Comparing Two Types of Rabbit ATG prior to Reduced Intensity Conditioning Allogeneic Hematopoietic SCT for Hematologic Malignancies

Different rabbit polyclonal antilymphocyte globulins (ATGs) are used in allogeneic hematopoietic stem cell transplantation (alloHSCT) to prevent graft-versus-host disease (GvHD). We compared 2 different ATGs in alloHSCT after reduced intensity conditioning (RIC) for hematological malignancies. We reviewed 30 alloHSCT for hematologic malignancies performed between 2007 and 2010 with fludarabine and i.v. busulfan as conditioning regimen. Patients alternatingly received Thymoglobulin or ATG-F. Median followup was 3.3 (2.5–4.5) years. Adverse events appeared to occur more frequently during Thymoglobulin infusion than during ATG-F infusion but without statistical significance (P=0.14). There were also no differences in 3-year overall survival (OS), disease-free survival (DFS), relapse incidence, and transplant related mortality (TRM) in the Thymoglobulin versus ATG-F group: 45.7% versus 46.7%, 40% versus 33.7%, 40% versus 33.3%, and 20% versus 33.3%. The same held for graft failure, rejection, infectious complications, immune reconstitution, and acute or chronic GvHD. In patients transplanted for hematologic malignancies after RIC, the use of Thymoglobulin is comparable to that of ATG-F in all the aspects evaluated in the study. However due to the small number of patients in each group we cannot exclude a possible difference that may exist.

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Rapid Immune Reconstitution after a Reduced-Intensity Conditioning Regimen and a CD3-Depleted Haploidentical Stem Cell Graft for Pediatric Refractory Hematologic Malignancies.

Blood ◽

10.1182/blood.v108.11.5311.5311 ◽

2006 ◽

Vol 108 (11) ◽

pp. 5311-5311

Author(s):

Xiaohua Chen ◽

Gregory A. Hale ◽

Raymond C. Barfield ◽

Ely Benaim ◽

Wing H. Leung ◽

...

Keyword(s):

Stem Cell ◽

Nk Cells ◽

Immune Reconstitution ◽

Acute Gvhd ◽

Conditioning Regimen ◽

Hematologic Malignancies ◽

Reduced Intensity Conditioning ◽

Hematopoietic Stem ◽

Reduced Intensity Conditioning Regimen ◽

Reduced Intensity

Abstract Haploidentical hematopoietic stem cell transplantation (HaploHSCT) from a mismatched family member (MMFM) donor offers an alternative option for patients who lack an HLA-matched donor. The main obstacles to successful haploidentical hematopoietic stem cell transplantation from a mismatched family member donor are delayed immune reconstitution, vulnerability to infections, and severe graft-versus-host disease (GvHD). Method: We designed a reduced-intensity conditioning regimen that excluded total body irradiation and anti-thymocyte globulin. The graft was immunomagnetically depleted of CD3+ T-cells (CD3 negative selection) and contained a large number of both CD34+ and CD34− stem cells and most other immune cells especailly NK cells. This protocol was used to treat 22 pediatric patients with refractory hematologic malignancies. Results and Discussion: After transplantation, 91% of the patients achieved full donor chimerism. They also showed rapid recovery of CD3+ T-cells, T-cell receptor excision circle counts, TCRβ repertoire diversity and NK-cells during first four months post-transplantation. The incidence and extent of viremia were limited and no lethal infection was seen. Only 9% of patients had grade 3 acute GvHD, while 27% patients had grade 1 and another 27% had grade 2 acute GvHD. This well-tolerated regimen appears to accelerate immune recovery and shorten the duration of early post-transplant immunodeficiency, thereby reducing susceptibility to viral infections. Rapid T-cell reconstitution, retention of NK-cells in the graft, and induction of low grade GvHD may also enhance the potential anti-cancer immune effect.

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Haploidentical stem cell transplantation after a reduced-intensity conditioning regimen for the treatment of advanced hematologic malignancies: posttransplantation CD8-depleted donor lymphocyte infusions contribute to improve T-cell recovery

Blood ◽

10.1182/blood-2008-10-183723 ◽

2009 ◽

Vol 113 (19) ◽

pp. 4771-4779 ◽

Cited By ~ 57

Author(s):

Anna Dodero ◽

Cristiana Carniti ◽

Anna Raganato ◽

Antonio Vendramin ◽

Lucia Farina ◽

...

Keyword(s):

Stem Cell ◽

T Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Conditioning Regimen ◽

Hematologic Malignancies ◽

Reduced Intensity Conditioning ◽

Hematopoietic Stem ◽

Reduced Intensity ◽

Donor Lymphocyte Infusions

Abstract Haploidentical hematopoietic stem cell transplantation provides an option for patients with advanced hematologic malignancies lacking a compatible donor. In this prospective phase 1/2 trial, we evaluated the role of reduced-intensity conditioning (RIC) followed by early add-backs of CD8-depleted donor lymphocyte infusions (DLIs). The RIC regimen consisted of thiotepa, fludarabine, cyclophosphamide, and 2 Gy total body irradiation. Twenty-eight patients with advanced lymphoproliferative diseases (n = 24) or acute myeloid leukemia (n = 4) were enrolled. Ex vivo and in vivo T-cell depletion was carried out by CD34+ cell selection and alemtuzumab treatment. The 2-year cumulative incidence of nonrelapse mortality was 26% and the 2-year overall survival (OS) was 44%, with a better outcome for patients with chemosensitive disease (OS, 75%). Overall, 54 CD8-depleted DLIs were administered to 23 patients (82%) at 3 different dose levels without loss of engraftment or acute toxicities. Overall, 6 of 23 patients (26%) developed grade II-IV graft-versus-host disease, mainly at dose level 2. In conclusion, our RIC regimen allowed a stable engraftment with a rather low nonrelapse mortality in poor-risk patients; OS is encouraging with some long-term remissions in lymphoid malignancies. CD8-depleted DLIs are feasible and promote the immune reconstitution.

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Long Term Results of Fludarabine/Melphalan as Reduced Intensity Conditioning Regimen (RIC) for Transplantation in Mantle Cell Lymphoma (MCL): Age Matters

Blood ◽

10.1182/blood.v112.11.4388.4388 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4388-4388

Author(s):

Jorge Gayoso ◽

Rodrigo Martino ◽

Pascual Balsalobre ◽

Javier De la Serna ◽

José Francisco Tomás ◽

...

Keyword(s):

Chronic Gvhd ◽

Conditioning Regimen ◽

Disease Free Survival ◽

Long Term Results ◽

Mixed Chimerism ◽

Reduced Intensity Conditioning ◽

Who Grade ◽

Reduced Intensity

Abstract Introduction: Myeloablative allogeneic stem cell transplantation in patients (pts) with MCL has been traditionally used only in young pts without co-morbidities due to its high toxicity. During the last 10 years, many different reduced intensity conditioning (RIC) regimens have been introduced into clinical practice trying to reduce this toxicity, preserving the establishment of a meaningful graft-tumor effect (GVT). However, few homogeneus pts series have been reported focused on MCL, with encouraging results in some studies. Thus, we report herein the outcome of 18 consecutive MCL pts who received an allo-PBSC-RIC from an HLA-identical sibling donor with a long follow-up. Patients and methods: The RIC consisted in iv fludarabine 125–150 mg/m2 from day-8 to -4 and iv melphalan 80 or 140 mg/m2 on day-3 to -2. Rituximab 375 mg/m2 was added to RIC in 8 pts on days-9, +1, +8 and +15. GVHD prophylaxis consisted in standard cyclosporine and methotrexathe. Gradual cyclosporine tappering from day +50 was initiated if mixed chimerism or persistent disease were present. We focus on engraftment kinetics, early toxicities, non-relapse mortality (NRM), chimerism kinetics, GVHD as well as estimated anti-tumoral efficacy, progression-free and overall survival (PFS and OS). Results: 18 MCL pts were included from 2000 to 2008, with a median follow-up of 50 months. Median age was 56 years (range: 43–68), 13 were males, with a median pre-RIC treatment lines of 2 (1–4) including 2 autoHSCT. Before alloRIC, 13 pts (72%) were in 1st or later CR, while 5 pts (28%) were in chemo-sensitive PR. Median CD34+/kg infused cells were 5,8 ×106 (4,3–10,8) and 2,0 ×108 (0,7–4,1) CD3+ lymphocytes/kg. All pts engrafted, reaching ANC>500 on day +16 (13–20) and platelets>20.000 on day +12 (8–32), with no graft failures. Early toxicity (<day +100) included WHO grade 3–4 mucositis in 8 (44%), febrile neutropenia in 6 (33%) and bacterial infections in 4 (22%) with 2 deaths (1 varicella-zoster encephalitis and 1 refractory acute GVHD). There were 2 other deaths during the 1st year, both due to infections in the setting of extensive chronic GVHD, for a 1-year NRM of 22%. Complete donor T-cell chimerism (CC) was present at day +30 in 71% of evaluated pts and in 100% pts at day +90. Acute grade II–IV GVHD ocurred in 39% of pts at risk, with 17% of grade III–IV. Chronic GVHD affected 12/16 pts (75%), wich was extensive in 6 (38%). Only 1 patient (trasplanted in PR after 2 treatment lines) relapsed (6%). The 5-year estimated PFS and OS were both 77% (CI95%=58–97%) and 14 pts remain alive in CR. The only apparent prognostic factor in our study is age: 8 pts aged 60 or older have an OS of 33,3% vs 100% for the 10 pts younger than 60 years (p<0.001). Conclusions: AlloRIC with fludarabine and melphalan in MCL pts offers a good toxicity profile, with high engraftment rate and good long term disease-free survival, especially in pts younger than 60. The very low long-term relapse rate seen in the context of a high incidence of chronic GVHD supports the continued sensitivity of MCL to a GVT effect. Figure Figure

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Favorable Outcomes with Acceptable Toxicity Using a Reduced Intensity Conditioning Regimen for Patients Otherwise Ineligible for Related Donor Allogeneic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v104.11.5137.5137 ◽

2004 ◽

Vol 104 (11) ◽

pp. 5137-5137

Author(s):

Peter Westervelt ◽

Wendy Holmes ◽

Robert Emmons ◽

Pamela Becker ◽

Phil Lowry ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Hematologic Malignancies ◽

Reduced Intensity Conditioning ◽

Reduced Intensity Conditioning Regimen ◽

Reduced Intensity

Abstract Allogeneic stem cell transplantation represents a potentially curative treatment modality for patients with advanced hematologic malignancies. However, the toxicity associated with fully myeloablative conditioning regimens has historically limited its use to younger, otherwise healthy patients. To investigate the feasibility of allogeneic stem cell transplantation in older (over 55 years) or otherwise higher risk patients (eg, prior transplant) with fully HLA-matched sibling donors, a reduced intensity conditioning regimen consisting of fludarabine (30 mg/M2 IV qd X 6, day −8 to −3), ATGAM 10 mg/kg IV qod X 4, day −7/−5/−3/−1) and melphalan (100 mg/M2 IV X 1, day −2) was employed in a single institution setting. GVHD prophylaxis consisted of cyclosporine (2 mg/kg IV bid, adjusted, beginning day −1) and methotrexate (10 mg/m2 IV, day +1/+3/+6). RESULTS: 21 patients with a variety of hematologic malignancies (AML=4, MDS=5, NHL=5, CML/MPD=3, HD=2, MM=1, CLL=1) were enrolled. Mean age was 54 years (range 28–66). 7 patients had undergone prior autologous transplants. Median followup among surviving patients was 42 months (range 3–58 months). Peripheral blood chimerism at day +100 was >95% donor in 16/18 patients, 80% (with subsequent conversion to 95%) in one patient, and >95% recipient (with documented relapse) in one patient. Acute GVHD grade 1–2 was seen in 52% and grade 3–4 in 10% of patients. Chronic GVHD was observed in 9/20 evaluable patients (45%). Infectious complications included documented bacteremia (6 cases), candida albicans fungemia (1), aspergillus pneumonitis (3), nocardia pneumonitis (2), CMV viremia (6), CMV colitis (1). Veno-occlusive disease (self-limited, grade 1–2) was observed in 4/21 patients (19%). Relapse was observed in 5/21 patients (24%) at a median 249 days post-transplant (range 97–328 days). Event-free survival was 90% (19/21) at 100 days, 58% (11/19) at 1 year and 47% (8/17) at 3 years. Overall survival was 95% (20/21) at 100 days, 68% (13/19) at 1 year and 47% (8/17) at 3 years. Primary causes of death were relapse (4/9), infection (4/9), and idiopathic pneumonitis/multi-organ failure (1/9). Chronic GVHD was a significant contributing factor in 3/4 fatal infections. PTLD was observed in one patient, who subsequently died of CMV infection/sepsis syndrome. CONCLUSIONS. Allogeneic BM/SCT using a reduced intensity conditioning regimen is feasible among older patients, and those who are otherwise poor candidates for myeloablative BM/SCT regimens; however, GVHD, infection, and relapse remain formidable obstacles to achieving successful outcomes.

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Outcome of Relapse after Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) - The Effect of the Underlying Disease on Survival Following Relapse.

Blood ◽

10.1182/blood.v110.11.5020.5020 ◽

2007 ◽

Vol 110 (11) ◽

pp. 5020-5020

Author(s):

Seema Singhal ◽

Olga Frankfurt ◽

Andrew Evens ◽

Leo Gordon ◽

Martin Tallman ◽

...

Keyword(s):

Acute Leukemia ◽

Salvage Therapy ◽

Performance Status ◽

Conditioning Regimen ◽

Disease Free Survival ◽

Hematologic Malignancies ◽

Underlying Disease ◽

Hematopoietic Stem ◽

Reduced Intensity

We have reported that the outcome of reduced-intensity allogeneic HSCT is not affected by the underlying diagnosis (Mehta et al, ASH 2006). With an additional year’s follow-up and a minimum follow-up of 18 months, this observation continues to remain valid in a series of 91 uniformly-treated patients with hematologic malignancies (19–71 years; median 53; 22% >60 years). 29 patients had acute leukemia, 38 had lymphoma (Hodgkin/NHL) or CLL, and 24 had myeloma. Two-thirds of the patients had refractory disease. Performance status (PS) was 0 in 31%, 1 in 47%, and 2/3 in 22%. Donors (55% aged >45 years) were HLA-matched siblings (n=51), 10/10 allele-matched unrelated individuals (n=29), or 9/10 allele-matched related/unrelated individuals (n=11). The conditioning regimen comprised 100 mg/m2 melphalan with (if no prior autograft) or without (prior autograft) 50 mg/kg cyclophosphamide. GVHD prophylaxis comprised cyclosporine-mycophenolate (HLA-matched sibling donors) or tacrolimus-mycophenolate (other type of donors). G-CSF or GM-CSF were not given routinely to accelerate engraftment. Supportive care was uniform. As the figure shows, the underlying disease did not affect overall survival (OS) after HSCT. Figure Figure The underlying disease did not affect disease-free survival, relapse risk or transplant-related mortality. 51 of these patients relapsed. Relapsed disease was treated with immunotherapy (withdrawal of immunosuppression and/or donor cell infusion), and/or non-immune salvage treatment options. The latter included conventional chemotherapy for all 3 disease groups, monoclonal antibodies for NHL, and drugs such as thalidomide, bortezomib and lenalidomide for myeloma. Some patients with poor performance status received only supportive therapy. 43 of the 51 relapsing patients, including all with acute leukemia, died of progressive disease or complications of salvage therapy. The 8 survivors have lymphoma or myeloma, and are in remission or have stable disease. As the figure shows, OS after relapse was significantly affected by the underlying disease. Figure Figure Other factors affecting OS significantly after relapse were LDH and performance status. These data suggest that the outcome of patients with hematologic malignancies is generally poor if the disease relapses after reduced-intensity HSCT. However, some patients with lymphoma or myeloma can survive for prolonged periods after relapse because of effective salvage therapy options. Patients with acute leukemia fare poorly because of lack of effective salvage therapy, and exploration of strategies such as a second allograft may be appropriate for them.

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Salvage HLA-haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide for graft failure in non-malignant disorders

Bone Marrow Transplantation ◽

10.1038/s41409-021-01323-9 ◽

2021 ◽

Author(s):

Michael H. Albert ◽

Mehtap Sirin ◽

Manfred Hoenig ◽

Fabian Hauck ◽

Catharina Schuetz ◽

...

Keyword(s):

T Cell ◽

Graft Failure ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Reduced Intensity Conditioning ◽

Post Transplantation ◽

Hematopoietic Stem ◽

Reduced Intensity

AbstractGraft failure requires urgent salvage HSCT, but there is no universally accepted approach for this situation. We investigated T-cell replete haploidentical HSCT with post-transplantation cyclophosphamide following serotherapy-based, radiation-free, reduced intensity conditioning in children with non-malignant disorders who had rejected their primary graft. Twelve patients with primary or secondary graft failure received T-cell replete bone marrow grafts from haploidentical donors and post-transplantation cyclophosphamide. The recommended conditioning regimen comprised rituximab 375 mg/m2, alemtuzumab 0.4 mg/kg, fludarabine 150 mg/m2, treosulfan 20–24 g/m2 and cyclophosphamide 29 mg/kg. After a median follow-up of 26 months (7–95), eleven of twelve patients (92%) are alive and well with complete donor chimerism in ten. Neutrophil and platelet engraftment were observed in all patients after a median of 18 days (15–61) and 39 days (15–191), respectively. Acute GVHD grade I was observed in 1/12 patients (8%) and mild chronic GVHD in 1/12 patients (8%). Viral reactivations and disease were frequent complications at 75% and 42%, respectively, but no death from infectious causes occurred. In summary, this retrospective analysis demonstrates that a post-transplantation cyclophosphamide-based HLA-haploidentical salvage HSCT after irradiation-free conditioning results in excellent engraftment and overall survival in children with non-malignant diseases.

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