered the gold standard for BCR-ABL1KD mutation screening, next-generation sequencing (NGS) has recently been assessed in retrospective studies. We conducted a prospective, multicenter study (NEXT-in-CML) to assess the frequency and clinical relevance of low-level mutations and the feasibility, cost, and turnaround times of NGS-based BCR-ABL1mutation screening in a routine setting. A series of 236 consecutive CML patients with failure (n = 124) or warning (n = 112) response to TKI therapy were analyzed in parallel by SS and NGS in 1 of 4 reference laboratories. Fifty-one patients (22 failure, 29 warning) who were negative for mutations by SS had low-level mutations detectable by NGS. Moreover, 29 (27 failure, 2 warning) of 60 patients who were positive for mutations by SS showed additional low-level mutations. Thus, mutations undetectable by SS were identified in 80 out of 236 patients (34%), of whom 42 (18% of the total) had low-level mutations somehow relevant for clinical decision making. Prospective monitoring of mutation kinetics demonstrated that TKI-resistant low-level mutations are invariably selected if the patients are not switched to another TKI or if they are switched to a inappropriate TKI or TKI dose. The NEXT-in-CML study provides for the first time robust demonstration of the clinical relevance of low-level mutations, supporting the incorporation of NGS-based BCR-ABL1 KD mutation screening results in the clinical decision algorithms.
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- 2020
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36. Prospective assessment of NGS-detectable mutations in CML patients with nonoptimal response: the NEXT-in-CML study
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Soverini, Simona, Bavaro, Luana, De Benedittis, Caterina, Martelli, Margherita, Iurlo, Alessandra, Orofino, Nicola, Sica, Simona, Sorà, Federica, Lunghi, Francesca, Ciceri, Fabio, Galimberti, Sara, Baratè, Claudia, Bonifacio, Massimiliano, Scaffidi, Luigi, Castagnetti, Fausto, Gugliotta, Gabriele, Albano, Francesco, Russo Rossi, Antonella Vita, Stagno, Fabio, di Raimondo, Francesco, D’Adda, Mariella, di Bona, Eros, Abruzzese, Elisabetta, Binotto, Gianni, Sancetta, Rosaria, Salvucci, Marzia, Capodanno, Isabella, Girasoli, Mariella, Coluzzi, Sabrina, Attolico, Immacolata, Musolino, Caterina, Calistri, Elisabetta, Annunziata, Mario, Bocchia, Monica, Stella, Stefania, Serra, Anna, Errichiello, Santa, Saglio, Giuseppe, Pane, Fabrizio, Vigneri, Paolo, Mignone, Flavio, Laginestra, Maria Antonella, Pileri, Stefano Aldo, Percesepe, Antonio, Tenti, Elena, Rosti, Gianantonio, Baccarani, Michele, Cavo, Michele, and Martinelli, Giovanni
- Abstract
In chronic myeloid leukemia (CML) patients, tyrosine kinase inhibitors (TKIs) may select for drug-resistant BCR-ABL1 kinase domain (KD) mutants. Although Sanger sequencing (SS) is considered the gold standard for BCR-ABL1 KD mutation screening, next-generation sequencing (NGS) has recently been assessed in retrospective studies. We conducted a prospective, multicenter study (NEXT-in-CML) to assess the frequency and clinical relevance of low-level mutations and the feasibility, cost, and turnaround times of NGS-based BCR-ABL1 mutation screening in a routine setting. A series of 236 consecutive CML patients with failure (n = 124) or warning (n = 112) response to TKI therapy were analyzed in parallel by SS and NGS in 1 of 4 reference laboratories. Fifty-one patients (22 failure, 29 warning) who were negative for mutations by SS had low-level mutations detectable by NGS. Moreover, 29 (27 failure, 2 warning) of 60 patients who were positive for mutations by SS showed additional low-level mutations. Thus, mutations undetectable by SS were identified in 80 out of 236 patients (34%), of whom 42 (18% of the total) had low-level mutations somehow relevant for clinical decision making. Prospective monitoring of mutation kinetics demonstrated that TKI-resistant low-level mutations are invariably selected if the patients are not switched to another TKI or if they are switched to a inappropriate TKI or TKI dose. The NEXT-in-CML study provides for the first time robust demonstration of the clinical relevance of low-level mutations, supporting the incorporation of NGS-based BCR-ABL1 KD mutation screening results in the clinical decision algorithms.
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- 2020
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37. The acetyltransferase GCN5 maintains ATRA-resistance in non-APL AML
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Kahl, Melanie, Brioli, Annamaria, Bens, Martin, Perner, Florian, Kresinsky, Anne, Schnetzke, Ulf, Hinze, Anna, Sbirkov, Yordan, Stengel, Sven, Simonetti, Giorgia, Martinelli, Giovanni, Petrie, Kevin, Zelent, Arthur, Böhmer, Frank-Dietmar, Groth, Marco, Ernst, Thomas, Heidel, Florian H., Scholl, Sebastian, Hochhaus, Andreas, and Schenk, Tino
- Abstract
To date, only one subtype of acute myeloid leukemia (AML), acute promyelocytic leukemia (APL) can be effectively treated by differentiation therapy utilizing all-trans retinoic acid (ATRA). Non-APL AMLs are resistant to ATRA. Here we demonstrate that the acetyltransferase GCN5 contributes to ATRA resistance in non-APL AML via aberrant acetylation of histone 3 lysine 9 (H3K9ac) residues maintaining the expression of stemness and leukemia associated genes. We show that inhibition of GCN5 unlocks an ATRA-driven therapeutic response. This response is potentiated by coinhibition of the lysine demethylase LSD1, leading to differentiation in most non-APL AML. Induction of differentiation was not correlated to a specific AML subtype, cytogenetic, or mutational status. Our study shows a previously uncharacterized role of GCN5 in maintaining the immature state of leukemic blasts and identifies GCN5 as a therapeutic target in AML. The high efficacy of the combined epigenetic treatment with GCN5 and LSD1 inhibitors may enable the use of ATRA for differentiation therapy of non-APL AML. Furthermore, it supports a strategy of combined targeting of epigenetic factors to improve treatment, a concept potentially applicable for a broad range of malignancies.
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- 2019
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38. An SDN-enabled multi-layer protection and restoration mechanism.
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Mirkhanzadeh, Behzad, Shakeri, Ali, Shao, Chencheng, Razo, Miguel, Tacca, Marco, Galimberti, Gabriele Maria, Martinelli, Giovanni, Cardani, Marco, and Fumagalli, Andrea
- Subjects
SOFTWARE-defined networking ,COMPUTER network management ,MPLS standard ,OPTICAL transport networks ,WAVELENGTH division multiplexing - Abstract
Transport networks consist of multiple layers, technologies, and areas of deployment. For example, they combine electronic packet and wavelength circuit switching in a single turnkey solution. Conventional solutions have for the longest time segregated the network management and control schemes of these layers, creating silos of operations. This legacy limits flexibility and programmability of extant solutions. In this paper, we describe PROnet, its SDN orchestrator, and a demonstration of its reliability while supporting an advanced manufacturing application running in decentralized mode. PROnet is a two-layer Research and Education Network (REN) under deployed at and around the UT Dallas campus. Resources in the PROnet Ethernet-over-Wavelength Division Multiplexing (WDM) two-layer architecture are managed by a hierarchical SDN orchestrator, which provides two critical functions: 1) on-demand multi-layer path provisioning and 2) coordinated fault handling at both layers. With the first function, the orchestrator automatically provisions optical circuits to efficiently meet the Ethernet flow fault-tolerant requirement as dictated by the application. With the second function, the orchestrator coordinates response procedures at both layers to overcome a first network outage and prepare the network to handle a potential second outage. We refer to this latter function as Multi-layer Protection (implemented at the Ethernet layer) and Restoration (implemented at the WDM layer) mechanism. [ABSTRACT FROM AUTHOR]
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- 2018
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39. Pivekimab Sunirine (PVEK, IMGN632), a CD123-Targeting Antibody-Drug Conjugate, in Combination with Azacitidine and Venetoclax in Patients with Newly Diagnosed Acute Myeloid Leukemia
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Daver, Naval, Montesinos, Pau, Altman, Jessica K., Wang, Eunice S., Martinelli, Giovanni, Roboz, Gail J., Begna, Kebede, Vyas, Paresh, Lunghi, Monia, Platzbecker, Uwe, Burke, Patrick W., Walter, Roland B., Advani, Anjali S., Garciaz, Sylvain, Gastaud, Lauris, Sallman, David A, Pemmaraju, Naveen, Torres, Laura, Abaza, Yasmin, Chan, Onyee, Kantarjian, Hagop M., Oshrine, Benjamin, Du, Yining, Malcolm, Kara, and Sweet, Kendra
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Background
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- 2023
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40. Safety and Tolerability of AZD0466 As Monotherapy for Patients with Advanced Hematologic Malignancies. Results from a Phase I/II Trial
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Arslan, Shukaib, Marconi, Giovanni, Martinelli, Giovanni, Fleming, Shaun, Curti, Antonio, Dinner, Shira N., Blachly, James S, Della Porta, Matteo Giovanni, Bajel, Ashish, Sauer, Tim, Crysandt, Martina, Pigneux, Arnaud, Fransecky, Lars, Baldus, Claudia D, Konopleva, Marina Y., Marmor, Yotvat, Sharma, Shringi, Elgeioushi, Nairouz, Cheung, Patricia, Rowe, Emily, Jahn, Ekaterina, Yu, Ting, Saeh, Jamal, Tibes, Raoul, Cader, Fathima Zumla, and Jain, Nitin
- Abstract
Background:Overexpressionof B-cell lymphoma 2 (BCL-2)-related pro-survival proteins allows cancer cells to evade apoptosis, and targeting these proteins has become important in anticancer therapy. BCL-2 inhibition by venetoclax (VEN) is beneficial in many patients (pts) with acute myeloid leukemia (AML), but resistance is common due to upregulation of other pro-survival proteins such as BCL-extra-large (BCL-xL) and myeloid cell leukemia-1. Dual inhibition of BCL-2/xL has potential for broader activity than agents such as VEN. However, BCL-xL is critical for platelet survival and inhibition can cause dose-limiting thrombocytopenia (Konopleva and Letai. Blood 2018). To broaden therapeutic activity, we developed AZD0466, a drug-dendrimer conjugate in which the BCL-2/xL dual inhibitor AZD4320 is covalently conjugated to a pegylated poly-L-lysine dendrimer and gradually released by hydrolysis. Preclinically, AZD4320 showed greater inhibition of tumor growth than VEN and navitoclax in VEN-resistant xenograft models (Balachander et al. Clin Cancer Res 2020). A first-in-human study (NCT04214093) in pts with advanced solid tumors indicated that AZD0466 is well tolerated with no reported dose-limiting toxicities (DLTs). We present preliminary data from NIMBLE, a Phase I/II trial of AZD0466 in pts with advanced hematologic malignancies (NCT04865419).
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- 2023
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41. Impact-AML: A European Master Framework for Cohort Studies and Pragmatic Clinical Trials in Relapse or Refractory Acute Myeloid Leukemia
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Marconi, Giovanni, Kountouris, Petros, Mayer, Jiri, Bullinger, Lars, Reinhardt, Dirk, Montesinos, Pau, Merli, Pietro, Vignetti, Marco, Dumortier, Jos, Hernández-Rivas, Jesús María, Heuser, Michael, Gerbutavicius, Rolandas, Maturo, Antonio Francesco, D'Errico, Gianni, Nier, Samantha, Zingaretti, Chiara, Azzali, Irene, Campacci, Federica, Mañú-Pereira, Maria Del Mar, Locatelli, Franco, Hehlmann, Rüdiger, Niederwieser, Dietger W., and Martinelli, Giovanni
- Abstract
Background and Significance:
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- 2023
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42. Final Analysis for the Primary End-Point of Gimema AML1718, a Safety Run-in and Phase 2 Open-Label Study of Venetoclax, Fludarabine, Idarubicin and Cytarabine (V-FLAI) in the Induction Therapy of Non Low-Risk Acute Myeloid Leukemia
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Marconi, Giovanni, Piciocchi, Alfonso, Audisio, Ernesta, Papayannidis, Cristina, Guolo, Fabio, Cerrano, Marco, Arena, Valentina, Saveria, Capria, Rondoni, Michela, Della Porta, Matteo Giovanni, Beltrami, Geramana, Bocchia, Monica, Lico, Albana, Giaccone, Luisa, Rossi, Marianna, Califano, Catello, Carrabba, Matteo Giovanni, Cattaneo, Chiara, Frigeni, Marco, Di Chio, Maria Chiara, Serio, Bianca, Freilone, Roberto, Curti, Antonio, Minetto, Paola, Marsili, Giovanni, Minotti, Clara, Zannetti, Beatrice, Cotugno, Francesca, Nanni, Jacopo, Simonetti, Giorgia, Bochicchio, Maria Teresa, Rosellini, Sara, Tedone, Elisabetta, Venditti, Adriano, Lemoli, Roberto Massimo, Vignetti, Marco, Fazi, Paola, and Martinelli, Giovanni
- Abstract
Background:Acute myeloid leukemia (AML) poses significant challenges, especially in intermediate and high-risk cases due to modest rates of complete remission (CR) of 50-60% yelding a 2-year survival probability of about 30-40%. Preliminary results from the AML1718 part 1 trial have demonstrated remarkable improvements, with a composite complete remission (CCR) rate reaching an impressive 82%, and a 1-year survival probability of 72%. These findings represent a substantial advancement compared to historical data. Hereby, we present the comprehensive results of the AML1718 study, with a primary focus on the CCR as the primary endpoint.
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- 2023
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43. Centralized MRD Assessment at Early Timepoints in Gimema AML1718 Trial, a Phase 2 Open-Label Study of Venetoclax, Fludarabine, Idarubicin and Cytarabine (V-FLAI) in the Induction Therapy of Non Low-Risk AML
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Minetto, Paola, Guolo, Fabio, Rosellini, Sara, Piciocchi, Alfonso, Marconi, Giovanni, Audisio, Ernesta, Priolo, Giorgio, Papayannidis, Cristina, Martelli, Maurizio, Paoloni, Francesca Paola, Bocchia, Monica, Lanza, Francesco, Lico, Albana, Ciceri, Fabio, Della Porta, Matteo Giovanni, Frigeni, Marco, Giaccone, Luisa, Beltrami, Germana, Borlenghi, Erika, Di Chio, Maria Chiara, Selleri, Carmine, Crea, Enrico, Urbino, Irene, Sartor, Chiara, Minotti, Clara, Arena, Valentina, Nanni, Jacopo, Simonetti, Giorgia, Bochicchio, Maria Teresa, Saglio, Giuseppe, Venditti, Adriano, Vignetti, Marco, Fazi, Paola, Tedone, Elisabetta, Martinelli, Giovanni, and Lemoli, Roberto M.
- Abstract
Background:New therapeutic strategies are strongly needed to improve the prognosis of high risk Acute Myeloid Leukemia (AML) patients, such as combination of novel agents and conventional chemotherapy. The Italian GIMEMA AML1718 trial (NCT03455504) investigate the safety and efficacy of the BCL-2 inhibitor venetoclax (VEN) in combination with intensive fludarabine-based induction (FLAI) [fludarabine 30 mg/sqm from day 1 to day 5, cytarabine 2000 mg/sqm from day 1 to day 5, and idarubicin 8 mg/sqm on days 1, 3 and 5] as first-line therapy for newly diagnosed non low-risk ELN AML patients. Results from the Planned Interim Analysis of Safety Run-in and Part 1 (early expansion cohorts) were presented at the last 2022 ASH Meeting. Median overall survival (OS) was not reached; probability of 12-month OS was 76%. Median disease-free survival was not reached. With a median follow-up of 10.5 months, 28 patients (49%) received allogeneic stem cell transplantation (HSCT) in first complete remission (CR).
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- 2023
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44. Pre-Existing Myeloid Subclones May Account for a Subset of Acute Myeloid Leukemias and Myelodysplastic Neoplasms in Patients with Pre-Existing or Contemporary Lymphoid Disorders
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Mattei, Agnese, Marconi, Giovanni, Ronconi, Sonia, Cangini, Delia, Ceccolini, Michela, Cerchione, Claudio, Zacheo, Irene, Giannini, Maria Benedetta, Norata, Marianna, Martinelli, Giovanni, Ferrari, Anna, Bochicchio, Maria Teresa, Ghetti, Martina, Marchesini, Matteo, Simonetti, Giorgia, Musuraca, Gerardo, and Nappi, Davide
- Abstract
Background:
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- 2023
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45. Novel Mechanisms of Venetoclax Resistance in Acute Myeloid Leukemia Based on Genomic Rearrangements
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Zacheo, Irene, Ferrari, Anna, Fonzi, Eugenio, Bochicchio, Maria Teresa, Capirossi, Giorgia, Nanni, Jacopo, Paganelli, Matteo, Servilli, Chiara, Ledda, Lorenzo, Ghetti, Martina, Jandoubi, Mouna, Marchesini, Matteo, Mattei, Agnese, Martinelli, Giovanni, Marconi, Giovanni, and Simonetti, Giorgia
- Abstract
Introduction:
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- 2023
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46. GIMEMA AML1310 trial of risk-adapted, MRD-directed therapy for young adults with newly diagnosed acute myeloid leukemia
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Venditti, Adriano, Piciocchi, Alfonso, Candoni, Anna, Melillo, Lorella, Calafiore, Valeria, Cairoli, Roberto, de Fabritiis, Paolo, Storti, Gabriella, Salutari, Prassede, Lanza, Francesco, Martinelli, Giovanni, Luppi, Mario, Mazza, Patrizio, Martelli, Maria Paola, Cuneo, Antonio, Albano, Francesco, Fabbiano, Francesco, Tafuri, Agostino, Chierichini, Anna, Tieghi, Alessia, Fracchiolla, Nicola Stefano, Capelli, Debora, Foà, Robin, Alati, Caterina, La Sala, Edoardo, Fazi, Paola, Vignetti, Marco, Maurillo, Luca, Buccisano, Francesco, Del Principe, Maria Ilaria, Irno-Consalvo, Maria, Ottone, Tiziana, Lavorgna, Serena, Voso, Maria Teresa, Lo-Coco, Francesco, Arcese, William, and Amadori, Sergio
- Abstract
We designed a trial in which postremission therapy of young patients with de novo acute myeloid leukemia (AML) was decided combining cytogenetics/genetics and postconsolidation levels of minimal residual disease (MRD). After induction and consolidation, favorable-risk patients (FR) were to receive autologous stem cell transplant (AuSCT) and poor-risk patients (PR) allogeneic stem cell transplant (AlloSCT). Intermediate-risk patients (IR) were to receive AuSCT or AlloSCT depending on the postconsolidation levels of MRD. Three hundred sixty-one of 500 patients (72%) achieved a complete remission, 342/361 completed the consolidation phase and were treatment allocated: 165 (48%) to AlloSCT (122 PR, 43 IR MRD-positive) plus 23 rescued after salvage therapy, for a total of 188 candidates; 150 (44%) to AuSCT (115 FR, 35 IR MRD-negative) plus 27 IR patients (8%) with no leukemia-associated phenotype, for a total of 177 candidates. Overall, 110/177 (62%) and 130/188 (71%) AuSCT or AlloSCT candidates received it, respectively. Two-year overall (OS) and disease-free survival (DFS) of the whole series was 56% and 54%, respectively. Two-year OS and DFS were 74% and 61% in the FR category, 42% and 45% in the PR category, 79% and 61% in the IR MRD-negative category, and 70% and 67% in the IR MRD-positive category. In conclusion, AuSCT may still have a role in FR and IR MRD-negative categories. In the IR MRD-positive category, AlloSCT prolongs OS and DFS to equal those of the FR category. Using all the available sources of stem cells, AlloSCT was delivered to 71% of the candidates.This trial was registered at www.clinicaltrials.gov as #NCT01452646 and EudraCT as #2010-023809-36.
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- 2019
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47. GIMEMA AML1310 trial of risk-adapted, MRD-directed therapy for young adults with newly diagnosed acute myeloid leukemia
- Author
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Venditti, Adriano, Piciocchi, Alfonso, Candoni, Anna, Melillo, Lorella, Calafiore, Valeria, Cairoli, Roberto, de Fabritiis, Paolo, Storti, Gabriella, Salutari, Prassede, Lanza, Francesco, Martinelli, Giovanni, Luppi, Mario, Mazza, Patrizio, Martelli, Maria Paola, Cuneo, Antonio, Albano, Francesco, Fabbiano, Francesco, Tafuri, Agostino, Chierichini, Anna, Tieghi, Alessia, Fracchiolla, Nicola Stefano, Capelli, Debora, Foà, Robin, Alati, Caterina, La Sala, Edoardo, Fazi, Paola, Vignetti, Marco, Maurillo, Luca, Buccisano, Francesco, Del Principe, Maria Ilaria, Irno-Consalvo, Maria, Ottone, Tiziana, Lavorgna, Serena, Voso, Maria Teresa, Lo-Coco, Francesco, Arcese, William, and Amadori, Sergio
- Abstract
We designed a trial in which postremission therapy of young patients with de novo acute myeloid leukemia (AML) was decided combining cytogenetics/genetics and postconsolidation levels of minimal residual disease (MRD). After induction and consolidation, favorable-risk patients (FR) were to receive autologous stem cell transplant (AuSCT) and poor-risk patients (PR) allogeneic stem cell transplant (AlloSCT). Intermediate-risk patients (IR) were to receive AuSCT or AlloSCT depending on the postconsolidation levels of MRD. Three hundred sixty-one of 500 patients (72%) achieved a complete remission, 342/361 completed the consolidation phase and were treatment allocated: 165 (48%) to AlloSCT (122 PR, 43 IR MRD-positive) plus 23 rescued after salvage therapy, for a total of 188 candidates; 150 (44%) to AuSCT (115 FR, 35 IR MRD-negative) plus 27 IR patients (8%) with no leukemia-associated phenotype, for a total of 177 candidates. Overall, 110/177 (62%) and 130/188 (71%) AuSCT or AlloSCT candidates received it, respectively. Two-year overall (OS) and disease-free survival (DFS) of the whole series was 56% and 54%, respectively. Two-year OS and DFS were 74% and 61% in the FR category, 42% and 45% in the PR category, 79% and 61% in the IR MRD-negative category, and 70% and 67% in the IR MRD-positive category. In conclusion, AuSCT may still have a role in FR and IR MRD-negative categories. In the IR MRD-positive category, AlloSCT prolongs OS and DFS to equal those of the FR category. Using all the available sources of stem cells, AlloSCT was delivered to 71% of the candidates.This trial was registered at www.clinicaltrials.govas #NCT01452646 and EudraCT as #2010-023809-36.
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- 2019
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48. Response of high-risk MDS to azacitidine and lenalidomide is impacted by baseline and acquired mutations in a cluster of three inositide-specific genes
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Follo, Matilde Y., Pellagatti, Andrea, Armstrong, Richard N., Ratti, Stefano, Mongiorgi, Sara, De Fanti, Sara, Bochicchio, Maria Teresa, Russo, Domenico, Gobbi, Marco, Miglino, Maurizio, Parisi, Sarah, Martinelli, Giovanni, Cavo, Michele, Luiselli, Donata, McCubrey, James A., Suh, Pann-Ghill, Manzoli, Lucia, Boultwood, Jacqueline, Finelli, Carlo, and Cocco, Lucio
- Abstract
Specific myeloid-related and inositide-specific gene mutations can be linked to myelodysplastic syndromes (MDS) pathogenesis and therapy. Here, 44 higher-risk MDS patients were treated with azacitidine and lenalidomide and mutations analyses were performed at baseline and during the therapy. Results were then correlated to clinical outcome, overall survival (OS), leukemia-free-survival (LFS) and response to therapy. Collectively, 34/44 patients were considered evaluable for response, with an overall response rate of 76.25% (26/34 cases): 17 patients showed a durable response, 9 patients early lost response and 8 patients never responded. The most frequently mutated genes were ASXL1, TET2, RUNX1, and SRSF2. All patients early losing response, as well as cases never responding, acquired the same 3 point mutations during therapy, affecting respectively PIK3CD (D133E), AKT3 (D280G), and PLCG2 (Q548R) genes, that regulate cell proliferation and differentiation. Moreover, Kaplan–Meier analyses revealed that this mutated cluster was significantly associated with a shorter OS, LFS, and duration of response. All in all, a common mutated cluster affecting 3 inositide-specific genes is significantly associated with loss of response to azacitidine and lenalidomide therapy in higher risk MDS. Further studies are warranted to confirm these data and to further analyze the functional role of this 3-gene cluster.
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- 2019
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49. Chronic myeloid leukemia stem cells
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Houshmand, Mohammad, Simonetti, Giorgia, Circosta, Paola, Gaidano, Valentina, Cignetti, Alessandro, Martinelli, Giovanni, Saglio, Giuseppe, and Gale, Robert Peter
- Abstract
Chronic myeloid leukemia (CML) is caused by BCRABL1in a cell with the biological potential, intrinsic or acquired, to cause leukemia. This cell is commonly termed the CML leukemia stem cell (LSC). In humans a CML LSC is operationally-defined by ≥1 in vitro or in vivo assays of human leukemia cells transferred to immune-deficient mice. Results of these assays are sometimes discordant. There is also the unproved assumption that biological features of a CML LSC are stable. These considerations make accurate and precise identification of a CML LSC difficult or impossible. In this review, we consider biological features of CML LSCs defined by these assays. We also consider whether CML LSCs are susceptible to targeting by tyrosine kinase inhibitors (TKIs) and other drugs, and whether elimination of CML LSCs is needed to achieve therapy-free remission or cure CML.
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- 2019
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50. Intrabone transplant provides full stemness of cord blood stem cells with fast hematopoietic recovery and low GVHD rate: results from a prospective study
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Bonifazi, Francesca, Dan, Elisa, Labopin, Myriam, Sessa, Mariarosaria, Guadagnuolo, Viviana, Ferioli, Martina, Rizzi, Simonetta, De Carolis, Sabrina, Sinigaglia, Barbara, Motta, Maria Rosa, Bontadini, Andrea, Giudice, Valeria, Martinelli, Giovanni, Arpinati, Mario, Cavo, Michele, Bonafé, Massimiliano, and Storci, Gianluca
- Abstract
Umbilical Cord Blood (UCB) represents a valid option for patients with hematopoietic malignancies lacking an HLA matched donor. To overcome the limitation of the low stem cell dose of UCB, the intrabone (IB) route has been proposed. We report the results of a prospective study on a poor-prognosis cohort of 23 patients receiving intrabone single UCB transplant (Clinicaltrials.gov NCT00886522). Cumulative incidence of hematological recovery at day 90 was 82 ± 9% (ANC > 0.5 × 109/L) and 70 ± 10% (platelet > 50 × 109/L) and correlated with CD34 + cells in the graft. NRM was 20 ± 9%. No severe aGVHD and only one extensive cGVHD occurred, with fast immune reconstitution. To test the hypothesis that the direct IB injection could affect the expression of stem cells regulatory pathways, CD34 + cells from BM aspirates at day + 10, + 20, + 30, processed in hypoxic conditions mimicking the BM-microenvironment (7%pO2), were studied for the expression of c-Mpl, Notch1 and CXCR4. We found that the expression of c-Mpl in CD34 + cells at day + 10 significantly correlated with hematological recovery. In conclusion, IB-UCB transplant success is associated with low incidence of GVHD and high-speed platelet recovery; intrabone route may preserve full hematopoietic stemness by direct delivery of UCB stem cells into the hypoxic HSC niche.
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- 2019
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