CONDITIONING REGIMEN FOR LANGERHANS HISTIOCYTOSIS

Langerhans cell histiocytosis (LCH) is a rare disease, with an estimated incidence of 0.5 per 100,000 children in the United States of America1. HCL occurs due to differentiation of myeloid precursors into CD1a+ / CD207+ cells and is characterized by constitutional activation of the MAPK2 signaling pathway, leading to a spectrum of organ involvement and dysfunction. Treatment of HCL is risk-adjusted: single lesions may respond to local treatment whereas multisystem disease requires systemic therapy. Although survival for patients without organ dysfunction is excellent3, mortality in those with compromised organs at risk (hematopoietic system, liver, and/or spleen) reaches 20%2,4. Despite the progress made in the treatment of HCL, disease reactivation rates remain above 30% and the best second-line treatment has not yet been established. Treatment failure is associated with increased morbidity and mortality, including an association with neurodegeneration2. As it is a rare disease and generally has a good prognosis, few scientific studies are evaluating the role of allogeneic hematopoietic stem cell transplantation (HSCT) in the treatment of this disease. In 2015 Veys et al5 published retrospective results of 87 high-risk patients transplanted between 1990 and 2013. Myeloablative conditioning regimens (MAC) based on total body irradiation or busulfan6 were the most used until the 2000s, and reduced-intensity conditioning regimens (RIC) – predominantly a combination of Melphalan and Fludarabine – were most used between 2000 and 2013. Transplant-associated mortality rates in 3 years were similar between RIC and MAC conditioning regimens (21% versus 15%, respectively). Recurrence was higher in the RIC group compared to the MAC group (28% versus 8%, respectively), however, the 3-year overall survival (OS) was similar (77% versus 71%, respectively), since the patients who relapsed after RIC transplantation could be rescued with chemotherapy. More recently, Kudo et al7 published a retrospective study with 30 patients with refractory LCH who underwent HSCT between 1996 and 2014. Eleven patients received myeloablative conditioning regimen based on total body radiotherapy (RCT) with a dose equal to or greater than 8 Gy or busulfan, and 19 of reduced intensity based on Fludarabine and Melphalan, associated or not with low dose of RCT. There was no significant difference between the conditioning regimen modalities, with OS of 56.8% for the RIC group and 63.6% for the MAC group. Disease status was the main prognostic factor, with a 5-year OS of 100% for patients who arrived at HSCT with disease in remission or with partial remission, versus 54.5% for those who had active disease at the time of the procedure. Regarding the type of donor used and the source of stem cells, there is great variation, with greater frequency for unrelated and extensive use of bone marrow and umbilical cord, and apparently, there is no impact on survival rates.5, 6 There are few case reports and extremely restricted performance of autologous HSCT in HCL.

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Concurrent Fludarabine and Cyclophosphamide As a Reduced Intensity Conditioning Regimen Prior to Allogeneic Hematopoietic Stem Cell Transplantation Ablates Host T-Cells and Results in Rapid Full Donor Chimerism

Blood ◽

10.1182/blood.v118.21.1937.1937 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1937-1937

Author(s):

Rachel B. Salit ◽

Michael R. Bishop ◽

Steven Z. Pavletic ◽

Frances T. Hakim ◽

Seth M. Steinberg ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Conditioning Regimen ◽

Reduced Intensity Conditioning ◽

Myeloablative Conditioning ◽

Hematopoietic Stem ◽

Donor Chimerism ◽

Conditioning Regimens ◽

Reduced Intensity

Abstract Abstract 1937 Background: Reduced intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (HSCT) is associated with decreased transplant-related mortality (TRM). However, RIC-HSCT is typically associated with higher rates of mixed chimerism and graft rejection compared to myeloablative conditioning. Host T-cell immunity has been demonstrated to be an important predictor of engraftment and establishment of full donor chimerism in clinical studies. It was previously demonstrated in murine models that concurrent fludarabine (F) and cyclophosphamide (C) ablated host T-cells to the extent of myeloablative total body irradiation with reduced myeloid cell toxicity and prevented rejection of fully MHC-disparate marrow allografts (Petrus et al, BBMT, 2000). While fludarabine and cyclophosphamide are agents commonly used in reduced intensity conditioning regimens, their concurrent use has never been reported. Here, we analyze results from 102 patients who received the reduced intensity conditioning FC regimen in the setting of matched related or unrelated allogeneic stem cell transplantation. Methods: On four consecutive protocols at the National Cancer Institute, hematologic malignancy patients received induction chemotherapy followed by the FC regimen: fludarabine 30 mg/m2/d, days −6 to −3 and cyclophosphamide 1200 mg/m2/d, days −6 to −3. Peripheral blood stem cells were infused on Day 0. GVHD prophylaxis was either a calcineurin inhibitor alone or in combination with other agents. Results: 102 patients (females, 36; males, 66) were enrolled on study. Median age was 50 yrs (range, 21–71). Diagnoses included AML/MDS (n = 2), HL (n = 12), DLBCL (n = 35), CLL (n = 13), FL (n = 12), MCL (n = 10) and TCL (n = 10). Median number of prior regimens = 3 (range, 1 – 9); 25 patients had prior autologous transplant. Transplants were performed using HLA - matched sibling donors (n = 82) or 10/10 matched unrelated donors (n = 20). At the time of study entry, disease status was defined as chemosensitive (n = 53) or chemorefractory (n = 49). Patients were in CR (n = 19), PR (n = 26), SD (n = 37), or PD (n = 19); one patient was not evaluable. 101 of 102 patients (99%) proceeded to transplant. Median CD3+, CD4+, and CD8+ lymphocyte counts after induction chemotherapy (pre-FC conditioning) were: 150 cells/μl (1–1557), 80 cells/μl (0–1332), and 52 cells/μl (52–1195), respectively. Following FC conditioning, median CD3+, CD4+, and CD8+ counts were: 3 cells/μl (0–65), 3 cells/μl (0–93), and 0 cell/μl (0–22) (each p< 0.0001). All patients engrafted. Median time to neutrophil engraftment (ANC > 500) was 10 days and platelet engraftment (plt > 20 48 hours post transfusion) was 11 days. At Day +14, median CD3+ chimerism was 100% (range 30–100%), CD14+/15+ chimerism was 100% (range 6–100%), and whole blood chimerism was 100% (range 11–100%). Patients maintained full donor chimerism as evidenced by median 100% (range 50–100%) whole blood chimerism at Day +100. By Day +28 post-transplant, 41 patients (40%) achieved (n=24) or maintained (n=17) a CR and 38 patients (37%) achieved or maintained a PR for an overall response rate of 77%. Fourteen patients had SD and 4 had PD. Day +100 and one year TRM were 7% and 15% respectively. With a median follow-up of 92.4 months, 1 yr and 2 yr EFS were 52% and 41% and 1 yr and 2 yr OS were 68% and 58% respectively. Both EFS (p = 0.0003) and OS (p = 0.01) were significantly associated with response to FC. Acute GVHD grades II-IV and III-IV occurred in 56% and 23% of patients respectively. The rate of chronic GVHD was 65%. Grade IV non-hematologic toxicities as of Day +28 post-transplant included cardiac (n = 7, n = 1 Grade V), pulmonary (n=9), GI (n=9), and neurologic (n=3). While 62% of patients had at least one Grade III infection, only 2 patients had a Grade IV infection. Conclusion: The concurrent FC conditioning regimen resulted in host T-cell ablation and rapid full donor chimerism characteristic of myeloablative conditioning regimens. Furthermore, RIC-HSCT using concurrent FC achieved a high rate of complete remissions with an acceptable safety profile. Disclosures: No relevant conflicts of interest to declare.

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Reduced Intensity Conditioning Compared With Myeloablative Conditioning Using Unrelated Donor Transplants in Patients With Acute Myeloid Leukemia

Journal of Clinical Oncology ◽

10.1200/jco.2008.20.9692 ◽

2009 ◽

Vol 27 (27) ◽

pp. 4570-4577 ◽

Cited By ~ 184

Author(s):

Olle Ringdén ◽

Myriam Labopin ◽

Gerhard Ehninger ◽

Dietger Niederwieser ◽

Richard Olsson ◽

...

Keyword(s):

Conditioning Regimen ◽

Multivariable Analysis ◽

Unrelated Donor ◽

Reduced Intensity Conditioning ◽

Myeloablative Conditioning ◽

Peripheral Blood Stem Cells ◽

Hematopoietic Stem ◽

Blood Stem Cells ◽

Total Body ◽

Reduced Intensity

Purpose Reduced intensity conditioning regimen (RIC) is increasingly used in hematopoietic stem cell transplantation (HSCT). Unrelated donor (UD) transplants have more complications. We wanted to examine if RIC is a valid treatment option using UD in acute myeloblastic leukemia (AML). Patients and Methods Between 1999 and 2005, 401 patients with AML were treated with RIC and 1,154 received myeloablative conditioning (MAC), using UD and reported to the European Group for Blood and Marrow Transplantation Registry. Patients < and ≥ 50 years of age were analyzed separately. Results Patients receiving RIC were older, received transplants more recently, received peripheral blood stem cells more frequently, and were treated with total-body irradiation less often. In multivariable analysis, in patients younger than 50 years of age, nonrelapse mortality (NRM) was similar using RIC (hazard ratio [HR], 0.85; P = .41), relapse was increased (HR, 1.46; P = .02) and leukemia-free survival (LFS) was the same (HR, 0.88; P = .28), as compared with MAC. In patients ≥ 50 years of age, NRM was decreased in the RIC group (HR, 0.64; P = .04), relapse probability was not significantly different (HR, 1.34; P = .16) and LFS was similar (HR, 1.04; P = .79) compared with MAC. Conclusion RIC-UD transplants are associated with higher relapse in AML patients younger than 50 years of age and decreased NRM in those ≥ 50 years compared with MAC-UD. LFS was similar after both conditioning regimens, regardless of age. Therefore, RIC-UD extend the use of allotransplants for elderly patients and strategies that decrease relapse should be considered mainly in younger patients with AML.

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Reduced Intensity Vs. Non-Myeloablative Conditioning Regimens for Haploidentical Transplantation in Complete Remission Acute Myeloid Leukemia: A Study from the ALWP of the EBMT

Blood ◽

10.1182/blood-2020-140657 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 9-9

Author(s):

Raynier Devillier ◽

Jacques-Emmanuel Galimard ◽

Myriam Labopin ◽

Didier Blaise ◽

Emanuele Angelucci ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Conditioning Regimen ◽

Myeloablative Conditioning ◽

Advisory Committees ◽

Significant Difference ◽

Conditioning Regimens ◽

Conditioning Intensity ◽

Reduced Intensity

Background: In the context of a haploidentical stem cell transplantation (Haplo-SCT) platform with post transplantation cyclophosphamide (PT-Cy) for acute myeloid leukemia (AML) patients, the optimal conditioning regimen remains unknown. A non-myeloablative conditioning (NMAC) regimen (cyclophosphamide + fludarabine + 2Gy TBI [CyFluTBI]) was initially reported by the Johns Hopkins group as a safe approach in this setting, notably to treat patients of advanced age and/or with comorbid conditions. However, relapse incidence after NMAC Haplo-SCT remains high in AML where it can reach 45%. Alternatively, a reduced intensity conditioning (RIC) regimen containing an antileukemic drug combination like thiotepa and reduced-dose busulfan in addition to fludarabine (TBF) may decrease AML relapse. However, this anticipated benefit may be counterbalanced by a higher incidence of toxicity, graft-versus-host disease (GVHD) and non-relapse mortality (NRM). To date, no study comparing TBF vs. CyFluTBI has been published in complete remission (CR) AML. We performed this retrospective comparison on behalf of the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT). Methods: We retrospectively analyzed 398 patients from the EBMT registry database with the following inclusion criteria: 1) adult patient in CR1 or CR2 AML; 2) T-replete Haplo-SCT with PT-Cy; 3) no in vivo depletion using antithymocyte globulin or alemtuzumab; and 4) receiving either TBF RIC (equivalent of 2-day iv busulfan dose) or CyFluTBI NMAC regimen. We compared separately TBF vs. CyFluTBI in patients younger (n=170, 82 TBF vs. 88 CyFluTBI) and older (n=228, 141 TBF vs. 87 CyFluTBI) than 60 years. Results: In patients younger than 60 years, the 2-year cumulative incidence of relapse (CIR) was significantly lower in the TBF group compared with the CyFluTBI group (TBF vs. CyFluTBI: 14% vs. 43%, p<0.01). No significant increase in 2-year NRM was observed (TBF vs. CyFluTBI: 22% vs. 16%, p=0.15). This led to a significantly higher 2-year leukemia-free survival (LFS) probability in the TBF group (64% vs. 41%, p=0.03). After adjustment in multivariate analysis, CyFluTBI was associated with a higher risk of relapse (hazard ratio [HR] 3.4, 95%CI [1.4-6.9], p<0.01), lower LFS (HR 1.8, 95%CI 1.1-3.0, p=0.03) and lower overall survival (OS) (HR 1.8, 95%CI 1.1-3.1, p=0.02), without significant impact of conditioning regimen on incidence of GVHD and NRM. In patients older than 60 years, univariate analysis did not show any significant difference in outcome according to the type of conditioning regimen (2-year NRM: TBF vs. CyFluTBI: 33% vs. 25%, p=0.23; 2-year CIR: TBF vs. CyFluTBI: 23% vs. 28%, p=0.20; 2-year LFS: TBF vs. CyFluTBI: 44% vs. 47%, p=0.96). Multivariate analysis showed a significant reduction in the risk of NRM after CyFluTBI (HR 0.5, 95%CI [0.2-0.9], p=0.04), while a non-significant increase in the risk of relapse was observed (HR 1.9, 95%CI [0.8-4.2], p=0.13). Finally, there was no significant difference in LFS (HR 0.9, 95%CI [0.5-1.5], p=0.67) and OS (HR 0.9, 95%CI [0.5-1.5], p=0.67). Conclusion: Our study suggests that in CR AML patients aged younger than 60 years, the use of TBF RIC provides better outcomes than NMAC CyFluTBI due to lower incidence of relapse, without significant increase in the risk of NRM. Conversely, it seems that older patients do not benefit from such conditioning intensification, due to a significantly higher risk of NRM after TBF RIC. Thus, in CR AML patients who will not receive a truly myeloablative regimen prior to PT-Cy Haplo-SCT, age could be used for determining the conditioning intensity from the wide variety of reduced toxicity conditioning regimens. Beyond the patient age, further prospective trials should assess patient-based parameters that may be useful for a fine tuning of conditioning intensity in a more individualized approach. Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Blaise:Jazz Pharmaceuticals: Honoraria. Bug:Sanofi: Other: Travel; Neovii: Other: Travel; Jazz: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Hexal: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Eurocept: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel. Mohty:Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Stemline: Consultancy, Honoraria, Research Funding, Speakers Bureau.

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Impacts of Total Body Irradiation in Allogeneic Umbilical Cord Blood Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood-2021-152893 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4852-4852

Author(s):

Jeffrey J. Pu ◽

Kristin N. Berger ◽

Hao Wang ◽

Wei Fu ◽

Elizabeth L Miller ◽

...

Keyword(s):

Stem Cell ◽

Cord Blood ◽

Umbilical Cord ◽

Umbilical Cord Blood ◽

Conditioning Regimen ◽

Hematopoietic Stem ◽

Significant Difference ◽

Conditioning Regimens ◽

Total Body ◽

Univariate Analyses

Abstract Background: Umbilical cord blood hematopoietic stem cell transplant (UCBT) has been practiced as an alternative source of hematopoietic stem cells for patients in need of transplantation. Double-units UCBT has been established as a means of achieving a cell dose of at least 2.5x10 7 nucleated cells per kilogram of body weight in adult recipients. The advantages of UCBT include its rapid availability, reduced stringency in terms of human leukocyte antigen (HLA) match requirements, and subsequent increase in access to transplants for racial minorities. Both related and unrelated UCBTs with single or double units have been performed with high rates of success in both pediatric and adult settings to treat a variety of medical conditions. Prior to undergoing UCBT, recipients must undergo a conditioning regimen to create space in the bone marrow, suppress the immune system to allow for donor stem cell engraftment, and reduce the tumor burden in cases of neoplastic disease. Total body irradiation (TBI) is commonly incorporated into conditioning regimens to enforce these efforts. Although intense myeloablation in general is associated with a lower risk of relapse and graft rejection, greater regimen intensity also leads to a higher rate of transplant related morbidity and mortality (TRM). Inclusion of TBI specifically in conditioning regimens has been shown to result in organ toxicity and subsequent malignant neoplasm. To help mitigate the risks of myeloablative conditioning (MAC) regimens, non-TBI and reduced-intensity conditioning (RIC) regimens have been investigated as a means of reducing TRM and increasing access of transplantation to patients with age disadvantages or significant comorbidities. Despite ongoing investigation, studies comparing conditioning regimens of UCBT, with and without TBI, remain limited. This study, using real-world data collected from 4 institutions, retrospectively analyzed the impact of TBI as part of MAC or RIC conditioning regimens in patients undergoing UCBT. Methods: This is a retrospective study that analyzed the outcomes of 136 patients receiving umbilical cord blood transplants at four institutions. Seventy-nine patients received myeloablative condition (MAC), in which 36 underwent TBI and 33 did not; 67 patients received reduced-intensity condition (RIC), in which 24 underwent TBI and 43 did not. Univariate and multivariate analyses were conducted to compare the outcomes and the post-transplant complications between patients who did and did not undergo TBI in MAC subgroup and RIC subgroup, respectively. Results: Characteristics of UCBT recipients who did and did not undergo TBI, stratified by conditioning regimen were compared with both multivariate and univariate analyses and didn't see significant difference. We didn't observe significant difference in GVHD and transplant-related infection incidence rates between patient subgroup that did and did not undergo TBI as part of their pre-UCBT conditioning regimen via both multivariate and univariate analyses. In RIC subgroup, the patients who underwent TBI appeared to have superior overall survival (adjusted hazard ratio [aHR]=0.25, 95% confidence interval [CI]: 0.09-0.66, p=0.005) (Figure 1), progression-free survival (aHR=0.26, 95% CI: 0.10-0.66, p=0.005) (Figure 2), and shorter time to neutrophil engraftment (aHR=6.26, 95% CI: 2.27 - 17.31, p=0.0004) (Figure 3). However, in MAC subgroup, there were no statistically significant difference between using and not using TBI. There were also no differences between the patients who either underwent or not underwent TBI in terms of acute or chronic GVHD rates or rates of transplant-related infections in both subgroups. Conclusion: Combining with RIC, TBI may improve OS, PFS, and neutrophil engraftment time. However, the incidences of other post-transplant complication were comparable between patients who underwent and did not undergo TBI as part of conditioning regimens during umbilical cord blood transplant. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Antibody-Based Depletion of Hematopoietic Stem Cells Empties Niches for Efficient Transplantation.

Blood ◽

10.1182/blood.v110.11.lb2.lb2 ◽

2007 ◽

Vol 110 (11) ◽

pp. LB2-LB2

Author(s):

Agnieszka Czechowicz ◽

Daniel L. Kraft ◽

Deepta Bhattacharya ◽

Irving L. Weissman

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Stem Cell ◽

Hematopoietic Stem Cells ◽

Conditioning Regimen ◽

Myeloablative Conditioning ◽

Hematopoietic Stem ◽

Exact Function ◽

Potential Applications ◽

Conditioning Regimens

Abstract Hematopoietic stem cells (HSCs) are used therapeutically in bone marrow/hematopoietic stem cell transplantation (BMT/HSCT) to correct hematolymphoid abnormalities. Upon intravenous transplantation, HSCs can home to specialized bone marrow niches, self-renew and differentiate and thus generate a new, complete hematolymphoid system. Unfortunately BMT has had limited applications, due to the risks associated with the toxic conditioning regimens, such as irradiation and chemotherapy, that are deemed necessary for HSC engraftment. Elimination of these toxic conditioning regimens could expand the potential applications of BMT to include many non-malignant hematologic disorders, a wide variety of autoimmune disorders such as diabetes and multiple sclerosis, as well as in the facilitation of organ transplantation. The exact function of these traditional myeloablative conditioning regimens is not clear. To elucidate the barriers of HSC engraftment, we transplanted 50–1000 purified HSCs (Ckit+Lin−Sca1+CD34+CD150−) into immunodeficient, Rag2−/− or Rag2−/−gc−/− recipient mice and show that HSC engraftment levels rarely exceed 0.5% following transplantation without toxic conditioning, indicating that the immune system is not the only barrier to engraftment. Additionally, we did not observe a significant increase in HSC engraftment when HSC doses of >250 cells were transplanted. Even when up to 18000 HSC were transplanted, we did not see a linear increase in HSC engraftment, indicating that the increased doses of HSCs transplant inefficiently. We believe this is due to the naturally low frequency of available HSC niches, which we postulate may result from the physiologic migration of HSCs into circulation. Conversely, separation of the graft into small fractions and the subsequent time-delayed transplantation of these doses did result in increased engraftment due to the natural physiologic creation of new available HSC niches. When 1800 HSC were transplanted daily for seven days, the engraftment was 6.1-fold higher than transplantation of 12800 HSC in a single bolus. Here, we provide evidence that, aside from immune barriers, donor HSC engraftment is restricted by occupancy of appropriate niches by host HSCs. Through elimination of host HSCs we are able to increase available HSC niches for engraftment. We have developed a novel system where HSCs can be eliminated by targeting C-kit, a cell surface antigen that is highly expressed on the surface of HSCs. Cultivation of HSCs with ACK2, a depleting antibody specific for c-kit, prevented stem-cell factor (SCF) dependent HSC proliferation in vitro and resulted in cell death. Administration of ACK2 to mice led to the rapid and transient removal of >98% of endogenous HSCs in vivo thus resulting in equal numbers of available niches for engraftment. Following ACK2 clearance from serum, transplantation of these animals with donor HSCs led to chimerism levels of up to 90%, representing a 180-fold increase as compared to unconditioned animals. This non-myeloablative conditioning regimen had few side effects, other than temporary loss of coat color. The HSCs in even untransplanted animals rapidly recovered and animals remained healthy and fertile. This work redefines the way we approach BMT/HSCT, and places great emphasis on the necessity to create available HSC niches prior to transplantation. Extrapolation of these methods to humans may enable efficient yet mild conditioning regimens for transplantation, thus expanding the potential applications of BMT/HSCT.

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Pharmacokinetic-Guided Busulfan Based Myeloablative Versus Fixed Dose Reduced Intensity Conditioning Regimen in Patients Older Than 55 Years Undergoing Allogeneic Stem Cell Transplantation for High Risk Hematological Malignancies

Blood ◽

10.1182/blood-2019-125994 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4503-4503

Author(s):

Margaux Damge ◽

Sabine Furst ◽

Bénédicte Devictor ◽

Samia Harbi ◽

Joseph Ciccolini ◽

...

Keyword(s):

Older Patients ◽

Hematological Malignancies ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Reduced Intensity Conditioning ◽

Research Support ◽

Myeloablative Conditioning ◽

Significant Difference ◽

Grade 3 ◽

Reduced Intensity

BACKGROUND Reduced intensity conditioning (RIC) combining fludarabine, busulfan and ATG is commonly used in patients with advanced age and/or comorbid conditions, thus deemed unfit for standard myeloablative conditioning (MAC) regimens (i.e. BuCy or CyTBI12). Although non-relapse mortality (NRM) is dramatically reduced with RIC, relapse remains a major concern. In younger patients, myeloablative doses of busulfan in combination with fludarabine (i.e. myeloablative reduced toxicity conditioning [MA-RTC] regimen) produce similar antitumor effect compared with standard MAC while keeping low NRM. The feasibility of such an approach for older patients is not known. We hypothesized that a pharmacokinetics (PK) guided strategy could improve the safety of busulfan administration, allowing the use of myeloablative doses in older patients. STUDY DESIGN AND METHODS We compared the outcome of patients older than 55 years with hematological malignancies included in a prospective monocentric single arm trial (BxPK: NCT02483325) evaluating the feasibility of PK-guided busulfan doses in myeloablative conditioning regimen (BxPK group: fludarabine 150 mg/m² + IV busulfan targeted AUC 5300 x 4 days + ATG 5 mg/kg) before matched sibling (MSD) or unrelated (URD) donor AlloSCT, with a retrospectively enrolled control cohort of patients with same inclusion criteria, treated during the same period but receiving fixed busulfan dose RIC regimen including fludarabine (150 mg/m²), IV busulfan (260 mg/m²) and ATG (5 mg/kg) [Bx2 group]. The primary objective was 2-year progression-free survival (PFS). Hazard ratio of BxPK vs. Bx2 were adjusted by age, disease risk index (DRI), donor type and hematopoietic cell transplantation comorbidity index (HCT-CI). RESULTS We analyzed 83 consecutive patients (BxPK: n=27; Bx2: n=56) without significant difference in baseline characteristics between both conditioning groups. In the BxPK and Bx2 groups: median age was 65 (range: 57-70) and 63 (range: 55-70) years, respectively (p = 0.552); 10/10 URDs were used for 15 (56%) and 37 (66%) patients, respectively (p = 0.493); HCT-CI was ≥ 3 in 18 (67%) and 28 (50%) patients , respectively (p = 0.232); and DRI was high in 5 (19%) and 5 (9%) patients, respectively (p = 0.369). Based on PK data from day-6 busulfan administration, 22 (81%) patients had dose adjustment (increased and decreased dose in 12 and 10 patients, respectively) in the BxPK group. Median busulfan AUC on day-2 (post adjustment) was 5287 µmol.min (range: 3326-7556). Four patients had AUC > 6000 µmol.min on day-2. Grade 3-4 mucositis (BxPK vs Bx2: 52% vs. 11%, p < 0.001) and nausea (BxPK vs Bx2: 11% vs 0%, p = 0.050) were more frequently observed in the BxPk group. No difference was observed between BxPK and Bx2 patients in grade 3-4 liver (BxPK vs Bx2: 15% vs 11%, p = 0.810), renal (BxPK vs Bx2: 0% vs 1.8%, p = 1) and gastrointestinal tract (BxPK vs Bx2: 11% vs 0%, p = 0.450) toxicities. There was a trend to higher cumulative incidence of grades 2-4 acute graft-versus-host disease (GVHD) at 100 days in the BxPK group (BxPK vs Bx2: 41% vs 29%, p = 0.058) while no difference was observed in 2-year chronic GVHD (BxPK vs Bx2: 41% vs. 36%, p = 0.547). Those trends were confirmed by multivariate analyses (acute GVHD: HR 2.22, 95Cl [1.10-4.48], p = 0.026; chronic GVHD: HR 1.30, 95Cl [0.60-2.80], p=0.502) With a median follow up of 33 months (range: 9-60), 2-year NRM was 19% and 18% (p=0.960) in the BxPK and Bx2 group, respectively. Multivariate analysis confirmed the absence of significant increase in the risk of NRM in the BxPK group (HR 1.11, 95CI [0.36-3.45], p = 0.859). The 2-year cumulative incidence of relapse was 19% and 31% (p=0.269) in the BxPK and Bx2 group, respectively (HR 0.55, 95IC [0.20-1.56], p = 0.264). No significant difference in 2-year PFS (BxPK vs Bx2: 62% vs. 51%, p = 0.391) and OS (BxPK vs Bx2: 70% vs. 61%, p = 0.667) was observed. CONCLUSION In patients older than 55 years who are usually candidates for RIC regimen, the use of PK-guided busulfan myeloablative dose allows delivering higher antitumor intensity without increasing NRM. Beyond the feasibility, we observed low incidence of relapse (19%) and promising OS (70%) suggesting that conditioning intensification may lead to long term disease control. These trends need to be confirmed in a larger comparative study for validating the optimal conditioning intensity in older and/or unfit patients. Disclosures Stoppa: takeda: Other: travel fees; celgene: Other: travel fees, lecture fees. Vey:Novartis: Consultancy, Honoraria; Janssen: Honoraria. Chabannon:Novartis: Other: speaker's fees; Celgene: Other: speaker's fees; Sanofi SA: Other: research support, speaker's fees, hospitalities; Gilead: Other: speaker's fees, hospitalities; EBMT: Other: Working Party Chair, Board member; Fresenius Kabi: Other: research support; Miltenyi Biotech: Other: research support; Terumo BCT: Other: speaker's fees. Blaise:Pierre Fabre medicaments: Honoraria; Sanofi: Honoraria; Molmed: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria.

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Effective Hematopoietic Stem Cell Transplantation with Reduced Intensity Conditioning for Patients with Chronic Granulomatous Disease.

Blood ◽

10.1182/blood.v114.22.3339.3339 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3339-3339

Author(s):

Yoko Mizoguchi ◽

Mizuka Miki ◽

Teruyuki Kajiume ◽

Hiroshi Kawaguchi ◽

Kazuhiro Nakamura ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Conditioning Regimen ◽

Granulomatous Disease ◽

Reduced Intensity Conditioning ◽

Myeloablative Conditioning ◽

Hematopoietic Stem ◽

Life Threatening ◽

Reduced Intensity

Abstract Abstract 3339 Poster Board III-227 Chronic granulomatous disease (CGD) is the most common inherited disorders of phagocytic function caused by abnormal nicotinamide adenine dinucleotide phosphate (NADPH) oxidase which produces reactive oxygen species. Defects in four of the NADPH components are responsible for CGD: gp91phox, p47phox, p67phox and p22phox. Due to the defects in production of superoxide, patients are highly susceptible to catalase-positive infections including fungi, as well as developing granuloma and autoimmune complications. To date, hematopoietic stem cell transplantation (HSCT) is the only curative treatment for patients with CGD. The HSCT for CGD patients using myeloablative conditioning regimen consisting of busulfan and cyclophosphamide (CY) has been proven to cure the disease. However, HSCT with this myeloablative conditioning regimen has considerable risk of transplantation-related morbidity (TRM) and mortality in patients with life-threatening infection and long-term complications including graft-versus host disease (GVHD), pulmonary late effects, and gonadal failure. To avoid the risk of TRM and long-term complications, we underwent bone marrow transplantation (BMT) with reduced-intensity conditioning (RIC) for 12 patients with CGD from 2002 to 2009 in Hiroshima University. Seven patients were transplanted from related donors and five patients from unrelated donors. Conditioning regimens consisted of fludarabine, CY and TBI (3 Gy) with or without antithymoglobulin or melphalan (L-PAM). Three of twelve patients who had severe life-threatening infections such as multiple brain abscesses, multiple liver abscesses or multiple pulmonary abscesses with high level of CRP (>15 mg/dl) underwent BMT. One of three patients who had suffered from severe fungal infection in both lungs was died from pulmonary hemorrhage due to the engraftment syndrome on day 45 after BMT. No TRM during the conditioning and early period after BMT was observed in the remaining 11 patients, irrespective of the presence of active and intractable infections/inflammation. The patients alive were eliminated from infections and/or inflammation with complete chimerism. Four patients undergoing BMT using fludarabine-based regimen without L-PAM required donor lymphocyte infusion to achieve complete donor chimerism. The addition of L-PAM to fludarabine-based RIC rapidly induced the complete engraftment of donor cells without any toxicity in 7 patients. The frequency and severity of acute or chronic GVHD were not significant and sufficiently tolerable. Karnofsky performance scale of all patients alive has been 100% after BMT. Furthermore, apparent endocrinological problems including gonadal function were not observed during the limited period after BMT. These results suggest HSCT using RIC with L-PAM is effective therapy for CGD patients for successful complete engraftment and minimal toxicity. Disclosures No relevant conflicts of interest to declare.

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A phase II pilot study of tacrolimus/sirolimus GVHD prophylaxis for sibling donor hematopoietic stem cell transplantation using 3 conditioning regimens

Blood ◽

10.1182/blood-2009-03-207563 ◽

2010 ◽

Vol 115 (5) ◽

pp. 1098-1105 ◽

Cited By ~ 68

Author(s):

Roberto Rodriguez ◽

Ryotaro Nakamura ◽

Joycelynne M. Palmer ◽

Pablo Parker ◽

Sepideh Shayani ◽

...

Keyword(s):

Thrombotic Microangiopathy ◽

Total Body Irradiation ◽

Cumulative Incidence ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Hematopoietic Stem ◽

Gvhd Prophylaxis ◽

Significant Difference ◽

Conditioning Regimens ◽

Total Body

Abstract Combination tacrolimus and sirolimus graft-versus-host disease (GVHD) prophylaxis for allogeneic transplant in patients conditioned with a fractionated total body irradiation–based regimen has shown encouraging results. We studied this prophylaxis combination in 85 patients receiving a matched-sibling transplant conditioned with 3 different regimens:fludarabine-melphalan (n = 46); total body irradiation–etoposide (n = 28), and busulfan-cyclophosphamide (n = 11). The conditioning regimens were completed on day −4. Sirolimus and tacrolimus were started on day −3 to avoid overlap with conditioning therapy. All patients engrafted, with a median time to neutrophil engraftment of 15 days. The cumulative incidence of acute GVHD grades II to IV and III to IV was 43% and 19%, respectively, with no significant difference by conditioning regimen. The 2-year cumulative incidence of chronic GVHD was 46%. With a median follow-up of 26 months, disease-free survival was 58% and overall survival, 66%. The day-100 and 2-year nonrelapse mortality was 4.8% and 10.2%, respectively. The overall incidence of thrombotic microangiopathy was 19%, and it was significantly higher with busulfan/cyclophosphamide (55%, P = .005). Tacrolimus plus sirolimus is an effective combination for acute GVHD prophylaxis and is associated with very low nonrelapse mortality. Thrombotic microangiopathy is a significant complication with this regimen, particularly in patients receiving busulfan/cyclophosphamide.

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