Basilico C. M.

Bonuomo V.

Buzzatti E.

Candoni A.

Cattaneo C.

Cerqui E.

Dargenio M.

De Marchi R.

Del Principe M. I.

Delia M.

Dragonetti G.

Fanin R.

Fracchiolla N.

Griguolo D.

Lazzarotto D.

Lessi F.

Luppi M.

Mellillo L.

Nadali G.

Olivieri A.

Pagano L.

Papayannidis C.

Pasciolla C.

Piccini M.

Piccioni A. L.

Riva M.

Sarlo C.

Sartor C.

Sciume M.

Spadea A.

Stulle M.

Tisi M. C.

English

Archivio istituzionale della ricerca - Università degli Studi di Udine

Prospective multicenter study on infectious complications and clinical outcome of 230 unfit acute myeloid leukemia patients receiving first-line therapy with hypomethylating agents alone or in combination with Venetoclax

CANDONI A.

Archivio istituzionale della ricerca - Università di Modena e Reggio Emilia

CO R R E S POND EN C EProspective multicenter study on infectious complications andclinical outcome of 230 unfit acute myeloid leukemia patientsreceiving first-line therapy with hypomethylating agents aloneor in combination with VenetoclaxTo the Editor:Hypomethylating agents (HMAs) are an important therapeutic optionfor older patients with acute myeloid leukemia (AML) and havebecome the backbone for combination regimens s1–s5. However,there are very limited real-life prospective studies investigating theinfectious complications in AML treated with HMAs ± Venetoclax(VEN) outside of clinical trials.1–5In this prospective study, designed and conducted by the SEIFEMgroup (Sorveglianza Epidemiologica Infezioni nelle Emopatie), we eval-uated the infectious complications in a cohort of patients unfit forintensive chemotherapy, treated in first-line with HMAs alone or incombination with VEN, immediately after the introduction of thiscombination in clinical practice in Italy (between 2019 and 2020).Methods are reported in the Appendix S1.We enrolled 230 consecutive patients with a median age of75 years (range 25–94); 157 patients (68%) had ≥2 relevant comor-bidities. Patients' and AML characteristics are reported in Table S1. Ofthe 230 cases, 132 (57%) received first-line therapy with a combina-tion of HMAs+VEN, while 98 (43%) were treated with HMA mono-therapy. A total of 1552 HMAs cycles were administered (888/1552with HMAs+VEN) with a mean number of cycles/patients of6.7 ± 5.5. Notably, 82.5% (1281/1552) of cycles were administered inan outpatient setting. Table S2A shows the characteristics and dura-tion of therapy. The best responses achieved with HMAs treatmentwere CR in 44% of cases with an ORR of 61% (72% for HMAs+VENand 46% for HMAs alone, p = .0007)-Table S2B. After a medianfollow-up of 10 months (range 1–24) from the start of HMAs therapy,144 (63%) patients had died and 86 (37%) were alive. The 1-yearOS probability of the entire patient population was 46% with amedian OS of 10.3 months (11 months in the HMAs+VEN cohortand 9 months in the HMAs alone cohort; p = ns)-Figure 1A. The pri-mary causes of death were AML progression (42%), infection(26%-37/144), infection+AML (24%-35/144), and other causes(8%-12/144). The Infectious Related Mortality (IRM) was 26%, and19/144 (13%) patients died of infectious complication while in AMLresponse (16 in HMAs+VEN group and only 3 in the HMAs group;p = .005)-Table S2C.Microbiologically or radiologically documented infectious compli-cations (at least one) occurred in 160/230 (70%) of patients(Figure 1B). A total of 272 episodes of infection were reported in160 patients (1.7 episodes per patient). The most common infectionswere pneumonia (104 episodes-42%), followed by bacteremia (89 epi-sodes-33%), abscess or cellulitis (28 episodes-10%), and urinary tractinfections (20 episodes-7%). In addition, 14 cases of COVID-19 werereported (5% of documented infections). Febrile neutropenia (one ormore episodes) occurred in 38% of patients. Patients treated withHMAs+VEN had more documented infectious complications thanthose treated with HMAs alone (99/132–75% vs. 61/98–62%,p = .04) but, according to the type of hypomethylating agent used(AZA or DEC), no differences were found in the two groups (HMAs+VEN or HMAs alone). Indeed, in the HMAs+VEN group, at least1 infection was documented in 79% of DEC + VEN-treated patientsand in 72% of AZA + VEN-treated patients (p = .41). In the HMA sin-gle agent group, at least 1 infection was documented in 68% of DEC-treated patients and in 59% of AZA-treated patients (p = .51).Table S3A summarizes the characteristics of pneumonia and bacter-emia, which were the most common infections. As reported, 42% ofpatients had at least one episode of pneumonia (a total of 104 epi-sodes of pneumonia in 97 patients), mainly occurring within the first3 treatment cycles (65%). The etiology of the pneumonia was bacterialin 46% of cases (47/104) or fungal in 25% of cases (26/104). At diag-nosis of pneumonia, the median neutrophil count was 250/μl (range0–19 500/μl). Notably, 86% of patients with pneumonia required hos-pitalization, and the related death rate (as a primary cause) was 16%(15/97 patients). The characteristics of bacteremias are reported inTable S3B. Overall, 29% of the entire patient population had at leastone episode of bacteremia (with a total of 89 bacteremias in67 patients), occurring mainly within the first three cycles of therapy.The most frequently isolated bacteria were Escherichia coli and Staph-ylococcus spp. At the onset of bacteremic fever, the median neutrophilcount was 190/μl (range 0–20 000/μl); 94% of patients with bacter-emia were hospitalized, and the related death rate was 33%(29/89 patients). Regarding antimicrobial prophylaxis in the entirepatient cohort, 115/230 (50%) patients received at least anti-bacterialprophylaxis (mainly with levofloxacin-102/115) and 126/230 (55%)received at least anti-fungal mold-active prophylaxis (mainly withposaconazole-105/126). Only 90/230 patients (39%) received bothprophylaxis (anti-bacterial+anti-mold). Interestingly, only 28% (13/47)Received: 25 November 2022 Revised: 4 January 2023 Accepted: 12 January 2023DOI: 10.1002/ajh.26846Am J Hematol. 2023;1–4. wileyonlinelibrary.com/journal/ajh © 2023 Wiley Periodicals LLC. 1 10968652, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ajh.26846 by CochraneItalia, Wiley Online Library on [12/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons LicenseF IGURE 1 (A) Overall survival: (a) All 230 cases. (b) OS in patients treated with HMAs alone versus HMAs+VEN. (B) (a) Number of patientswith one more infectious episodes (clinically or radiologically documented). (b) 272 documented infections. (C) Factors affecting OS in univariateand multivariate analysis.2 CORRESPONDENCE 10968652, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ajh.26846 by CochraneItalia, Wiley Online Library on [12/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons Licenseof patients with bacterial pneumonia had received anti-bacterial pro-phylaxis, compared to 63% (84/133) of patients who did not developany pneumonia (133/230) during treatment (p = .0002). In addition,only 31% (8/26) of patients with fungal pneumonia had receivedmold-active prophylaxis compared to 61% (81/133) of those who didnot develop any fungal pneumonia (p = .008). A total of 28/67patients (31.5%) with bacteremia had received anti-bacterial prophy-laxis, compared to 90/163 patients (55%) without bacteremia(p = .08). Table S4 shows the factors affecting OS for all 230 cases. Inmultivariate analysis, the only factor affecting OS in the entire patientpopulation and in the HMAs alone subgroup, was the achievement ofAML response during therapy (p < .0001, 95% CI 4.26–8.95 andp < .0001, 95% CI 4.63–16.51, respectively). However, in the HMAs+VEN group, the OS was influenced not only by the achievement ofAML response but also by the development of pneumonia (p < .0001,95% CI 3.53–9.9, and p = .046, 95% CI 0.4-1.03, respectively)(Figure 1C). The following baseline factors were tested, in univariateand multivariate models, as possible factors affecting infection onset(predictive or protective factors) during HMAs±VEN therapy: antimi-crobial prophylaxis (anti-bacterial+anti-mold), age ≥ 75 years, leuko-penia at onset (WBC < 2000/μl), leukocytosis at onset(WBC > 30 000/μl), marrow blasts percentage (>or <50%), molecularcytogenetic risk (high risk vs. other) and secondary AML. Univariateand multivariate analysis showed secondary AML as a predictivefactor for infection (p = .05 in univariate analysis and p = .02 inmultivariate analysis), while combined antimicrobial prophylaxis(anti-bacterial+anti-mold agent) was a protective factor against pneu-monia development (p = .0003 in univariate analysis and p = .0001 inmultivariate analysis).Although relevant to patients' outcomes, the issue of infectiouscomplications in AML treated with HMAs±VEN, has not been pro-spectively investigated, and only retrospective studies are available.s6–s10 Some information on infectious complications is obtainedfrom pivotal studies, which, however, did not include infections ineither primary or secondary trial endpoints and, therefore, reportedincomplete data. 2,s5 Recently, a few large retrospective observa-tional studies on infectious complications in patients treated withHMAs+VEN, primarily focusing on invasive fungal infections (IFIs),have been published. However, these studies are not easily compara-ble due to differences in patients' characteristics and endpoints (somereporting only the incidence of fungal or bacterial infections). Further-more, available information on prophylaxis (anti-bacterial, antifungal,or antiviral) and infection features (type of complication, timing ofevent, type of isolates, related mortality) is often incomplete. In addi-tion, all these retrospective studies include patients who were treatedwith HMAs + VEN not only at diagnosis but also in a relapsed/refrac-tory AML setting, thus making the treated population veryheterogeneous.3–5 The results of these studies are reported in theSupplementary Material.The analysis of our study population (100% receiving a first-linetherapy) reveals that infectious complications are very common (at leastone infectious complication in 70% of patients), as reported in theVIALE-A trial (documented infections in 84% of patients), accounting forthe primary cause of death in 26% of cases and being a contributingcause (associated with AML) in another 24%. Furthermore, in our study,infectious complications were found to affect the patients' outcome andsurvival, especially in the HMAs + VEN treated group. Indeed, in multi-variate analysis, one of the factors that significantly and adverselyaffected OS in patients treated with the combo therapy, was the pres-ence of pneumonia. Regrettably, a high rate of deaths in the CR phasewas reported in the HMAs+VEN cohort (16/78–21%), 94% of whomwere due to pneumonia or other infectious complications. Consequently,even if this prospective study confirms, in a real-life setting, a higheroverall response rate (ORR) of HMAs + VEN therapy compared tomonotherapy (ORR 72% vs. 46%), this finding did not translate into a sig-nificant OS benefit (median OS of 11 months in the HMA + VEN groupversus 9 months in the HMAs monotherapy group; p = ns). However, itmust be underlined that the patients included in this prospective obser-vational study were the first cohort of patients treated with the HMAs+ VEN combination in Italy. Therefore, the observed unsatisfactoryresults in terms of OS also probably reflect an early learning phase in themanagement of this treatment, in which the high risk of serious infec-tious complications was probably not properly assessed, being prophy-laxis of complications is very heterogeneous and, perhaps, not alwaysappropriate. In fact, we found that only 28% (13/47) of patients with abacterial pneumonia had received anti-bacterial prophylaxis, only 31%(8/26) of patients with fungal pneumonia had received mold-active pro-phylaxis and only 31.5% (28/67) of patients with bacteremia hadreceived anti-bacterial prophylaxis. Notably, the multivariate analysisdemonstrated a significant preventive role against pneumonia for antimi-crobial prophylaxis, while secondary AML represents a predictive factorfor infection (this is in line with the results of Lee et al.).5In conclusion, the results of this multicentric, prospective studyconfirm a higher ORR rate in patients treated with HMAs+VEN com-pared to HMAs alone (p = .0001). However, we found a high rate ofinfectious complications with a higher infection-related deaths inresponder patients who were treated with the HMAs+VEN combina-tion (p = .005). Multivariate analysis showed a significant preventiverole against pneumonia of antimicrobial prophylaxis (anti-bacterial+mold-active prophylaxis). From a practical point of view, this studyshows that infectious mortality adversely impacts the OS of this frailAML population and highlights the relevance of anti-infective prophy-laxis during HMAs+VEN therapy in AML.2,6DATA AVAILABILITY STATEMENTAll relevant data are within the paper. The full database are availablefrom the Division of Hematology, University of Modena (IT) (contact:acandoni@unimore.it) for researchers who meet the criteria for accessto confidential data.Anna Candoni1 , Davide Lazzarotto2 , Cristina Papayannidis3,Matteo Piccini4, Giampaolo Nadali5, Michelina Dargenio6 ,Marta Riva7, Nicola Fracchiolla8, Lorella Mellillo9, Giulia Dragonetti10,Maria Ilaria Del Principe11 , Chiara Cattaneo12, Manuela Stulle13,Crescenza Pasciolla14, Roberta De Marchi15, Mario Delia16 , MariaChiara Tisi17, Valentina Bonuomo5 , Mariarita Sciumè7 ,CORRESPONDENCE 3 10968652, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ajh.26846 by CochraneItalia, Wiley Online Library on [12/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons LicenseAntonio Spadea18 , Chiara Sartor3, Davide Griguolo13,Elisa Buzzatti11 , Claudia Maria Basilico19, Chiara Sarlo20, AnnaLina Piccioni21, Elisa Cerqui12, Federica Lessi22, Attilio Olivieri23,Renato Fanin2, Mario Luppi1, Livio Pagano101Section of Hematology, Department of Medical and Surgical Sciences,Azienda Ospedaliera Universitaria di Modena, Università di Modena eReggio Emilia, Modena, Italy2Division of Hematology and Stem Cell Transplantation, ASUFC,University of Udine, Udine, Italy3Institute of Hematology and Medical Oncology "L. and A. Seragnoli",University of Bologna, Bologna, Italy4Division of Hematology, Azienda Ospedaliero-Universitaria Careggi,Florence, Italy5Division of Hematology, AOUI, Policlinico GB Rossi, Verona, Italy6Division of Hematology, Ospedale Vito Fazzi, Lecc, Italy7Dipartimento di Ematologia ed Oncologia, Niguarda Cancer Center ASSTGrande Ospedale Metropolitano, Milan, Italy8U.O. Oncoematologia, Fondazione IRCCS Ca' Granda OspedaleMaggiore Policlinico, University of Milan, Milan, Italy9Division of Hematology, Foggia and IRCCS Casa Sollievo dellaSofferenza, San Giovanni Rotondo, Italy10Division of Hematology, Polo Onco-Ematologico, Fondazione PoliclinicoA. Gemelli-IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy11Hematology, Fondazione Policlinico Tor Vergata, Rome, Italy12Section of Hematology, Spedali Civili, Brescia, Italy13Division of Hematology, ASUGI, Trieste, Italy14Haematology Unit, IRCCS Istituto Tumori “Giovanni Paolo II”,Bari, Italy15Onco Hematology, Department of Oncology, Veneto Institute ofOncology IOV, IRCCS, Padova, Italy16Hematology and Bone Marrow Transplantation Unit, AziendaOspedaliero-Universitaria Consorziale Policlinico-University of Bari,Bari, Italy17Cell Therapy and Hematology, San Bortolo Hospital, Vicenza.7 U.O. Oncoematologia, Fondazione IRCCS Ca' Granda OspedaleMaggiore Policlinico, University of Milan, Milan, Italy18Hematology and Stem Cell Transplant Unit, IRCCS Regina ElenaNational Cancer Institute,Rome, Italy19Division of Hematology, ASST Sette Laghi, Ospedale Circolo eFondazione Macchi, Varese, Italy20Hematology and Stem Cell Transplantation Unit, University CampusBio-Medico, Rome, Italy21Dipartimento di Ematologia, Azienda Ospedaliera San GiovanniAddolorata, Rome, Italy22Hematology Unit, Department of Medicine (DIMED), AziendaOspedaliera Universitaria di Padova, Padova, Italy23Division of Hematology, Azienda Ospedaliero-Universitaria OspedaliRiuniti di Ancona, Ancona, ItalyCorrespondenceAnna Candoni, Section of Hematology, Department of Medical andSurgical Sciences, University of Modena and Reggio Emilia, AOUPoliclinico, Modena, Italy.Email: acandoni@unimore.itORCIDAnna Candoni https://orcid.org/0000-0003-4436-1310Davide Lazzarotto https://orcid.org/0000-0001-7568-9656Michelina Dargenio https://orcid.org/0000-0003-0924-4629Maria Ilaria Del Principe https://orcid.org/0000-0002-3958-0669Mario Delia https://orcid.org/0000-0002-6486-8912Valentina Bonuomo https://orcid.org/0000-0001-6491-8337Mariarita Sciumè https://orcid.org/0000-0001-7958-4966Elisa Buzzatti https://orcid.org/0000-0002-3478-5083Livio Pagano https://orcid.org/0000-0001-8287-928XREFERENCES1. DiNardo CD, Wei AH. How I treat acute myeloid leukemia in the era ofnew drugs. Blood. 2020;135(2):85-96.2. DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and Venetoclax inpreviously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617-629.3. Aldoss I, Dadwal S, Zhang J, et al. Invasive fungal infections in acutemyeloid leukemia treated with Venetoclax and hypomethylatingagents. Blood Adv. 2019;3(23):4043-4049.4. On S, Rath CG, Lan M, et al. Characterisation of infections in patientswith acute myeloid leukaemia receiving Venetoclax and a hypomethy-lating agent. Br J Haematol. 2022;197(1):63-70.5. Lee R, Cho SY, Lee DG, et al. Infections of Venetoclax-based chemo-therapy in acute myeloid leukemia: rationale for proper antimicrobialprophylaxis. Cancer. 2021;13(24):6285.6. Pollyea DA, Bixby D, Perl A, et al. NCCN guidelines insights: acutemyeloid leukemia, version 2.2021. J Natl Compr Cancer Netw. 2021;19(1):16-27.SUPPORTING INFORMATIONAdditional supporting information can be found online in the Support-ing Information section at the end of this article.4 CORRESPONDENCE 10968652, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ajh.26846 by CochraneItalia, Wiley Online Library on [12/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

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Prospective multicenter study on infectious complications and clinical outcome of 230 unfit acute myeloid leukemia patients receiving first-line therapy with hypomethylating agents alone or in combination with Venetoclax

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