Post‐remission intensive treatment after induction chemotherapy is feasible in selected elderly patients with acute myeloid leukemia and age ≥75 years: A retrospective analysis of the <scp>R</scp>ete <scp>E</scp>matologica <scp>L</scp>ombarda
Authors: Massimo Bernardi, Patrizia Zappasodi, Nicola Fracchiolla, Laura Marbello, Elisabetta Todisco, Chiara Pagani, Matteo Carrabba, Marianna Rossi, Francesca Guidotti, Valentina Mancini, Armando Santoro, Erika Borlenghi, Fabio Ciceri, Enrica Morra, Giuseppe Rossi
Journal: American Journal of Hematology (2015)

The prognosis of elderly pts with AML is poor with 2- and 5-year overall survival (OS) rates of approximately 10% and 2%, respectively 1. In elderly pts, the complete remission (CR) rate after induction is around 50% and the relapse rate is of almost 90%. To prevent relapse, pts in CR should receive some form of postremission treatment 2. There are no comparative trials defining which postremission treatments benefit older pts. Moreover, allogeneic haematopoietic stem cell transplantation is still offered to a minority of pts over 65 years of age 3. Recently, published guidelines define age 75 as the upper limit to consider pts fit for intensive chemotherapy (IC) 4. Anyway, it is becoming evident that age alone is not always appropriate to select pts to receive IC. AML pts older than 75 and even 80 years old, otherwise healthy, can receive an intensive therapeutic approach 5. The Italian regional haematological network "Rete Ematologica Lombarda" has recently promoted a survey among regional centers to explore the local real-life experience in management of elderly AML pts. Six centers referred detailed data of 34 consecutive AML pts ≥75 yrs old, considered "fit" for aggressive treatment and that received at least one cycle of induction chemotherapy, between March 2005 and March 2014 (Table 1). All induction cycles included standard-dose cytarabine plus an anthracyclin or mitoxantrone. Postremission treatments included intermediate cytarabine (IDaraC) in all but two cases. General criteria for selection of "fit" pts were PS (ECOG) ≤2, renal and hepatic parameters <2 UNL, left ventricular ejection fraction ≥50%, absence of uncontrolled infections and/or concomitant malignancies. Overall, 44 induction cycles were administered, 30 with standard drug dosage (SD) to 24 pts (3 + 7, 2 + 7, MICE, ICE, FLAGIDA) and 12 with reduced dosage (RD) to 10 pts (1 + 5). One patient died for treatment-related cause (TRM 4%) and 4 pts for disease progression, within 25 days after start of induction. Overall CR rate was 56% (19 pts), 75% (18 pts) after SD and 10% (1 patient) after RD induction, respectively. Of the 19 pts in CR 18 (95%) received 32 postremission cycles of chemotherapy. Twenty-seven cycles containing IDaraC (6–10 gr/sqm total dose/cycle) were administered to 16 pts, 2 pts received a SD postremission cycle. Three pts received an autologous transplantation. The mean number of postremission cycles per patient was 1.7 (range 1–4), TRM was 11% (2/18 pts), 6% if related to the total number of postremission cycles. Relapse incidence was 72% (13 pts). At last, FU (median 612 days, 302–1238) 6 pts were alive (33%), 3 (17%) in CR. Median OS from diagnosis of all 34 pts and of the 18 pts who received any postremission intensive treatment were 325 (5–2023) and 788 (169–2023) days, respectively (Fig. 1). Median DFS was 208 (27–1871) days (18 pts) (Fig. 1). A landmark analysis at day 30 after start of induction showed that 29 pts were alive with an estimated projected survival advantage for the 18 pts who reached the CR and received a postremission intensive treatment compared to the 11 pts who received supportive and palliative care only until death: median OS was 786 and 147 days, respectively (P = 0.004), hazard ratio of mortality was 3.25 (95% CI 1.66–15.56) for patients receiving supportive and palliative care vs. those receiving postremission therapy (Fig. 2). A) OS from diagnosis of pts who obtained the CR and received at least one cycle of post-remission chemotherapy; B) DFS of the same pts. OS of 29 pts from day 30 after start of induction: 18 pts who obtained the CR and received an intensive post-remission treatment (2 SD cycles, 16 IDaraC cycles) are compared to 11 pts who did not obtain the CR (10 pts) or who did not receive any post-remission intensive treatment after obtaining CR (1 patient) (P = 0.004). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] Our data and recently published studies suggest that intensive therapeutic approaches are feasible in selected older AML pts aged ≥75 yrs and may improve their OS. Older pts with AML and good PS (ECOG 0-2) should be fully evaluated for appropriate therapeutic decision 5, 6. The REL includes several Italian health centers of excellence and Haematologic and BM Transplant Units, located within a regional area (Regione Lombardia), with homogeneous economic resources and scientific and academic background. Nevertheless, our analysis revealed that IC approaches were heterogeneous in terms of induction chemotherapy and postremission cytarabine dosage and number of cycles. This confirms that there is a need for shared guidelines among haematologic centers to define appropriate management of elderly AML pts. In the present study, treatment-related toxicities were well tolerated and most pts in CR (16 out of 19) could receive at least one cycle with IDaraC. Moreover, multiple postremission cycles with cytarabine dosages from 6 to 10 gr/sqm/cycle have been feasible. Our pts received higher dosages than those usually reported in elderly pts (500 to 1000 mg/sqm/day for 3–5 days), with tolerable toxicities. Prolonged OS has been obtained in pts who reached the CR and received postremission treatments. The median OS > 2 yrs in a population of pts with a median age of 76 yrs represents a significative gain of survival, compared to the expected one with only palliative and supportive care or low-dose chemotherapy. It should be noted that only 15% of pts evaluated at diagnosis had poor risk karyotype, whereas the described incidence of poor risk cytogenetic abnormalities in AML pts older than 70 is ≥50%. This suggests that our series was highly selected, not only on fitness but also on biological grounds. In conclusion, age should not be per se an exclusion criterion to IC, which remains the cornerstone of treatment for elderly pts when they are fit and have favorable disease characteristics. Pts who will plausibly benefit from IC should be identified by readily available genetic testing. The therapeutic strategy should include intensive postremission treatment with intermediate- or even high-dose cytarabine. Strategies to prevent relapse, including new agents with low toxicity profile, should be explored. Crocchiolo R, MD, IRCCS Humanitas, Rozzano (Milan), for review of statistical analysis. Massimo Bernardi1*, Patrizia Zappasodi2, Nicola Fracchiolla3, Laura Marbello4, Elisabetta Todisco5, Chiara Pagani6, Matteo Carrabba1, Marianna Rossi2, Francesca Guidotti3, Valentina Mancini4, Armando Santoro5, Erika Borlenghi6, Fabio Ciceri1, Enrica Morra4, and Giuseppe Rossi6 1Haematology and Bone Marrow Transplant Unit, IRCCS San Raffaele Scientific Institute, via Olgettina 60, Milan, Italy 2Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Viale Camillo Golgi 19, Pavia, Italy 3Haematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, via Francesco Sforza 35, Milan, Italy 4Department of Haematology, Niguarda Ca' Granda Hospital, Piazza Dell'ospedale Maggiore 3, Milan, Italy 5Haematology Unit, Humanitas Cancer Center, via Manzoni 56, Rozzano, Milan, Italy 6Haematology Unit, Spedali Civili, Piazzale Spedali Civili 1, Brescia, Italy