Acute Leukemia and High-Risk Myelodysplastic Syndromes in HIV-Positive Patients: 25-Years' Experience of the Rete Ematologica Lombarda (REL)
Authors: Cattaneo Chiara , Bernardi Massimo , Mancini Valentina , Pagani Chiara , Fumagalli Monica , Zappasodi Patrizia , Borlenghi Erika , Re Alessandro , Ciceri Fabio , Sciumé Margherita , Cairoli Roberto , Rossi Giuseppe 
Published: November 2019

Introduction. Acute leukemia (AL) and high-risk myelodysplastic syndromes (HR-MDS) are relatively uncommon among HIV-positive (HIV-pos) patients (pts) and epidemiologic studies are very limited. A dismal outcome for these patients has been reported in the past; however more recently an improvement of prognosis was observed using intensive approaches, such as allogeneic stem cell transplantation (alloSCT) (Kwon, AIDS 2019). In order to better define the clinical characteristics of AL/HR-MDS HIV-pos pts, the feasibility of any specific treatment and the outcome in this setting, we evaluated all HIV-pos AL and HR-MDS pts diagnosed at 5 Hematology Centers participating to Rete Ematologica Lombarda (REL). Patients and Methods. We asked to the Centers to retrospectively report all cases of HIV-pos adult pts with AL or HR-MDS. We sent a database asking information about the characteristics of hematological disease, HIV infection, therapy, toxicities and outcome of pts. AL and MDS were classified according to WHO classification. The response to therapy was defined by European Leukemia Net criteria. Results. Between 1994 and 2019, 23 pts have been retrieved: 3 affected by HR-MDS, 15 by acute myeloid leukemia (AML) and 5 by acute lymphoblastic leukemia (ALL). Median age at AL/MDS diagnosis was 49y (range 28-67), M/F ratio 17/6. Median CD4 count was 336/mcl (range 50-2048). HIV infection was antecedent to AL/MDS diagnosis in 20/21 evaluable cases, with a median duration of 115 months (range 0-396); these pts were already on HAART at AL/MDS diagnosis. In 6 (29%) pts AIDS was also documented (1 Kaposi sarcoma, 1 P. jirovecii pneumonia and 4 non Hodgkin B-cell lymphoma). Six (30%) of the 20 evaluable cases had an adverse cytogenetics (complex karyotype), while only 1 pt showed a favorable karyotype (inv16). NPM1 mutation was observed in 2 AML cases, FLT3 ITD and p53 mutation in 1 case each. No bcr/abl rearrangement was observed in ALL cases. Three pts (13%) did not receive any treatment due to poor performance status (1 ALL, 2 AML) and died of progressive disease after a median of 2 months (mo, 0.5-2). Two HR-MDS pts received azacytidine but they rapidly progressed after 2 courses and died at +7 and +8mo respectively. Eighteen pts were treated with intensive therapy: 17 underwent induction chemotherapy (cht) and 1 alloSCT upfront. All the pts received HAART during AL/MDS treatment. Eleven out of the 17 pts (65%) receiving induction cht achieved a complete remission (CR); 4 pts received further induction cht, which was successful in 2/4 (50%) the overall CR rate being therefore 76.5%. A further pt received venetoclax+azacytidine as fourth-line treatment and achieved a morphological CR. Ten pts (9 AML and 1 HR-MDS) underwent stem cell transplantation at first-line: 3 autologous (ASCT) and 7 allogeneic. Overall 5 out of 13 (38%) pts achieving CR after induction cht relapsed; only one of the 5 receiving salvage treatment achieved a durable CR and proceeded to salvage alloSCT. Five pts (22%) died of toxicity: 2 (1 P, jirovecii pneumonia and 1 septic shock) during induction cht (2/17, 12%), 1 during aplastic phase after ASCT (hemorrhagic stroke), 2 after alloSCT (1 aGVHD, 1 infection); overall, SCT therapy-related morality was 3/10 (30%). After a median follow up of 21mo, 10 pts are alive in CR, with a median overall survival (OS) of 17mo and a 2y OS of 41.2±22.7SEM. A trend for a better OS was observed in pts with AL/HR-MDS diagnosis in the last years (2y OS: 2011-2019: 64.2% vs 1994-2010 27.3%, p=0.12) (Fig.1), even if median age was significantly higher in the second period (55.5y vs 44.5y, p=0.02). A complex karyotype was predictive of poor outcome in pts evaluable for cytogenetics (45% vs 10%, p=0.04), whereas no correlation between age, CD4 count, HIV duration and OS was observed. Conclusions. Intensive chemotherapy and stem cell transplantation are feasible and effective in AL/HR-MDS HIV-pos pts, with an acceptable toxicity profile, similar to the HIV-neg counterpart. The more frequent curative intent approach to AL HIV-pos pts is probably the main responsible for the improved survival in the last years also in the elderly; antiviral, antibiotic and antifungal prophylactic strategy, together with a prompt diagnosis and a careful management of infectious events, should be carefully considered in this setting of pts. HIV infection responsive to HAART should no longer be considered a contraindication to standard AL/HR-MDS treatment.

Disclosures
Rossi: Sandoz: Honoraria; Daiichi-Sankyo: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Mundipharma: Honoraria; BMS: Honoraria.