Publications by authors named "Luca Castagna"

164 Publications

The association of graft-versus-leukemia effect and graft-versus host disease in haploidentical transplantation with post-transplant cyclophosphamide for AML.

Bone Marrow Transplant 2022 Jan 13. Epub 2022 Jan 13.

Division of Hematology, Chaim Sheba Medical Center, Tel-Hashomer and Sackler Medical School Tel-Aviv University, Tel-Aviv, Israel.

The association of graft-versus-host disease (GVHD) and graft-versus-leukemia effect after stem-cell transplantation (SCT) is well established but with limited data in the setting of haploidentical SCT (haploSCT) with post-transplant cyclophosphamide (PTCy). We used a series of landmark analyses to investigate this association in 805 AML patients following haploSCT. On day +100, 707 patients were alive and leukemia-free, 500 had no prior acute GVHD, 137 had acute GVHD grade II and 70 had grade III-IV. Subsequent relapse rates were 20.3%, 23.2% and 15.0%, respectively (P = 0.52). Subsequent non-relapse mortality (NRM) was 8.6%, 17.8% and 38.6%, respectively (P < 0.0001). Leukemia-free survival (LFS) was 71.0%, 59.0% and 46.3%, respectively (P < 0.0001). Multivariate analysis showed that acute GVHD grade II and grade III-IV were not associated with relapse (HR 1.21, P = 0.37 and HR 1.03, P = 0.94), but were associated with increased NRM (HR 2.09, P = 0.005 and HR 6.41, P < 0.0001) and lower LFS (HR 1.47, P = 0.02 and HR 2.59, P = < 0.0001). Chronic GVHD was not associated with subsequent relapse. Extensive chronic GVHD was associated with higher NRM (HR 6.72, P < 0.0001) and inferior LFS (HR 3.29, P = < 0.0001). GVHD of any type or grade is not associated with lower relapse after haploSCT with PTCy. Severe forms are associated with higher NRM and lower survival.
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http://dx.doi.org/10.1038/s41409-021-01493-6DOI Listing
January 2022

Risk Factors for early CMV reactivation and Impact of early CMV reactivation on Clinical Outcomes after T Cell-replete Haploidentical Transplantation with Post-transplant Cyclophosphamide.

Transplant Cell Ther 2021 Dec 23. Epub 2021 Dec 23.

Bone Marrow Transplantation Unit, Humanitas Clinical and Research Center, Rozzano, Italy.

Background: Risk factors for cytomegalovirus (CMV) reactivation and the impact of CMV reactivation on patients' outcomes have been extensively investigated after matched related or unrelated donor transplants, but little is known in the setting of haploidentical stem cell transplant (Haplo-SCT) with post-transplant cyclophosphamide (PT-Cy), where recipients are supposed to be more severely immune-compromised.

Methods: We retrospectively analyzed a cohort of 554 consecutive patients undergoing Haplo-SCT with PT-Cy at 3 different centers.

Results: Early CMV reactivation, taking place within the first 120 days after transplant, occurred in 242 patients for an estimated cumulative incidence of 44%. Out of those patients, 74 (30%) had recurrent CMV and 20 (8%) CMV disease. By multivariable analysis, positive recipient CMV serostatus (Hazard ratio [HR] > 2.5, p<0.001), disease histology (lymphoid vs myeloid: HR 0.66, p=0.003) and increasing recipient age (HR 1.01, p=0.015) were independent predictors of CMV reactivation. At four months landmark analysis, CMV reactivation was associated with higher 1-year and 5-year cumulative incidence of non-relapse mortality (NRM) relative to patients without reactivation: 13% vs 5% and 22% vs 9%, respectively (p<0.001). By multivariable analysis, CMV reactivation was an independent negative predictor of non-relapse mortality (NRM) (HR 2.69, p<0.001) and was close to statistical significance for overall survival (OS) (HR: 1.38, p=0.062).

Conclusions: Our results suggest that CMV reactivation plays an important role at determining NRM. Because patient CMV serostatus is the main predictor of CMV reactivation, it should be considered when evaluating strategies for preventing CMV reactivation.
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http://dx.doi.org/10.1016/j.jtct.2021.12.014DOI Listing
December 2021

Outcome of Allogeneic Transplantation for Mature T-cell Lymphomas: Impact of Donor Source and Disease Characteristics.

Blood Adv 2021 Dec 3. Epub 2021 Dec 3.

University of Heidelberg, Heidelberg, Germany.

Mature T-cell lymphomas constitute the most common indication of allogeneic hematopoietic cell transplantation (allo-HCT) in lymphomas. Large studies evaluating contemporary outcomes of allo-HCT in mature T-cell lymphomas, relative to commonly used donor sources are not available. Included in this registry study were adult patients who had undergone allo-HCT for anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma (AITL), or peripheral T-cell lymphoma-NOS (PTCL-NOS) between 2008 and 2018. HCT platforms compared were post-transplant cyclophosphamide-based haploidentical (haplo-) HCT, matched sibling donor (MSD) HCT, matched unrelated donor HCT with in-vivo T-cell depletion (MUD TCD+), and MUD HCT without TCD (MUD TCD-). Co-primary endpoints were overall survival (OS) and progression-free survival (PFS); secondary endpoints included non-relapse mortality (NRM), and relapse/progression incidence (RI). 1942 patients were eligible (haplo-HCT 237; MSD 911; MUD-TCD+ 468; MUD TCD- 326). Cohorts were comparable for baseline characteristics except higher proportions of patients with decreased performance status (PS) and marrow graft recipients in the haplo-HCT group. On univariate and multivariate comparisons, OS and PFS, RI, and NRM were not significantly different between haplo-HCT, MSD, MUD-TCD+, and MUD-TCD- cohorts, with 3-year OS and PFS of 60%, 63%, 59%, and 64%; and 50%, 50%, 48%, and 52%, respectively. Significant predictors of inferior OS and PFS on multivariate analysis were active disease status at HCT and decreased PS. AITL was associated with significantly reduced relapse risk and better PFS compared to PTCL-NOS. Allo-HCT can provide durable PFS in patients with mature T-cell lymphoma. Outcomes of haplo-HCT were comparable to that of matched donor allo-HCT.
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http://dx.doi.org/10.1182/bloodadvances.2021005899DOI Listing
December 2021

Post-Transplantation Cyclophosphamide for Graft-versus- Host Disease Prophylaxis in Multiple Myeloma Patients Who Underwent Allogeneic Hematopoietic Cell Transplantation: First Comparison by Donor Type. A Study from the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation.

Transplant Cell Ther 2021 Dec 17;27(12):999.e1-999.e10. Epub 2021 Sep 17.

Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.

Graft-versus-host disease (GVHD) remains among the major causes of treatment failure in patients with multiple myeloma (MM) undergoing allogeneic hematopoietic cell transplantation (allo-HCT). The use of post-transplantation cyclophosphamide (PT-Cy) is now a well-established and widely used method for GVHD prophylaxis after HLA haploidentical HCT. However, the rationale for using PT-Cy in the setting of matched donor transplantation is less apparent, given the lesser degree of bidirectional alloreactivity. In this retrospective study, we investigated the role of PT-Cy as GVHD prophylaxis in patients with multiple myeloma underoing allo-HCT, among different donor types, to determine cumulative incidence of acute and chronic GVHD and impact on engraftment, progression-free survival (PFS), GVHD-free/relapse- free survival (GRFS), overall survival (OS), and NRM A total of 295 patients with MM underwent allo-HCT using grafts from a matched related donor (MRD; n = 67), matched unrelated donor (MUD; n = 72), mismatched related or unrelated donor (MMRD/MMUD, 1 antigen; n = 27), or haploidentical donor (haplo; n = 129) using PT-Cy between 2012 and 2018. In addition to PT-Cy, agents used in GVHD prophylaxis included calcineurin inhibitors in 239 patients (81%), with mycophenolate mofetil in 184 of those 239 (77%). For grade II-IV acute GVHD, the cumulative incidence at day +100 was 30% (95% confidence interval [CI], 25% to 36%), 9% (95% CI, 5% to 12%) for grade III-IV acute GVHD, and 27% (95% CI, 21% to 32%) for chronic GVHD (limited, 21%; extensive, 6%), with no differences by donor type. The median time to neutrophil engraftment was 19d (95% CI, 18-19), with no significant difference by donor type. The median time to platelet engraftment was delayed in haploidentical donor graft recipients (27 days versus 21 days; P < .001). Two-year OS, PFS, GRFS, and NRM were 51% (95% CI, 45% to 58%), 26% (95% CI, 20% to 32%), 24% (95% CI, 18% to 30%), and 19% (95% CI, 14% to 24%), respectively, with no significant difference between different donor types. In multivariable analyses, compared with the haplo donors, the use of MRDs was associated with significantly better OS (hazard ratio [HR], 0.6; 95% CI, 0.38 to 0.95; P = .029), and the use of MUDs was associated with a significantly higher GRFS (HR, 0.63; 95% CI, 0.42 to 0.97; P = .034). There was a trend toward improved PFS with use of MUDs (HR, 0.69; 95% CI, 0.46 to 1.04; P = .08). Our data show that PT-Cy in MM patients undergoing allo-HCT resulted in low rates of acute and chronic GVHD and led to favorable survival, especially in the matched related donor setting. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
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http://dx.doi.org/10.1016/j.jtct.2021.09.008DOI Listing
December 2021

Feasibility and Efficacy of a Pharmacokinetics-Guided Busulfan Conditioning Regimen for Allogeneic Stem Cell Transplantation with Post-Transplantation Cyclophosphamide as Graft-versus-Host Disease Prophylaxis in Adult Patients with Hematologic Malignancies.

Transplant Cell Ther 2021 Nov 14;27(11):912.e1-912.e6. Epub 2021 Aug 14.

IRCCS Humanitas Research Hospital-Humanitas Cancer Center, Milan, Italy. Electronic address:

Busulfan (Bu) is an alkylating agent routinely used for conditioning regimens before allogeneic stem cell transplantation (allo-SCT). Bu shows wide pharmacokinetic (PK) variability among patients. Patients can have a higher systemic exposure (expressed as area under the curve [AUC]) with an increased risk of toxicity or a lower AUC with a higher probability of graft rejection and/or disease relapse. After i.v. administration, an optimal Bu therapeutic window (AUC target of 16,000 to 24,000 μM·minute) has been identified. The use of PK-guided Bu dosing leads to improved overall survival (OS) and progression-free survival (PFS) compared with fixed-dose administration in a variety of hematologic diseases. The aim of this study was to evaluate the outcomes and feasibility of a reduced-toxicity conditioning (RTC) regimen comprising thiotepa, Bu, and fludarabine (TBF) with therapeutic drug monitoring of Bu in patients with hematologic disorders. We report on 41 adult patients with myeloid or lymphoid malignancies who underwent an allo-SCT with a PK-guided Bu-based RTC regimen between January 2019 and October 2020. Patients received a total Bu dose to achieve a target AUC of 16,000 μM·minute in combination with Flu and thiotepa. The median time to absolute neutrophil count recovery and transfusion-independent platelet count recovery was 23 days (range, 15 to 42 days) and 29 days (range, 14 to 97 days), respectively. The cumulative incidence (CI) of nonrelapse mortality was 7% at 100 days and 13% at 1 year. Grade 3 liver toxicity was observed in 6 patients. One patient developed sinusoidal obstruction syndrome at day +27. Grade 3 mucositis occurred in 18 patients. Looking at grade ≥3 infections, the CI was 29% at 30 days, 34% at 60 days, 44% at 100 days, and 56% at 1 year. The 180-day CI of grade II-IV acute graft-versus-host disease (GVHD) was 15%, and the 1-year CI of overall chronic GVHD was 20%. With a median follow-up of alive patients of 14.4 months (range, 3.2 to 24 months), the CI of relapse at 1 year was 6%. The 1-year PFS was 81%, and 1-year OS was 84%. In conclusion, these data support the efficacy of PK-guided Bu dose in the context of a TBF conditioning regimen and the feasibility of therapeutic dosage monitoring of i.v. Bu for patients with hematologic diseases. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
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http://dx.doi.org/10.1016/j.jtct.2021.08.006DOI Listing
November 2021

Cytokine release syndrome after haploidentical hematopoietic cell transplantation: an international multicenter analysis.

Bone Marrow Transplant 2021 Nov 14;56(11):2763-2770. Epub 2021 Jul 14.

BMT and Cellular Therapy Program, Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.

Haploidentical related donor transplantation (haplo-HCT) is associated with cytokine release syndrome (CRS). We conducted a multicenter retrospective study to analyze risk factors for CRS and outcomes after haplo-HCT. We included 451 patients from four academic centers receiving both peripheral blood and bone marrow grafts. Severe CRS was more common with PB vs. BM grafts (19.5% vs 4.9%, OR 2.9, p = 0.05). Multivariable analysis identified recipient CMV sero-positivity, prior transplant, HCT-CI score and donor-recipient sex mismatch as risk factors for severe CRS. Outcomes were analyzed with no CRS as the comparison group. Overall survival (OS) was superior with mild CRS (HR 0.64, p = 0.05) and worst with severe CRS (HR 2.12, p = 0.0038). Relapse risk was significantly decreased in both mild CRS (HR 0.38, p < 0.0001) and severe CRS (HR 0.17, p < 0.0001) groups. The risk of non-relapse mortality was notably higher in severe CRS group (HR 8.0, p < 0.0001), but not in mild CRS group. Acute GVHD was similar among groups. Chronic GVHD at 1 year was 18.5% for no CRS, 23% for mild CRS, and 4.3% for severe CRS (p = 0.0023), with the competing risk of early mortality and short follow up of surviving patients contributing to the low chronic GVHD rates in the severe CRS group.
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http://dx.doi.org/10.1038/s41409-021-01403-wDOI Listing
November 2021

Single-cell profiling identifies impaired adaptive NK cells expanded after HCMV reactivation in haploidentical HSCT.

JCI Insight 2021 06 22;6(12). Epub 2021 Jun 22.

Unit of Clinical and Experimental Immunology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.

Haploidentical hematopoietic stem cell transplantation (h-HSCT) represents an efficient curative approach for patients affected by hematologic malignancies in which the reduced intensity conditioning induces a state of immunologic tolerance between donor and recipient. However, opportunistic viral infections greatly affect h-HSCT clinical outcomes. NK cells are the first lymphocytes that recover after transplant and provide a prompt defense against human cytomegalovirus (HCMV) infection/reactivation. By undertaking a longitudinal single-cell computational profiling of multiparametric flow cytometry, we show that HCMV accelerates NK cell immune reconstitution together with the expansion of CD158b1b2jpos/NKG2Aneg/NKG2Cpos/NKp30lo NK cells. The frequency of this subset correlates with HCMV viremia, further increases in recipients experiencing multiple episodes of viral reactivations, and persists for months after the infection. The transcriptional profile of FACS-sorted CD158b1b2jpos NK cells confirmed the ability of HCMV to deregulate NKG2C, NKG2A, and NKp30 gene expression, thus inducing the expansion of NK cells with adaptive traits. These NK cells are characterized by the downmodulation of several gene pathways associated with cell migration, the cell cycle, and effector-functions, as well as by a state of metabolic/cellular exhaustion. This profile reflects the functional impairments of adaptive NK cells to produce IFN-γ, a phenomenon also due to the viral-induced expression of lymphocyte-activation gene 3 (LAG-3) and programmed cell death protein 1 (PD-1) checkpoint inhibitors.
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http://dx.doi.org/10.1172/jci.insight.146973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262468PMC
June 2021

Nonmyeloablative Conditioning Regimen Including Low-Dose Total Marrow/Lymphoid Irradiation Before Haploidentical Transplantation with Post-Transplantation Cyclophosphamide in Patients with Advanced Lymphoproliferative Diseases.

Transplant Cell Ther 2021 06 15;27(6):492.e1-492.e6. Epub 2021 Mar 15.

BMT Unit, Humanitas Clinical and Research Center-IRCCS, Humanitas Cancer Center, Milan, Italy. Electronic address:

Low-dose total body irradiation (TBI) has long been used in nonmyeloablative conditioning (NMAC) regimens before allogeneic stem cell transplantation from haploidentical donors (haplo-SCT). More recently, the use of total marrow lymphoid irradiation (TMLI) instead of TBI in conditioning is increasing. This study aimed to evaluate outcomes in a cohort of patients treated with low-dose TMLI in terms of engraftment, full donor chimerism status, graft-versus-host disease (GVHD), and extrahematologic toxicities, and to compare these outcomes with those in a cohort of patients receiving conventional TBI-containing conditioning. This retrospective single-center study included 100 patients with advanced hematologic malignancies who underwent haplo-SCT. Between 2009 and 2011, the NMAC regimen consisted of cyclophosphamide, fludarabine, and low-dose TBI (2 Gy), and after 2011, TBI was replaced with TMLI (2 Gy). Patients received post-transplantation cyclophosphamide, calcineurin inhibitor, and mycophenolate mofetil as GVHD prophylaxis. For all patients, the median time to absolute neutrophil count (ANC) recovery to >0.5 × 10/L was 21 days (range, 15 to 49 days), the 30-day incidence of ANC recovery was 97% (95% confidence interval [CI], 89% to 99%), the median time to achieve an unsupported platelet count >20 × 10/L was 26 days (range, 12 to 67 days), and the 60-day rate of platelet engraftment was 99% (95% CI, 89% to 100%). Cumulative incidence of full donor chimerism by day 100 was 88% (95% CI 79-90). Grade II-IV acute GVHD occurred in 35% of the patients (95% CI, 26% to 45%) at a median of 40 days (range, 23 to 166 days). The incidence of moderate to severe chronic GVHD was 5% (95% CI, 2% to 10%). No differences between the TBI and TMLI cohorts were seen in terms of engraftment, full donor chimerism, and GVHD. No organ toxicity was observed in the first months after transplantation in either cohort. The overall 2-year OS and PFS rates were 63%, and 54%, respectively, and were comparable in the 2 groups (P = .548). The strongest finding was that TBI can be safely replaced by TMLI in terms of engraftment, achievement of full donor chimerism status, GVHD incidence, and extrahematologic toxicities.
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http://dx.doi.org/10.1016/j.jtct.2021.03.013DOI Listing
June 2021

Multicenter Phase II Study on Haploidentical Bone Marrow Transplantation Using a Reduced-Intensity Conditioning Regimen and Posttransplantation Cyclophosphamide in Patients with Poor-Prognosis Lymphomas.

Transplant Cell Ther 2021 04 17;27(4):328.e1-328.e6. Epub 2021 Jan 17.

BMT Unit, Humanitas Clinical and Research Center, IRCCS, Rozzano, Italy; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.

Allogeneic stem cell transplantation from haploidentical donors using unmanipulated bone marrow and posttransplantation cyclophosphamide has been largely employed to cure high-risk lymphomas. However, the increased incidence of relapse associated with the use of a nonmyeloablative conditioning regimen is still considered a concerning issue. The aim of our study was to prospectively evaluate the efficacy and feasibility of a reduced-intensity conditioning regimen, including thiotepa, cyclophosphamide, and fludarabine, in high-risk lymphoma patients. This was a prospective multicenter study. We enrolled 49 patients, of whom 47 were evaluable. Graft source (bone marrow) and graft-versus-host disease (GVHD) prophylaxis were the same for all patients. The primary endpoint was the proportion of patients free of disease progression at 1 year. The primary endpoint was met, as 29 out of 47 patients were alive and free of disease at 1 year (1-year progression-free survival, 60%). Forty-five recipients engrafted and achieved full donor chimerism at day 100. The cumulative incidences (CIs) of ANC engraftment at 30 days and platelet engraftment at 60 days were 89% and 83%, respectively. Two patients experienced graft failure. The CIs of day 100 grades 2 to 4 acute GVHD and 2-year moderate-to-severe chronic GVHD were 26% and 16%, respectively. With a median follow-up of 47.5 months (range, 22 to 74), the 4-year progression-free survival and overall survival were 54% and 64%, respectively. The 4-year CI of relapse was 28%, and the 4-year nonrelapse mortality was 15%. Thiotepa-based reduced-intensity conditioning was well tolerated with encouraging survival in a cohort of patients with poor-prognosis lymphoma. Both the incidence of relapse and nonrelapse mortality were acceptable.
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http://dx.doi.org/10.1016/j.jtct.2021.01.007DOI Listing
April 2021

Feasibility and Efficacy of CD45RA+ Depleted Donor Lymphocytes Infusion After Haploidentical Transplantation With Post-Transplantation Cyclophosphamide in Patients With Hematological Malignancies.

Transplant Cell Ther 2021 06 11;27(6):478.e1-478.e5. Epub 2021 Mar 11.

Laboratory of Translational Immunology, Humanitas Clinical and Research Center - IRCCS, Milan, Italy.

Allogeneic stem cell transplantation from haploidentical donor using post-transplantation cyclophosphamide has been used to cure hematological diseases. Because of slow immunological reconstitution, there is an increased incidence of viral infection. The aim of our study was to prospectively evaluate the efficacy and the feasibility of a CD45RA+ depleted donor lymphocytes infusion (DLI) in terms of reduction of viral infection early after haploidentical transplantation. This a prospective single-center study. We enrolled 23 patients, of whom 19 were evaluable. Graft-versus-host disease (GVHD) prophylaxis was the same for all patients. The primary endpoint was 100-day cumulative incidence of viral infections. The primary endpoint was met, because the 100-day cumulative incidence of viral infection was 32%. The median time from transplantation to first CD45RA+ depleted DLI was 55 days (range, 46-63). 28% of patients had cytomegalovirus reactivation, no patients reactivated human herpesvirus-6; 1 patient developed BK virus related hemorrhagic cystitis. Most of the patients received the planned 3 infusions. Only 1 patient had development of grade 2 acute GVHD, and 2 patients had moderate chronic GVHD. All evaluable patients were off immunosuppressive therapy at last follow-up. The median follow-up was 12 months (range, 3-23), the 1-year overall survival and progression-free survival were 79% and 75%, respectively; the 100-day and 1-year non-relapse mortality were 5% and 12%, respectively. CD45RA+ depleted DLI are feasible in patients treated with haploidentical transplantation. The toxic profile is good with a low risk for development of both acute and chronic GVHD.
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http://dx.doi.org/10.1016/j.jtct.2021.03.010DOI Listing
June 2021

Chemotherapy-based versus chemotherapy-free stem cell mobilization (± plerixafor) in multiple myeloma patients: an Italian cost-effectiveness analysis.

Bone Marrow Transplant 2021 08 22;56(8):1876-1887. Epub 2021 Mar 22.

Department of Cellular Therapy and Transfusion Medicine, Careggi University Hospital, Florence, Italy.

Given the availability and efficacy of the mobilizing agent plerixafor in augmenting hematopoietic progenitor cell mobilization with granulocyte colony-stimulating factor (G-CSF), there is a strong case for comparing the cost-effectiveness of mobilization with G-CSF + cyclophosphamide versus G-CSF alone. This study investigated the cost and effectiveness (i.e., successful 4 million-CD34 collection) of G-CSF alone versus high-dose cyclophosphamide (4 g/m) + G-CSF mobilization (± on-demand plerixafor) in patients with multiple myeloma (MM) eligible for autograft in Italy. A decision tree-supported cost-effectiveness analysis (CEA) model in MM patients was developed from the societal perspective. The CEA model compared G-CSF alone with cyclophosphamide 4 g/m + G-CSF (± on-demand plerixafor) and was populated with demographic, healthcare and non-healthcare resource utilization data collected from a questionnaire administered to six Italian oncohematologists. Costs were expressed in Euro (€) 2019. The CEA model showed that G-CSF alone was strongly dominant versus cyclophosphamide + G-CSF ( ± on-demand plerixafor), with incremental savings of €1198.59 and an incremental probability of a successful 4 million-CD34 apheresis (+0.052). Sensitivity analyses confirmed the robustness of the base-case results. In conclusion, chemotherapy-free mobilization (± on-demand plerixafor) is a "good value for money" option for MM patients eligible for autograft.
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http://dx.doi.org/10.1038/s41409-021-01251-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8338551PMC
August 2021

Prognostic factors for neutrophil engraftment after haploidentical cell transplantation with PT-Cy in patients with acute myeloid leukemia in complete remission, on behalf of the ALWP-EBMT.

Bone Marrow Transplant 2021 08 5;56(8):1842-1849. Epub 2021 Mar 5.

Department of Haematology and EBMT Paris Study Office/CEREST-TC, Saint Antoine Hospital, Paris, France.

The use of haplo-HCT with posttransplant cyclophosphamide (PT-Cy) is a new standard in the treatment of hematological diseases. A paucity of data exists on risk factors for engraftment failure in haplo-HCT with PT-Cy. We analyzed 1939 adults with acute myeloid leukemia (AML) who received a first haplo-HCT from 2010 to 2019. Status at haplo-HCT was first complete remission (CR1) in 72.5% of patients, secondary AML was reported in 9.9%. Median follow-up was 24.4 months and median age at haplo-HCT was 51 years. Stem cell source was bone marrow (BM) in 42% and peripheral blood stem cell (PBSC) in 58%, and 64% of patients received a myeloablative conditioning (MAC) regimen. Cumulative incidence of primary graft failure (GF) was 6%; GF was reported in 110 patients and 54 died before day +30 with no sign of cell recovery. Overall, 33 patients underwent a second HCT in a median time of 45 days and 13 were alive at last follow-up, the 2-year overall survival (OS) after second HCT being 32.4%. In multivariate analysis, factors independently associated with the risk of nonengraftment were: secondary AML (HR 1.30, p = 0.003), use of RIC (HR 1.22, p < 0.001), and use of BM (HR 1.21, p < 0.001). At 2 years, leukemia-free survival (LFS) and OS for the entire population was 55.2% (95% CI: 52.6-57.6) and 60.9% (95% CI: 58.4-63.3), respectively. Incidence of GF after haplo-HCT with PT-Cy is lower than reported T-cell-depleted haplo-HCT. Optimization of conditioning regimen and graft source should be considered for reducing the risk of GF in haplo-HCT recipients using PT-Cy.
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http://dx.doi.org/10.1038/s41409-021-01248-3DOI Listing
August 2021

Allogeneic transplantation after PD-1 blockade for classic Hodgkin lymphoma.

Leukemia 2021 09 3;35(9):2672-2683. Epub 2021 Mar 3.

Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.

Anti-PD-1 monoclonal antibodies yield high response rates in patients with relapsed/refractory classic Hodgkin lymphoma (cHL), but most patients will eventually progress. Allogeneic hematopoietic cell transplantation (alloHCT) after PD-1 blockade may be associated with increased toxicity, raising challenging questions about the role, timing, and optimal method of transplantation in this setting. To address these questions, we assembled a retrospective cohort of 209 cHL patients who underwent alloHCT after PD-1 blockade. With a median follow-up among survivors of 24 months, the 2-year cumulative incidences (CIs) of non-relapse mortality and relapse were 14 and 18%, respectively; the 2-year graft-versus-host disease (GVHD) and relapse-free survival (GRFS), progression-free survival (PFS), and overall survival were 47%, 69%, and 82%, respectively. The 180-day CI of grade 3-4 acute GVHD was 15%, while the 2-year CI of chronic GVHD was 34%. In multivariable analyses, a longer interval from PD-1 to alloHCT was associated with less frequent severe acute GVHD, while additional treatment between PD-1 and alloHCT was associated with a higher risk of relapse. Notably, post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis was associated with significant improvements in PFS and GRFS. While awaiting prospective clinical trials, PTCy-based GVHD prophylaxis may be considered the optimal transplantation strategy for this patient population.
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http://dx.doi.org/10.1038/s41375-021-01193-6DOI Listing
September 2021

Addition of Rituximab in Reduced Intensity Conditioning Regimens for B-Cell Malignancies Does Not Influence Transplant Outcomes: EBMT Registry Analyses Following Allogeneic Stem Cell Transplantation for B-Cell Malignancies.

Front Immunol 2020 2;11:613954. Epub 2021 Feb 2.

Department of Hematology and Oncology, Medical University of Graz, Graz, Austria.

Rituximab (R) is increasingly incorporated in reduced intensity conditioning (RIC) regimens for allogeneic hematopoietic cell transplantation (alloHCT) in patients with B-cell malignancies, not only to improve disease control, but also to prevent graft-versus-host disease (GVHD). There are no randomized prospective data to validate this practice, although single center data and the CIBMTR analysis have shown promising results. We aimed at validation of these findings in a large registry study. We conducted a retrospective analysis using the EBMT registry of 3,803 adult patients with B-cell malignancies undergoing alloHCT (2001-2013) with either rituximab (R-RIC-9%) or non-rituximab (RIC-91%) reduced intensity regimens respectively. Median age and median follow up were 55 years (range 19.1-77.3) and 43.2 months (range 0.3-179.8), respectively. There was no difference in transplant outcomes (R-RIC vs RIC), including 1-year overall survival (69.9% vs 70.7%), 1-year disease-free survival (64.4% vs 62.2%), 1-year non-relapse mortality (21% vs 22%), and day-100 incidence of acute GVHD 2-4° (12% vs 12%). In summary, we found that addition of rituximab in RIC regimens for B-cell malignancies had no significant impact on major transplant outcome variables. Of note, data on chronic GVHD was not available, limiting the conclusions that can be drawn from the present study.
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http://dx.doi.org/10.3389/fimmu.2020.613954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884746PMC
June 2021

Haploidentical related donor compared to HLA-identical donor transplantation for chemosensitive Hodgkin lymphoma patients.

BMC Cancer 2020 Nov 24;20(1):1140. Epub 2020 Nov 24.

Hematology Department, Transplantation and Cellular Therapy Unit, Institut Paoli-Calmettes, Marseille, France.

Background: Allogeneic stem cell transplantation from haploidentical donor using an unmanipulated graft and post-transplantation cyclophosphamide (PT-Cy) is growing. Haploidentical transplantation with PT-Cy showed a major activity in Hodgkin lymphoma (HL), reducing the relapse incidence. The most important predictive factor of survival and toxicity was disease status before transplantation, which was better in patients with well controlled disease.

Methods: We included 198 HL in complete (CR) or partial remission (PR) before transplantation. Sixty-five patients were transplanted from haploidentical donor and 133 from a HLA identical donor (both sibling and unrelated donors). Survival analysis was defined according to the EBMT criteria. Survival curves were generated by using Kaplan-Meier method and differences between groups were compared by the log rank test or by the log rank test for trend when appropriated.

Results: The PFS, OS, and RI were significantly better in patients in CR compared to PR (55% vs 29% p = 0.001, 74% vs 55% p = 0.03, 27% vs 55% p <  0.001, respectively). The 2-year PFS was significantly better for HAPLO than HLA-id (63% vs 37%, p = 0.03), without difference in OS. The 1-year NRM was not different. The 2-year relapse incidence (RI) was lower in the HAPLO group (24% vs 44%, p = 0.008). Patients in CR receiving haplo HSCT showed higher 2-year PFS and lower 2-year RI than those allografted with HLA-id donor (75% vs 47%, p <  0.001 and 11% vs 34%, p < 0.001, respectively). In multivariate analysis, donor type and disease status before transplantation were independent predictors of PFS as well as they predict the risk of relapse. Disease status at transplantation and age were independently associated to OS.

Conclusions: Nonetheless this is a retrospective study, limiting the wide applicability of results, data from this analysis suggest that HLA mismatch can induce a strong graft versus lymphoma effect leading to an enhanced PFS.
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http://dx.doi.org/10.1186/s12885-020-07602-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685618PMC
November 2020

Allogeneic stem cell transplantation in poor prognosis peripheral T-cell lymphoma: the impact of different donor type on outcome.

Bone Marrow Transplant 2021 04 15;56(4):883-889. Epub 2020 Nov 15.

Haematology Department, Institut Paoli-Calmettes, Aix-Marseille Université, Marseille, France.

We report the outcome of 68 patients with advanced peripheral T-cell lymphoma receiving transplantation from haploidentical or from conventional donors. The 4-year OS, PFS, 2-year cumulative incidence of relapse and 2-year GRFS was 75%, 70%, 21%, and 51%, respectively. Survival was not affected by donor type. The 2-year NRM was 9%, lower after related or haploidentical donor (21% vs 0% vs 7%; p = 0.06). Grade 2-4 aGVHD cumulative incidence was significantly different after transplantation from haploidentical vs matched sibling vs unrelated donor, and (24% vs 35% vs 58%, p = 0.024). The familial donor cohort was compared to the unrelated cohort. Familial donor induced less grade 2-4 aGVHD, with a trend to less grade 3-4 aGVHD or moderate-severe cGVHD. The OS and PFS were not different, while the relapse risk and NRM were reduced. Allo-SCT is highly effective in T-cell lymphoma, with low NRM and low relapse rate. The incidence of aGVHD was lower after haploidentical transplantation. Related donor may challenge unrelated transplant reducing the risk of relapse and NRM.
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http://dx.doi.org/10.1038/s41409-020-01133-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666822PMC
April 2021

Haploidentical Stem Cell Transplantation in Lymphomas-Expectations and Pitfalls.

J Clin Med 2020 Nov 7;9(11). Epub 2020 Nov 7.

Bone Marrow Transplant Unit, Humanitas Clinical and Research Center, 20089 Rozzano, Italy.

T-cell replete Haploidentical stem cell transplantation (Haplo-SCT) with Post-transplant cyclophosphamide (PT-Cy) is an emerging therapeutic option for patients with advanced relapsed or refractory lymphoma. The feasibility of this platform is supported by several retrospective studies showing a toxicity profile that is improved relative to umbilical cord blood and mismatched unrelated donor (UD) transplant and comparable to matched unrelated donor transplant. In particular, cumulative incidence of chronic graft-versus-host disease (GVHD) is reduced after Haplo-SCT relative to UD and matched related donor (MRD) transplant thanks to PT-Cy employed as GVHD prophylaxis. This achievement, together with a similar incidence of acute GVHD and disease relapse, results in a promising advantage of Haplo-SCT in terms of relapse-free/GVHD free survival. Unmet needs of the Haplo-SCT platform are represented by the persistence of a not negligible rate of non-relapse mortality, especially due to infections and disease relapse. Future efforts are warranted in order to reduce life-threatening infections and to employ Halo-SCT with PT-Cy as a platform to build new immunotherapeutic strategies.
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http://dx.doi.org/10.3390/jcm9113589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695017PMC
November 2020

Salvage Therapy for Hodgkin's Lymphoma: A Review of Current Regimens and Outcomes.

J Blood Med 2020 27;11:389-403. Epub 2020 Oct 27.

Humanitas Clinical and Research Center, IRCCS, Rozzano, Milan 20089, Italy.

Relapse/refractory Hodgkin lymphoma patients are still a clinical concern. Indeed, despite more effective first-line chemotherapy regimens and better stratification of unresponsive patients by clinical factors and use of early PET, roughly one-third of such patients need salvage chemotherapy and consolidation with high-dose chemotherapy. In this paper, the authors review the different salvage treatments, with special emphasis on newer combinations with brentuximab vedotin or check point inhibitors. The overall response rate is constantly increasing, with a complete remission rate approaching 80%. Functional response evaluation by PET imaging is a strong predictive factor of longer survival, and more sophisticated tools, such as detection of circulating tumour DNA, are emerging to refine the disease-status assessment after treatment. Consolidation by high-dose chemotherapy is still considered the standard of care in chemosensitive patients, leading to a high fraction of patients towards long-term disease control. Maintenance therapy with BV is now approved, reducing disease relapse/progression. An increasing number of Hodgkin lymphoma patients will be cured after first- and second-line therapy, and long-term toxicity needs to be continuously assessed and avoided.
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http://dx.doi.org/10.2147/JBM.S250581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603406PMC
October 2020

Impact of spleen size and splenectomy on outcomes of allogeneic hematopoietic cell transplantation for myelofibrosis: A retrospective analysis by the chronic malignancies working party on behalf of European society for blood and marrow transplantation (EBMT).

Am J Hematol 2021 01 27;96(1):69-79. Epub 2020 Oct 27.

CHU de Lille, Université de Lille, Lille, France.

The role of spleen size and splenectomy for the prediction of post-allogeneic hematopoietic stem cell transplant (allo-HCT) outcome in myelofibrosis remains under debate. In EBMT registry, we identified a cohort of 1195 myelofibrosis patients transplanted between 2000-2017 after either fludarabine-busulfan or fludarabine-melphalan regimens. Overall, splenectomy was performed in 202 (16.9%) patients and its use decreased over time (28.3% in 2000-2009 vs 14.1% in 2010-2017 period). By multivariate analysis, splenectomy was associated with less NRM (HR 0.64, 95% CI 0.44-0.93, P = .018) but increased risk of relapse (HR 1.43, 95% CI 1.01-2.02, P = .042), with no significant impact on OS (HR 0.86, 95% CI 0.67-1.12, P = .274). However, in subset analysis comparing the impact of splenectomy vs specific spleen sizes, for patients with progressive disease, an improved survival was seen in splenectomised subjects compared to those patients with a palpable spleen length ≥ 15 cm (HR 0.44, 95% CI 0.28-0.69, P < .001), caused by a significant reduction in NRM (HR 0.26, 95% CI 0.14-0.49, P < .001), without significantly increased relapse risk (HR 1.47, 95% CI 0.87-2.49, P = .147). Overall, despite the possible biases typical of retrospective cohorts, this study highlights the potential detrimental effect of massive splenomegaly in transplant outcome and supports the role of splenectomy for myelofibrosis patients with progressive disease and large splenomegaly.
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http://dx.doi.org/10.1002/ajh.26020DOI Listing
January 2021

Tandem autologous-reduced intensity allogeneic stem cell transplantation in high-risk relapsed Hodgkin lymphoma: a retrospective study of the Lymphoma Working Party-EBMT.

Bone Marrow Transplant 2021 03 12;56(3):655-663. Epub 2020 Oct 12.

Institut Català d'Oncologia (ICO)-Hospitalet, IDIBELL, Universitat de Barcelona, Barcelona, Spain.

Autologous hematopoietic stem cell transplantation (ASCT) is curative for a proportion of patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL). However, there is a small group of patients with high-risk of relapse after ASCT that might benefit from other approaches. We conducted a retrospective analysis on 126 patients treated with tandem ASCT-reduced intensity conditioning (RIC)-allogeneic-SCT and reported to the EBMT registry to analyze the efficacy and safety of this approach. Patients were included if they had received an ASCT followed by a planned RIC-SCT in <6 months without relapse between the procedures. The median time between diagnosis and ASCT was 16 months (2-174). The median number of lines prior to ASCT was two (33% of the patients received >3 lines). Forty-one percent were transplanted with active disease. The median follow-up was 44 months (6-130). Three-year-progression-free survival (PFS), overall survival (OS), incidence of relapse (IR), and non-relapse mortality (NRM) after the tandem were 53% (45-64), 73% (65-81), 34% (24-42), and 13% (8-21), respectively. This is the largest series analyzing the efficacy and safety of a tandem approach in R/R HL. The low NRM and IR with promising PFS and OS suggest that this might be an effective procedure for a high-risk population.
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http://dx.doi.org/10.1038/s41409-020-01075-yDOI Listing
March 2021

Acute Graft-versus-Host-Disease Other Than Typical Targets: Between Myths and Facts.

Transplant Cell Ther 2021 02 2;27(2):115-124. Epub 2020 Oct 2.

Bone Marrow Transplant Unit, Humanitas Clinical and Research Center, Rozzano, Italy.

Donor alloreactivity after allogeneic hematopoietic stem cell transplantation results in graft-versus-host reaction (GVHR) that may affect different organs. While skin, liver, and gastrointestinal tract are well-recognized targets of such alloreactivity early after transplant, commonly identified as acute graft-versus-host-disease (aGVHD), there is accumulating evidence from the literature that early GVHR may be directed also against other tissues. In particular, organs such as kidney, bone marrow, central nervous system, and lungs may be involved in patients experiencing aGVHD, but whether these sites represent targets or collateral damages of donor alloreactivity is matter of debate. This review summarizes the current knowledge, the potential applications, and the clinical relevance of GFHR in nontypical target organs during aGVHD. The objective of this article is to lay the basis for future efforts aiming at including these organs in grading and management of aGVHD.
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http://dx.doi.org/10.1016/j.bbmt.2020.09.033DOI Listing
February 2021

Nonmyeloablative Conditioning Regimen before T Cell Replete Haploidentical Transplantation with Post-Transplant Cyclophosphamide for Advanced Hodgkin and Non-Hodgkin Lymphomas.

Biol Blood Marrow Transplant 2020 12 19;26(12):2299-2305. Epub 2020 Aug 19.

Hematology Department, Institut Paoli-Calmettes, Aix-Marseille Université, Marseille, France.

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a valid option in patients with refractory lymphomas. HLA haploidentical stem cell transplantation (haplo-SCT) expanded the accessibility to allogeneic hematopoietic cell transplantation. The aims of study were to retrospectively assess the toxicity and efficacy of haplo-SCT using nonmyeloablative conditioning in patients with advanced lymphoma. In total, 147 patients with advanced lymphoma at 2 partner institutions were included. Patients received a uniform nonmyeloablative conditioning regimen and graft-versus-host disease (GVHD) prophylaxis. The primary endpoints were progression-free survival (PFS), overall survival (OS), GVHD, nonrelapse mortality, and GVHD, relapse-free survival (GRFS). Median follow-up was 39 months (range, 6 to 114 months). The median age was 46 years (range, 19 to 71 years). Sixty-five percent of patients were in complete remission (CR) at transplantation. Cumulative incidence of grade II to IV acute GVHD was 30% (95% confidence interval [Cl], 23% to 38%). Two-year cumulative incidence of all grades of chronic GVHD was 13% (95% CI, 8% to 20%). Two-year cumulative incidence of disease relapse was 19% (95% CI, 14% to 27%), with a higher incidence in patients not being in CR at allo-HCT (CR versus not CR: 12% versus 33%, P = .006). Two-year PFS, OS, and GRFS were 66% (95% CI, 59-75), 73% (95% CI, 66-81), and 56% (95% CI, 48-65), respectively. Haplo-SCT with post-transplantation cyclophosphamide may be considered a valid option for patients with aggressive lymphoma and deserves further evaluation.
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http://dx.doi.org/10.1016/j.bbmt.2020.08.014DOI Listing
December 2020

Impact of donor age and kinship on clinical outcomes after T-cell-replete haploidentical transplantation with PT-Cy.

Blood Adv 2020 08;4(16):3900-3912

Bone Marrow Transplant Unit, Humanitas Clinical and Research Center, Rozzano, Italy.

Donor selection contributes to improve clinical outcomes of T-cell-replete haploidentical stem cell transplantation (haplo-SCT) with posttransplant cyclophosphamide (PT-Cy). The impact of donor age and other non-HLA donor characteristics remains a matter of debate. We performed a multicenter retrospective analysis on 990 haplo-SCTs with PT-Cy. By multivariable analysis, after adjusting for donor/recipient kinship, increasing donor age and peripheral blood stem cell graft were associated with a higher risk of grade 2 to 4 acute graft-versus-host-disease (aGVHD), whereas 2-year cumulative incidence of moderate-to-severe chronic GVHD was higher for transplants from female donors into male recipients and after myeloablative conditioning. Increasing donor age was associated with a trend for higher nonrelapse mortality (NRM) (hazard ratio [HR], 1.05; P = .057) but with a significant reduced risk of disease relapse (HR, 0.92; P = .001) and improved progression-free survival (PFS) (HR, 0.97; P = .036). Increasing recipient age was a predictor of worse overall survival (OS). Risk of relapse was higher (HR, 1.39; P < .001) in patients aged ≤40 years receiving a transplant from a parent as compared with a sibling. Moreover, OS and PFS were lower when the donor was the mother rather than the father. Pretransplant active disease status was an invariably independent predictor of worse clinical outcomes, while recipient positive cytomegalovirus serostatus and hematopoietic cell transplant comorbidity index >3 were associated with worse OS and PFS. Our results suggest that younger donors may reduce the incidence of aGVHD and NRM, though at higher risk of relapse. A parent donor, particularly the mother, is not recommended in recipients ≤40 years.
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http://dx.doi.org/10.1182/bloodadvances.2020001620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448598PMC
August 2020

Timing of Post-Transplantation Cyclophosphamide Administration in Haploidentical Transplantation: A Comparative Study on Behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Biol Blood Marrow Transplant 2020 10 6;26(10):1915-1922. Epub 2020 Jul 6.

Hematology Department, Service d'Hématologie et Thérapie Cellulaire, Hôpital Saint Antoine, Paris, France; Sorbonne Universités, INSERM, Centre de Recherche Saint-Antoine, UPMC Univ Paris 06, Paris, France; European Society for Blood and Marrow Transplantation, Paris, France.

The timing of immunosuppressive therapy used in combination with post-transplantation cyclophosphamide (PTCY) in haploidentical hematopoietic stem cell transplant (haplo-HSCT) is not standardized. We evaluated the schedules of immunosuppression therapy after haplo-HSCT in 509 patients with acute leukemia receiving PTCY on days +3 and +4 along with tacrolimus (group 1; n = 215), with cyclosporine A (CSA) and mycophenolate mofetil (MMF) from day +5 (group 2; n = 170), or CSA + MMF from day 0 or 1 with PTCY on days +3 and +5 (group 3; n = 124). Compared with the other 2 groups, patients in group 3 were younger (median age, 46 years; P = .02) and more often received bone marrow (77%; P < .01) and a regimen containing thiotepa, fludarabine, and busulfan (84%; P< .01). At 2 years, overall survival was 44% was in group 1, 48% in group 2, and 59% in group 3 (P= .15); leukemia-free survival (LFS) was 43%, 46%, and 53% (P= .05); and refined graft-versus-host disease-free, relapse-free survival (rGRFS) was 33%, 39%, and 36% (P = .02). The incidence of grade II-IV acute GVHD was 25% in group 1, 39% in group 2, and 18% in group 3 (P< .01); incidence of chronic GVHD was 25%, 21%, and 24% (P= .50); relapse incidence was 36%, 37%, and 26% (P= .02); and nonrelapse mortality was 26%, 20%, and 21% (P= .35). On multivariate analysis, early start of immunosuppression therapy at day +1 followed by PTCY was associated with a better LFS (hazard ratio [HR], .58; P= .02) and improved rGRFS (HR, .62; P = .02). In this study, the timing of immunosuppression influenced the outcomes of haplo-HSCT with PTCY. An early start of CSA + MMF with PTCY administered on days +3 and +5 improves LFS and rGRFS.
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http://dx.doi.org/10.1016/j.bbmt.2020.06.026DOI Listing
October 2020

Impact of Adding Antithymocyte Globulin to Posttransplantation Cyclophosphamide in Haploidentical Stem-Cell Transplantation.

Clin Lymphoma Myeloma Leuk 2020 09 20;20(9):617-623. Epub 2020 Apr 20.

Institut Paoli Calmettes, Transplant and Cellular Therapy Unit, Marseille, France.

Background: Graft-versus-host disease (GVHD) is a major cause of mortality after allogeneic stem-cell transplantation. Posttransplantation cyclophosphamide (PT/CY) has become standard prophylaxis of GVHD in T-replete haploidentical transplantation. The question is whether adding antithymocyte globulin (ATG) to PT/CY may further reduce the incidence of GVHD compared to PT/CY only.

Patients And Methods: We retrospectively studied 268 patients undergoing myeloablative haploidentical transplantation with thiotepa, busulfan, and fludarabine (TBF) conditioning. Sixty-nine patients (26%) received ATG.

Results: In the ATG group, 3% died due to GVHD versus 8% in the no ATG group. The 100-day and 1-year nonrelapse mortality (NRM) was 0% and 19%, respectively, in the whole cohort. On univariate analysis, the 1-year NRM was 8% versus 23% in patients receiving ATG and no ATG, respectively (P = .005). The no ATG group had a higher incidence of acute GVHD at 12 months compared to the ATG group (22% vs. 12%, respectively, P = .029). The ATG group had better overall survival at 12 months compared to the no ATG group (79% vs. 69%, P = .029). On multivariate analysis, adding ATG to PT/CY had no significant impact on any of the outcomes. A low disease risk index was associated with better overall survival and lower NRM, while Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) score ≥ 3 was associated with higher NRM.

Conclusion: ATG can be safely used as part of the pretransplantation conditioning and does not increase the incidence of relapse or complications after transplantation.
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http://dx.doi.org/10.1016/j.clml.2020.04.003DOI Listing
September 2020

Post-transplant cyclophosphamide after matched sibling, unrelated and haploidentical donor transplants in patients with acute myeloid leukemia: a comparative study of the ALWP EBMT.

J Hematol Oncol 2020 05 6;13(1):46. Epub 2020 May 6.

Department of Hematology, Hopital Saint Antoine, Sorbonne University, Paris, France.

Background: The use of post-transplant cyclophosphamide (PTCy) is highly effective in preventing graft-versus-host disease (GVHD) in the haploidentical (Haplo) transplant setting and is being increasingly used in matched sibling (MSD) and matched unrelated (MUD) transplants. There is no information on the impact of donor types using homogeneous prophylaxis with PTCy.

Methods: We retrospectively compared outcomes of adult patients with acute myeloid leukemia (AML) in first complete remission (CR1) who received a first allogeneic stem cell transplantation (SCT) with PTCy as GVHD prophylaxis from MSD (n = 215), MUD (n = 235), and Haplo (n = 789) donors registered in the EBMT database between 2010 and 2017.

Results: The median follow-up was 2 years. Haplo-SCT carried a significantly increased risk of acute grade II-IV GVHD (HR 1.6; 95% CI 1.1-2.4) and NRM (HR 2.6; 95% CI 1.5-4.5) but a lower risk of relapse (HR 0.7; 95% CI 0.5-0.9) that translated to no differences in LFS (HR 1.1; 95% CI 0.8-1.4) or GVHD/relapse-free survival (HR 1; 95% CI 0.8-1.3). Interestingly, the use of peripheral blood was associated with an increased risk of acute (HR 1.9; 95% CI 1.4-2.6) and chronic GVHD (HR 1.7; 95% CI 1.2-2.4) but a lower risk of relapse (HR 0.7; 95% CI 0.5-0.9).

Conclusions: The use of PTCy in patients with AML in CR1 receiving SCT from MSD, MUD, and Haplo is safe and effective. Haplo-SCT had increased risk of acute GVHD and NRM and lower relapse incidence but no significant difference in survival.
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http://dx.doi.org/10.1186/s13045-020-00882-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201995PMC
May 2020

Checkpoint inhibition before haploidentical transplantation with posttransplant cyclophosphamide in Hodgkin lymphoma.

Blood Adv 2020 04;4(7):1242-1249

Department of Hematology, Humanitas Clinical and Research Center-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rozzano, Italy.

We report on 59 Hodgkin lymphoma patients undergoing haploidentical stem cell transplantation (SCT; haplo-SCT) with posttransplant cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis, comparing outcomes based on pretransplant exposure to checkpoint inhibitors (CPIs). Considering pretransplant characteristics, the 2 cohorts (CPI = 29 patients vs no-CPI = 30 patients) were similar, except for the number of prior lines of therapy (6 vs 4; P < .001). With a median follow-up of 26 months (range, 7.5-55 months), by univariate analysis, the 100-day cumulative incidence of grade 2-4 acute GVHD was 41% in the CPI group vs 33% in the no-CPI group (P = .456), whereas the 1-year cumulative incidence of moderate to severe chronic GVHD was 7% vs 8%, respectively (P = .673). In the CPI cohort, the 2-year cumulative incidence of relapse appeared lower compared with the no-CPI cohort (0 vs 20%; P = .054). No differences were observed in terms of overall survival (OS), progression-free survival (PFS), and nonrelapse mortality (NRM) (at 2 years, 77% vs 71% [P = .599], 78% vs 53% [P = .066], and 15% vs 21% [P = .578], respectively). By multivariable analysis, CPI before SCT was an independent protective factor for PFS (hazard ratio [HR], 0.32; P = .037). Stable disease (SD)/progressive disease (PD) was an independent negative prognostic factor for both OS and PFS (HR, 14.3; P < .001 and HR, 14.1; P < .001, respectively) . In conclusion, CPI as a bridge to haplo-SCT seems to improve PFS, with no impact on toxicity profile.
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http://dx.doi.org/10.1182/bloodadvances.2019001336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160255PMC
April 2020

Development of an Immobilization Device for Total Marrow Irradiation.

Pract Radiat Oncol 2021 Jan-Feb;11(1):e98-e105. Epub 2020 Mar 8.

Radiation Oncology Department, Humanitas Clinical and Research Hospital, Rozzano-Milan, Italy; Department of Biomedical Sciences, Humanitas University, Milan, Rozzano, Italy.

Purpose: A body frame dedicated to total marrow (lymph node) irradiation (TMI/TMLI) could minimize patient motion during the potentially extended beam-on time with this technique. We present the development of a dedicated immobilization system for TMI/TMLI using volumetric modulated arc therapy.

Methods And Materials: Since 2010, 59 adult patients were treated with TMI/TMLI using a multi-isocenter volumetric modulated arc therapy technique. Two computed tomographies (CTs) were required (1 head-first supine and 1 feet-first supine) to cover the whole volume. For the first 10 patients, 2 standard commercial frames with personalized masks (with/without personalized vacuum cushion for the lower extremities) were used without specific interfixation (frame A). For the next 49 patients a homemade 3-frame immobilization system was adopted (frame B), where each frame was interlocked with the next one and thermoplastic masks used to fix the patient. The effectiveness of the 2 immobilization systems was assessed by offline/online matching between daily cone beam CT of each isocenter and the simulation CTs.

Results: Mean offline shifts for frame A were 3 to 12 mm in anterior-posterior, 2 to 5 mm in cranilal-caudal, and 2 to 6 mm in left-right directions. Larger shifts were found for feet-first supine series (shifts up to 23 mm). In frame B, mean offline shifts were 1 to 4 mm in anterior-posterior, 1 to 4 mm in cranial-caudal, and 1 to 4 mm in left-right directions. Mean online adjustments were -1 ± 4 mm in anterior-posterior, 0 ± 2 mm in cranial-caudal, and 0 ± 4 mm in left-right directions.

Conclusions: The patient positioning shifts for TMI/TMLI irradiation were mitigated by a homemade immobilization system and the use of individualized masks.
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http://dx.doi.org/10.1016/j.prro.2020.02.012DOI Listing
August 2021

Effect of the Thiotepa Dose in the TBF Conditioning Regimen in Patients Undergoing Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia in Complete Remission: A Report From the EBMT Acute Leukemia Working Party.

Clin Lymphoma Myeloma Leuk 2020 05 27;20(5):296-304. Epub 2020 Jan 27.

Hopital Saint Antoine, Department of Hematology, Paris, France.

Background: Allogeneic stem cell transplantation is a potentially curative therapy for patients with acute myeloid leukemia (AML) after achieving complete remission (CR). The aim of this study is to evaluate the optimal dose of thiotepa, administered as part of the thiotepa-busulfan-fludarabine (TBF) conditioning regimen for allogeneic stem cell transplantation in adults with AML in CR.

Patients And Methods: In a retrospective multicenter analysis, we identified 240 patients allotransplanted from matched related or unrelated donors or T replete haplo-identical donors. We compared the transplantation outcomes of patients who received 5 mg/kg thiotepa and 2 days of intravenous busulfan at 6.4 mg/kg (T1B2F) versus those who received 10 mg/kg thiotepa with 2 days of intravenous busulfan at 6.4 mg/kg (T2B2F). The median follow-up was 20 months.

Results: On univariate analysis, the incidence of acute graft versus host disease (GVHD) grade II to IV was significantly lower in the T1B2F group (19%) versus 32% in the T2B2F group (P = .029). This result was confirmed on multivariate analysis; acute GVHD was higher for patients receiving T2B2F (hazard ratio, 2.22; P = .024). No significant change in non-relapse mortality, progression-free survival, or overall survival was observed between the 2 groups.

Conclusion: T2B2F is associated with a higher incidence of acute GVHD compared with T1B2F. These results suggest that a lower dose-intensity of thiotepa and busulfan in the TBF regimen may yield better results in patients with AML in CR.
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http://dx.doi.org/10.1016/j.clml.2020.01.007DOI Listing
May 2020
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