Post-Transplant Cyclophosphamide and Tacrolimus-Mycophenolate Mofetil Combination Governs GVHD and Immunosuppression Need, Reducing Late Toxicities in Allogeneic Peripheral Blood Hematopoietic Cell Transplantation from HLA-Matched Donors

Fabrizio Carnevale-Schianca, Daniela Caravelli, Susanna Gallo, Paolo Becco, Luca Paruzzo, Stefano Poletto, Alessandra Polo, Monica Mangioni, Milena Salierno, Massimo Berger, Rosanna Pessolano, Francesco Saglio, Daniela Gottardi, Delia Rota-Scalabrini, Giovanni Grignani, Marco Fizzotti, Ivana Ferrero, Pio Manlio Mirko Frascione, Lorenzo D'Ambrosio, Valentina Gaidano, Loretta Gammaitoni, Dario Sangiolo, Andrea Saglietto, Elena Vassallo, Alessandro Cignetti, Massimo Aglietta, Franca Fagioli, Fabrizio Carnevale-Schianca, Daniela Caravelli, Susanna Gallo, Paolo Becco, Luca Paruzzo, Stefano Poletto, Alessandra Polo, Monica Mangioni, Milena Salierno, Massimo Berger, Rosanna Pessolano, Francesco Saglio, Daniela Gottardi, Delia Rota-Scalabrini, Giovanni Grignani, Marco Fizzotti, Ivana Ferrero, Pio Manlio Mirko Frascione, Lorenzo D'Ambrosio, Valentina Gaidano, Loretta Gammaitoni, Dario Sangiolo, Andrea Saglietto, Elena Vassallo, Alessandro Cignetti, Massimo Aglietta, Franca Fagioli

Abstract

Combined direct antineoplastic activity and the long-lasting immunological effects of allogeneic hematopoietic cell transplant (HCT) can cure many hematological malignancies, but broad adoption requires non-relapse mortality (NRM) rates and graft-versus-host disease (GVHD) control. Recently, posttransplant cyclophosphamide (PTCy) given after a bone marrow transplant significantly reduced GVHD-incidence, while PTCy given with tacrolimus/mofetil mycophenolate (T/MMF) showed activity following allogeneic peripheral blood stem cell transplantation (alloPBSCT). Here, we report the experience of a larger cohort (85 consecutive patients) and expanded follow-up period (03/2011-12/2019) with high-risk hematological malignancies who received alloPBSCT from Human-Leukocyte-Antigens HLA-matched unrelated/related donors. GVHD-prophylaxis was PTCy 50 mg/kg (days+3 and +4) combined with T/MMF (day+5 forward). All patients stopped MMF on day+28 with day+110 = median tacrolimus discontinuation. Cumulative incidences were 12% for acute and 7% for chronic GVHD- and no GVHD-attributed deaths. For surviving patients, the 12, 24, and 36-month probabilities of being off immunosuppression were 92, 96, and 96%, respectively. After a 36-month median follow-up, NRM was 4%; median event-free survival (EFS) and overall survival (OS) had yet to occur. One- and two-year chronic GVHD-EFS results were 57% (95% CI, 46-68%) and 53% (95% CI, 45-61%), respectively, with limited late infections and long-term organ toxicities. Disease relapse caused the most treatment failures (38% at 2 years), but low transplant toxicity allowed many patients (14/37, 38%) to receive donor lymphocyte infusions as a post-relapse strategy. We confirmed that PTCy+T/MMF treatment effectively prevented acute and chronic GVHD and limited NRM to unprecedented low rates without loss of disease control efficacy in an expanded patient cohort. This trial is registered at U.S. National Library of Medicine as #NCT02300571.

Keywords: allogeneic hematopoietic cell transplantation; graft-versus-host disease; immunosuppression modulation; long term outcomes; post-transplant cyclophosphamide.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Transplant-related complications. (A) Cumulative incidence of acute graft-versus-host disease (aGVHD). (B) Cumulative incidence of chronic graft-versus-host disease (cGVHD). (C) Non-relapse mortality.
Figure 2
Figure 2
Immunosuppression Burden (A) Reversible multistate modeling the instantaneous probability of being in 1 of 3 states: (1) alive, off immunosuppression (off immunosuppression, yellow zone), (2) alive, on immunosuppression (immunosuppression, green zone), or (3) dead (death, orange zone). All patients begin in state 1 on day +5 after transplant, after receiving cyclophosphamide 50 mg/kg on days +3 and +4. Patients may have reversible transition between states (1) and (2) but death was an absorbing state. (B) Nonreversible multistate modeling the instantaneous probability of being in 1 of five states: (1) alive, on immunosuppression (IS), (2) alive, off first IS, (3) alive, on second IS, (4) alive, off subsequent IS, or (5) Dead.
Figure 3
Figure 3
Kaplan–Maier survival curves. (A) Overall survival (OS) in the overall population. (B) Event-free survival (EFS) in the overall population (C) cGVHD-EFS in the overall population, (D) Relapse-rate in the overall population (blue line) vs. CR (green line) p = 0.336), (E) OS stratified by depth of response (CR (blue line) > not CR (green line), p = 0.008). (F) EFS stratified by depth of response (CR (blue line) > not CR (green line), p = 0.003).

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Source: PubMed

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