HEMATOPOIETIC STEM CELL TRANSPLANTATION IN HIVINFECTED PATIENTS Chiara

HEMATOPOIETIC STEM CELL TRANSPLANTATION IN HIV-INFECTED PATIENTS Chiara Cattaneo Hematology - ASST Spedali Civili Brescia, Italy

HIV infections and hematological malignancies • HIV-infected patients still have a risk of developing non-Hodgkin lymphoma (NHL) 24. 2 times greater than does the general population • The risk of Hodgkin lymphoma (HL) is increased nearly 15 -fold • Patients with HIV also remain at increased risk of acute leukemia, myelodysplastic syndromes and myeloma Alvarnas Blood 2017

HAART: impact on cancer epidemiology Non Hodgkin Lymphoma Non AIDS defining cancer Cobucci J Infect Public Health 2015

Chemotherapy in HIV-pos patients: feasibility Standard chemotherapy feasible • • Well tolerated Few infectious events High Dose chemotherapy + • • Navarro Br J Haematol 2001 Autologous stem cell transplantation Allogeneic stem cell transplantation

Hematopoietic stem cell transplantation in HIV-infected patients • Autologous SCT (ASCT) – Lymphoprolipherative disesases • Salvage treatment • First line treatment – Acute Leukemia – Myeloma • Allogeneic SCT • HIV cure

Hematopoietic stem cell transplantation in HIV-infected patients • Autologous SCT (ASCT) – Lymphoprolipherative disesases • Salvage treatment • First line treatment – Acute Leukemia – Myeloma • Allogeneic SCT • HIV cure

16 relapsed/refractory HIV-ly • 8 NHL • 8 HL 10 pts received transplant • Prompt engrafment • Acceptable toxicity 7 CR out of 9 evaluable pts

Efficacy of ASCT in relapsed/refractory HIV-related ly N°Pts NHL/HL Status at salvage tx Status at PBSCT Outcome Relapse Survival (follow-up) Gabarre (Haematologica, 2004) 14 (8/6) Rel 1(9) Rel>1 (3) Ref (2) CR 1 (4) CR>1 (4) PR (3) NR (3) CR 10 NR 4 4/10 40% OS 36% (32 m) Krishnan (Blood, 2005) 20 (18/2) “High risk” CR 1 (4) CR>1 (2) PR (5) Rel 1 (7) Rel>1 (2) Chemosens. CR 19 Early death 1 (MOF) 2/19 11% OS 85% PFS 85% (32 m) Serrano (Exp Hematol, 2005) 11 (8/3) _ High risk CR 1 (6) CR 2 (3) PR (2) CR 10 NR 1 1/10 10% OS 81% EFS 65% (28 m) Spitzer (BBMT, 2008) 20 (15/5) Ref and Rel CR (6) PR (2) Chemosens. (12) CR 10 at +100 PD 9 at +100 Early death 1 (VOD) OS 74% EFS 50% (6 m) Re (Blood 2009) PR (1) 27 Rel 1 (11) Rel>1 (3) (19/8) Ref (12) Alvarnas (Blood 2016) 40 (25/15) CR>1 (30) PR (9) Rel/PD (1) Chemosens. CR 24 NR 3 3/24 12% OS 75% PFS 76% (44 m) Chemosens. CR 36 PR 1 Early death 1 2/49 (5%) OS 82% PFS 80% (24 m)

Toxicity of ASCT in relapsed/refractory HIV-related ly Regimen (N° of Pts) Tox-WHO Gabarre BEAM (6) “Mucositis” (Haematologic HDC+TBI (8) a, 2004) Infections bacterial pneum. (1) minor bacterial infections (13) OI Toxic death CMV viremia (2) (1 + aspergillosis) NO HZ (2) CMV viremia (2) CMV retinitis (1) PCP (2) 1/20 (5%) (MOF) bacteremia (6) bacterial pneum. (2) lung aspergillosis (1) Cl. colitis (2), FUO (3) HZ (2) CMV viremia (1) NO Bacteremia (4) FUO (6) Cl. colitis (3) IVU (1) HSV (1) CMV infection (4) 1/20 (5%) (VOD) Re (Blood 2009) mucositis-III-IV (10) BEAM (27) hepatic-III (2) DMSO reaction (1) bacteremias (2) Other bacterial (3) P. aeruginosa pneum (1) Cl. colitis (1), FUO (9) Esoph candidiasis (2) HZ (7) CMV viremia (4) CMV retinitis (1) NO Alvarnas (Blood 2016) Thrombosis (2) Enteritis (1) BEAM (40) Hyperglicemia (1) Appendicitis (1) hyponatremia (1) AMI (1) bacterial (25) viral (22) fungal (6) protozoa (2) Esoph candidiasis (1) 2/40 (5. 1%) (1 MOF, 1 IFI) Krishnan (Blood, 2005) hepatic III-IV (3) bacteremia (4) CBV (17) mucositis III-IV(3) VRE (BAL) (1) HDC+TBI (3) MOF (1), engraft. syndr. (2) FUO (8) interstitial pneum(1) Pericarditis (1) Serrano (Exp Hematol, 2005) mucositis II (7) BEAM (10) hepatic II (1) BEAC (1) subdural hematoma (1) mucositis III (1) VOD (1) Spitzer Low BU + Cy Thromboembolism (1) (20) Thr. microangiopaty (1) (BBMT, 2008) Hemorrage (4) Mental st change (2)

The GICAT experience Relapsed/refractory HIV-Ly Re Blood 2009

EBMT retrospective study: 53 patients within each cohort → 66% non-Hodgkin lymphoma and 34% Hodgkin lymphoma Non relapse mortality within the 1 st year after ASCT: 8% (HIV-ly group) vs 2% (HIV-neg group) (NS)

‘Patients with HIV-related lymphomas should not be precluded from participating in AHCT clinical trials’

Immune reconstitution after ASCT: no differences between HIV-pos and HIV-neg Thymic function recovery Simonelli Clin Infect Dis 2010

B- and T-cell recovery HIV-pos and HIV-neg lymphoma undergoing ASCT Bertoli Sci Rep 2016

• Retrospective multicenter study (10 European centers) • Success (collection ≥ 2 x 10^6 CD 34/kg) vs Failure (<2 x 10^6 CD 34/kg) • 113/155 (73%) succesful mobilization • Optimal yeld (≥ 5 x 10^6 CD 34/kg) 74/155 (48%)

ASCT as 1 st line High risk non Hodgkin Lymphoma • 20 DLCL • 6 Plasmablastic • 1 Anaplastic ITT (27 pts) Transplanted pts (16 pts) Re Bone Marrow Transplant 2018

ASCT outcome according to disease status 62 HIV-ly (Brescia) Re ASH 2018

A particular setting: plasmablastic lymphoma • HIV-associated • Frequent oral cavity involvement • CD 20 neg • Poor prognosis Transplanted pts (n=10) Entire cohort (n=20) Cattaneo Leuk Lymphoma 2014 Al-Malki Biol Blood Marrow Transplant 2014

Acute leukemia in HIV-pos patients • About 2 -fold risk increase than general population Median OS: 11 months • Sporadic reports/ retrospective studies for HIV-AML • Intensive chemotherapy feasible and high percentage of remission, but limited survival • Low CD 4 count predictive of poor response Sutton Br J Haematol 2001 Aboulafia AIDS 2002 Evans leuk Lymph 2012 Hagiwara AIDS 2013

Acute leukemia in HIV-positive patients: the REL’s experience (1994 -2011) 14 HIV-AL/HR-MDS pts • 3 patients received only palliative care • Induction treatment: 9 pts → 3 ASCT → 3 Allo. SCT • 1 front-line allogeneic stem cell transplantation • 1 azacytidine (HRMDS) Pagani SIE 2013

REL study: outcome of HIV-pos AL 3 -y survival 20% Pagani SIE 2013

REL study: toxicity of HIV-pos AL 2 Toxic deaths → 1 induction → 1 allo. SCT

Multiple myeloma in HIV-pos patients • HIV-infected patients have increased risks for plasma cell disorders • Incidence of monoclonal gammopathy: 3. 8% to 26% (vs 3. 2% HIV-neg population) • SIRs for MM range between 2. 6 and 5 in different epidemiological studies Coker Biomark res 2013

MM in HIV-pos: ASCT • Few data in literature, mainly sporadic • Feasible 5 -y OS: HIV-pos 61% vs HIV-neg 63% • Japanese registry: similar OS in HIV-pos and HIVneg pts Yoshinaga Biol Blood Marrow Transplant 2018

Hematopoietic stem cell transplantation in HIV-infected patients • Autologous SCT (ASCT) – Lymphoprolipherative disesases • Salvage treatment • First line treatment – Acute Leukemia – Myeloma • Allogeneic SCT • HIV cure

Allo. SCT in HIV-pos patients: data from the CIBMTR 23 patients (1987 -2003) • 10 Non Hodgkin Lymphoma • 7 Acute Leukemia • 2 Chronic Myelogenous Leukemia • 1 Severe Aplastic Anemia • 1 Erytrocyte inherited disorders 2 -y OS: 30% † 17 pts only 1 disease relapse Gupta Biol Blood Bone Marrow Transplant 2009

Allo. SCT in HIV-pos patients: impact of HAART pts 25 -years experience (1983 -2008) Hütter Clin Exp Immunol. 2011

Allo. SCT in HIV-infected patients: the spanish experience • 1999 -2018 • 22 high risk HM • All patients c. ART • NRM 14% at 12 mo • Relapse 24% at 24 mo Median OS and EFS: 46% • Grade II-IV a. Gv. HD: 40% • 68% of patients with infectious complications viral infections as the most frequent cause Kwon AIDS 2019

Allogeneic hematopoietic cell transplant (allo. HCT) for hematologic malignancies in human immunodeficiency virus infected (HIV) patients (pts): Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0903)/AIDS Malignancy Consortium (AMC-080) trial Ambinder RF, et al. J Clin Oncol 2017; 35(15 suppl): 7006 • • First prospective cooperative group trial of matched related or unrelated allogeneic allo. SCT (c. ART-treatable HIV infection and standard indication for Allo) 17 pts (2012 -2015): acute myeloid leukemia (9), acute lymphoblastic leukemia (2), myelodisplasia (2) or lymphoma (4) Full ablative (8) or reduced-intensity allo. HCT (investigator’s discretion); c. ART not interrupted NRM at 100 days (primary endpoint): 0% At 100 days: 13 CR; 4 Rel/PD (8 complete chimerism) Grade II-IV GVHD 41%; Infections in 11 pts (3 gr 2; 8 gr 3) 1 year OS 57% (median follow-up 24 ms) Cause of death: disease relapse (5), a. GVHD (1), liver failure (1), ARDS (1) Allo. SCT should be considered for HIV patients with treatable HIV-infection with standard indications for allo. SCT

Hematopoietic stem cell transplantation in HIV-infected patients • Autologous SCT (ASCT) – Lymphoprolipherative disesases • Salvage treatment • First line treatment – Acute Leukemia – Myeloma • Allogeneic SCT • HIV cure

Blocking chemokine coreceptors Kiem Cell Stem cell 2012

BERLIN PATIENT • 40 -year-old HIV-AML patient • Allo. SCT at first and second relapse • Stem cells from a donor who was homozygous for CCR 5 delta 32

LONDON PATIENT • HIV-Hodgkin lymphoma patient • Reduced intensity regimen • CCR 5Δ 32/Δ 32 donor • Antiretroviral therapy interrupted 16 months after transplantation • HIV-1 remission maintained over a further 18 months

Gene therapy for HIV cure gene-modified autologous hematopoietic stem cells Kiem Cell Stem cell 2012

Conclusions (I) • High dose therapy and autologous stem cell transplantation feasible and well tolerated in the HAART era • HIV-related lymphoma and other hematological malignancies • Similar outcome to HIV-negative patients

Conclusions (II) • Selected HIV-infected patients with hematologic malignancies for allo. HSCT when indicated, in expert centers • Homozygous for CCR 5 D 32 preferred donors HIV cure • Gene therapy as a future approach for HIVcure

Thanks to… Alessandro Re Chiara Pagani Giuseppe Rossi Hematology ASST-Spedali Civili Brescia

Acute myeloid leukemia in HIV-positive patients: the REL’s experience Pagani SIE 2013 Time HIV-LA (yrs) HAART >6 mo CD 4+/ul HIV load (cp/ml) Previous AIDS np 7, 7 nr nr 46, XY np 8, 9 yes 600 14000 no complex np nr nr <100 nr nr 46 XY, +8 np nr no 132 nr nr B-ALL 46, XY bcr/abl neg 2, 9 yes 372 0 yes (NHL) 33/M T-ALL 46 XY bcr/abl neg 10, 4 yes 640 37000 no 7 53/M AML inv(16) np 2, 3 yes 2048 0 yes (Kaposi sarcoma) 8 41/F t(7; 11) np 21, 7 yes 139 <50 no 9 49/M nr increased WT 1 2, 3 yes 270 400, 857 no 10 60/M 46 XY bcr/abl neg 0 no 100 1395 no 11 56/M complex FLT 3, inv(16), RUNX 1 T neg 11, 5 yes nr 0 no 12 47/M np np 13, 96 yes 176 nr yes (NHL) 13 59/M -5, -7, -13, -19 np 9, 2 yes 950 <70 no 14 48/M 46 XY np 24, 5 yes 300 0 no Pt Age/Sex Diagnosis 1 28/M AML np 2 45/M 3 44/F 4 34/M AML B lymphoblastic leukemia/lymphoma AML 5 44/M 6 Tp-related myeloid neoplasms-MDS AML with MDS related changes B-ALL AML with MDS related changes Myelodysplastic syndrome with del(5 q) RAEB 1 AML Cytogenetics Molecular genetics