Haploidentical Stem Cell Transplantation for Children with High-Risk Leukemia In Chile: Report of the First 15 Cases.

Abstract Abstract 4581 The Chilean population is ethnically diverse, and more than 50% of the children referred for hematopoietic stem cell transplantation lack a suitable donor. To expand the donor pool we assessed the feasibility, tolerance, and efficacy of using a parental haploidentical (HI) donor and a reduced-intensity conditioning regimen for patients with high-risk leukemia; this study was preceded by 2 years of technology transfer from St. Jude Children's Research Hospital. Between March 2006 and November 2009 fifteen patients (median age, 9.6 years) received T cell-depleted grafts at Calvo Mackenna Hospital, from peripheral stem cells mobilized with G-CSF from parental donors. N° aphaeresis/patient = one; 6/15 products required a second depletion, final Log of depletion= 3, 11 (5, 05-1, 64). Median cell doses were CD34+: 9.5 × 106 cells/kg (range, 2.13 – 20.0), CD3+: 1.0 ×105cells/kg (0.11 – 1.59), and CD56+: 67, 9 × 106cells/kg (7, 6–131, 8). 14/15 patients engrafted one1ry primary engraftment failure and in 2 cases a 2ry engraftment failure (CMV and Toxoplasmosis treatment). Eight remain alive and clinically well at a median follow up of 12.4 months post-transplant (7.2 – 52.2). Four patients died after bone marrow relapse, while only one died of transplant-related causes. Virus reactivation was the main post-transplant complication: 9/15 had positive CMV PCR but none had CMV disease. One patient developed acute GvHD > grade II and one had chronic GvHD. In this setting, HI transplantation offers a rational option for children who lack suitable stem cell donors. This information is especially relevant for populations that are poorly represented in international donor registries. On the other hand HISCT with RIC with ATG and TNI permits a good OS and EFS in this especially high risk population low TRM. This approach is associated with low incidence of GvHD and high viral reactivation incidence but no lethal infection even without CD3+ lymphocyte recovery due probably to pre-emptive treatment and fast NK cell recovery. Disclosures: No relevant conflicts of interest to declare.

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A Phase II Study of Decitabine Followed By Allogeneic Hematopoietic Stem Cell Transplantation in High-Risk Patients with Myeloid Malignancies

Blood ◽

10.1182/blood-2018-99-112670 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2107-2107

Author(s):

Christopher R. D'Angelo ◽

Aric C. Hall ◽

Kyungmann Kim ◽

Ryan J. Mattison ◽

Walter L. Longo ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Chronic Gvhd ◽

Infectious Complications ◽

Myeloablative Conditioning ◽

Hematopoietic Stem ◽

Post Transplant ◽

Risk Patients

Abstract Introduction: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy for myelodysplastic syndrome (MDS) and high-risk acute myeloid leukemia (AML). Patients with high-risk disease have a markedly increased risk of relapse and death following transplant (Armand et al, Blood, 2014). Those who remain disease-free are at risk of severe morbidity from graft-versus- host-disease (GvHD). These issues highlight the importance of improved allo-HSCT platforms designed to reduce relapse rate without increasing risk of GvHD. Decitabine has minimal non-hematologic toxicity and proven efficacy in myeloid diseases (Blum et al, PNAS, 2010). Use of post-transplant cyclophosphamide has demonstrated improved rates of GvHD following allo-HSCT using haplo-identical donors (Bashey et al, JCO, 2013). No studies have reported on outcomes in patients undergoing decitabine immediately prior to transplantation followed by post-transplant cyclophosphamide (PTCy). We hypothesized that the combination of decitabine induction prior to transplant and PTCy would be safe and result in improved disease control with low rates of GVHD, translating into improved survival in a high-risk transplant cohort. Methods In this single-arm, single institution trial, eligible patients received 10 days of IV decitabine at 20mg/m2 no sooner than 24 days and no later than 17 days prior to conditioning. Myeloablative conditioning included fludarabine (50mg/m2 day-5-2), busulfan (IV 3.2mg/kg/day -5-2), and 4 Gy total body irradiation on day -1. Patients above age 65 received a 25% busulfan dose reduction. Patients received a fully or partially matched related bone marrow graft on day 0. GvHD prophylaxis included 50mg/kg of IV cyclophosphamide on day +3-4. Patients with fully matched donors received only PTCy while those with partially matched donors also received mycophenolate mofetil through day +35 and tacrolimus through day +180. Results We enrolled 20 patients, fifteen patients with AML and 5 with MDS. The cohort had a median age of 64 (29-73) and was predominantly male (14/20, 70%). Eight (40%) patients scored as high risk by the HSCT comorbidity index. Eighteen patients (90%) had a high or very high-risk score by the refined disease risk index. All patients received decitabine and 18/20 (90%) underwent transplantation; 2 patients did not receive a transplant due to infectious complications. The majority of patients received a haplo-identical graft (13/18, 72%), and the remaining 5 received a matched related graft. Outcomes are reported in table 2 and figure 1. There were no engraftment failures. Five patients, 3 MDS and 2 AML, are long-term survivors with median follow-up over 3 years. One patient developed donor derived MDS and required a second transplant. Most transplanted patients (13/18, 72%) survived to day 100 with a median post-transplant survival of 138 days. There were 15 deaths on study with the majority due to underlying disease. Six patients (6/20, 30%) died of infectious complications or did not receive a transplant due to infection. Incidence of grade 3-4 acute GvHD was low among those surviving at least 40 days from transplant (3/17, 17%). There were also low rates of chronic GvHD among the 12 patients alive without ongoing GvHD at day 100 (2/12, 17%). Conclusions Decitabine induction followed by myeloablative conditioning in this high-risk population resulted in a high treatment related mortality of 40%. Still, outcomes fell into an expected range for high-risk myeloid disease in an elderly and comorbid population. Based on expected outcomes for high-risk patients from the literature (Armand et al, Blood, 2014), decitabine did not markedly improve overall survival outcomes, recognizing that no direct comparisons are available in our limited study population. Decitabine may increase the risk of peri-transplant infections by contributing to a cumulative immunologic insult combined with disease-related immunosuppression and transplant-related toxicity, highlighting the importance of strict vigilance for infections within this setting. Diligent monitoring may improve infectious outcomes as shown in the second half of the cohort; only two out of the latter 10 patients on protocol died of treatment related complications. There were no cases of engraftment failure. Rates of acute and chronic GvHD using a PTCy platform were low and support other studies reporting this benefit. Disclosures No relevant conflicts of interest to declare.

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FLAMSA-RIC for Stem Cell Transplantation in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndromes: A Systematic Review and Meta-Analysis

Journal of Clinical Medicine ◽

10.3390/jcm8091437 ◽

2019 ◽

Vol 8 (9) ◽

pp. 1437 ◽

Cited By ~ 1

Author(s):

Weerapat Owattanapanich ◽

Patompong Ungprasert ◽

Verena Wais ◽

Smith Kungwankiattichai ◽

Donald Bunjes ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Stem Cell ◽

High Risk ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Myeloid Leukemia ◽

Meta Analysis ◽

Chronic Gvhd ◽

Hematopoietic Stem ◽

Acute Myeloid

Reduced-intensity conditioning (RIC) regimens are established options for hematopoietic stem cell transplantation (HSCT) for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). However, the efficacy of RIC regimens for patients with high-risk disease is limited. The addition of a fludarabine, amsacrine, and cytarabine (FLAMSA)-sequential conditioning regimen was introduced for patients with high-risk MDS and AML to combine a high anti-leukemic activity with the advantages of RIC. The current systematic literature review and meta-analysis was conducted with the aim of identifying all cohort studies of patients with AML and/or MDS who received FLAMSA-RIC to determine its efficacy and toxicity. Out of 3044 retrieved articles, 12 published studies with 2395 overall patients (18.1–76.0 years; 96.8% AML and 3.2% MDS; follow-up duration of 0.7–145 months; 50.3% had active AML disease before HSCT) met the eligibility criteria and were included in the meta-analysis. In the pooled analysis, the 1- and 3-year overall survival (OS) rates were 59.6% (95% confidence interval (CI), 47.9–70.2%) and 40.2% (95% CI, 28.0–53.7%), respectively. The pooled 3-year OS rate of the patients who achieved CR1 or CR2 prior to HSCT was 60.1% (95% CI, 55.1–64.8%) and the percentage of those with relapse or refractory disease was 27.8% (95% CI, 23.3–32.8%). The pooled 3-year leukemia-free survival (LFS) rate was 39.3% (95% CI, 26.4–53.9%). Approximately 29% of the patients suffered from grades 2–4 acute graft-versus-host disease (GVHD), while 35.6% had chronic GVHD. The pooled 1- and 3-year non-relapse mortality (NRM) rates were 17.9% (95% CI, 16.1–19.8%) and 21.1% (95% CI, 18.8–23.7%), respectively. Our data indicates that the FLAMSA-RIC regimen is an effective and well-tolerated regimen for HSCT in patients with high-risk AML and MDS.

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Hematopoeitic Stem Cells and Their Progenitors Critically Require Autophagy to Promote Early Engraftment Following Allogeneic Stem Cell Transplantation

Blood ◽

10.1182/blood.v126.23.34.34 ◽

2015 ◽

Vol 126 (23) ◽

pp. 34-34

Author(s):

Katie E Lineburg ◽

Lucie Leveque-El Mouttie ◽

Laetitia Le Texier ◽

Bianca Teal ◽

Rachel D Kuns ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Graft Failure ◽

Term Survival ◽

Hematopoietic Stem ◽

Post Transplant ◽

Engraftment Failure ◽

And Function

Abstract Stem cell transplantation (SCT) is the only curative therapy for the majority of hematological malignancies and relies on successful engraftment of donor hematopoietic stem cells (HSC) to reconstitute the patient's hematopoiesis and immunity. Graft-versus-host disease (GVHD) and graft failure are complications of SCT that contribute to significant morbidity and mortality. Recent studies have established a role for autophagy in the long-term survival and function of HSCs and as a regulator of hematopoiesis. We investigated the contribution of autophagy to HSC in the setting of allogeneic transplantation. Using LC3-GFP bone marrow as a graft source in the well-established B6 into F1 model of GVHD, together with imaging flow cytometry, we demonstrated increased autophagy (LC3-GFP punctae) within donor HSC and progenitor cells in GVHD compared to non-GVHD recipients. To assess the contribution of autophagy to HSC development and function we used mice deficient in Atg5, an essential protein for the autophagy pathway. In primary transplants, ATG5 KO foetal liver (FL) had reduced ability to engraft lethally irradiated congenic recipient mice compared to WT FL. Furthermore, competitive transplantation of 50% ATG5 KO FL cells together with 50% WT FL cells demonstrated that ATG5 KO cells had a reduced capacity to reconstitute compared to congenic WT FL cells. Finally, to address the role of autophagy in HSC in the setting of GVHD, we transplanted WT or ATG5 KO FL ± T cells into lethally irradiated B6D2F1 recipients. At D10 post-transplant ATG5 KO recipients failed to establish tri-lineage engraftment in peripheral blood and lacked expansion of myeloid precursor cells in the BM, leading to engraftment failure and significantly reduced survival compared to WT FL recipients (50% WT vs 10% Atg5 KO p<0.0001). This early engraftment failure was confirmed to be autophagy specific using VAVcre x Atg7fl/fl donor mice, in which Atg7 deficiency is restricted to hematopoietic cells. Furthermore, the essential requirement for autophagy in early progenitors and HSC was confirmed using LysMcre Atg7fl/fl mice, which ablate Atg7 from the granulocyte-macrophage progenitor population onwards. Survival, or engraftment, in mice receiving the LysMcre Atg7fl/fl donor graft did not differ significantly from those receiving a WT graft. We demonstrate that autophagy is increased in the GVHD setting and that without autophagy early myeloid precursors fail to provide short term reconstitution leading to primary graft failure and mortality. Thus, intervention to increase autophagy in these cells post-transplant may improve engraftment in the clinic. Disclosures No relevant conflicts of interest to declare.

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Donor Lymphocyte Infusion after Haploidentical Transplantation with Post-Transplant Cyclophosphamide

Blood ◽

10.1182/blood.v128.22.5863.5863 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5863-5863 ◽

Cited By ~ 1

Author(s):

Clemence Roux ◽

Samia Harbi ◽

Raynier Devillier ◽

Faezeh Legrand ◽

Sabine Fürst ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Stem Cell Transplantation ◽

Disease Progression ◽

Cell Transplantation ◽

Risk Index ◽

Chronic Gvhd ◽

Post Transplantation ◽

Hematopoietic Stem ◽

Gvhd Prophylaxis

Abstract Background Although allogeneic hematopoietic stem cell transplantation (alloSCT) is a curative option to treat hematologic malignancies, disease recurrence remains a concern in the setting of high risk diseases. Thus, post alloSCT therapeutic strategies are needed to treat and/or prevent disease progression. In this setting, donor lymphocytes infusion (DLI) is an option as post alloSCT immunotherapy aiming to enhance graft versus leukemia (GVL) effect. Although DLI may induce persistent remission, graft versus host disease (GVHD) is a potential complication following DLI. Because of the suspected higher incidence of GVHD in the presence of HLA mismatches, few series focused on DLI following haploidentical stem cell transplantation (HaploSCT) so far. We therefore report our experience of DLI following HaploSCT using post-transplantation cyclophosphamide (PT-Cy) platform. Methods: We included in this single center study all consecutive adult patients with hematological malignancies who received DLI after HaploSCT with PT-Cy as part of GVHD prophylaxis from 2013 to 2016 (n=21). Conditioning regimens were non-myeloablative (low dose TBI-based) or with reduced toxicity (various dose of busulfan according to disease and patient characteristics). Ciclosporine A and mycophenolate mofetil were given as additional GVHD prophylaxis in all cases. DLI were given at escalating doses, expressed as CD3+cells/kg, without GVHD prophylaxis, and ranged from 1x105 to 5x107 cells/kg. Results: Eleven patients (52%) were transplanted for high risk disease according to the disease risk index (DRI, Armand et al., blood 2015). Twelve patients (57 %) received haploSCT in complete remission,.18 patients received first transplant and 3 patients their second transplant. After HaploSCT, 21 patients (median age: 56 years [range: 23-73]) received either therapeutic (treatment of hematological post transplantation relapse, n=6) or prophylactic (n=15) DLI. The median interval from HaploSCT to the first DLI was 128 days (range: 79-1011). The average number of DLI per patient was 1.8 (range, 1-3). Clinical characteristics are outlined in Table 1. Patients with AML and MDS received DLI alone (n = 13) or in association with azacytidine (n = 2). Patients with MM received DLI in association with Revlimid (n=3). Chimerism before first DLI was complete in 19 patients. 6 patients (33%) developed post DLI GVHD in a median time of 42 days (range: 30-210) with exclusively chronic features. 2 patients (9 %) had severe forms of chronic GVHD. GVHD-related death occurred in 1 patient No response was achieved when DLI were given as therapeutic and 4 of 6 patients died from disease progression. Otherwise, only 3 of 16 patients who received prophylactic DLI experienced relapse. With a median follow up of 129 days, overall survival was 63%. Conclusion Our study suggests that DLI following HaploSCT with PT-Cy is feasible. GVHD is frequent but with a relatively low incidence of severe forms. No response rate was achieved in the context of hematological relapse, underlining that preemptive or prophylactic strategy might be preferred. Indeed, the overall good outcome in patients receiving prophylactic DLI is promising taking into account the poor prognostic of the diseases indicated for alternative donor transplantation. Further prospective studies are needed in specific disease settings to assess the benefit for using such post alloHSCT immune-intervention. Table 1 Table 1. Disclosures No relevant conflicts of interest to declare.

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Allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning in intermediate- or high-risk patients with myelofibrosis with myeloid metaplasia

Blood ◽

10.1182/blood-2004-11-4299 ◽

2005 ◽

Vol 105 (10) ◽

pp. 4115-4119 ◽

Cited By ~ 150

Author(s):

Damiano Rondelli ◽

Giovanni Barosi ◽

Andrea Bacigalupo ◽

Josef T. Prchal ◽

Uday Popat ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Chronic Gvhd ◽

Reduced Intensity Conditioning ◽

Hematopoietic Stem ◽

Myeloid Metaplasia ◽

Myelofibrosis With Myeloid Metaplasia ◽

Reduced Intensity

AbstractA total of 21 patients with myelofibrosis with myeloid metaplasia (MMM), with a median age of 54 years (range, 27-68 years), were prepared with a reduced-intensity conditioning (RIC) regimen. The patients received an allogeneic marrow (n = 3) or peripheral blood stem-cell (n = 18) transplant from HLA-matched related (n = 18) or unrelated (n = 2), or 1 Ag-mismatched related (n = 1), donors. RIC regimens included fludarabine/total body irradiation 200 cGy (n = 5) or 450 cGy (n = 1), fludarabine/melphalan (n = 7), thiotepa/cyclophosphamide (n = 7), and thiotepa/fludarabine (n = 1). At the time of transplantation, all of the patients were at intermediate (n = 13) or high (n = 8) risk, according to the Dupriez classification. Of the patients, 19 had grade III or IV marrow fibrosis. All of the patients achieved full engraftment but one. Posttransplantation chimerism analysis showed more than 95% donor cells in 18 patients, while 2 patients achieved complete donor chimerism after donor leukocyte infusion (DLI). Acute graft-versus-host disease (GVHD) grades II to IV was observed in 7 patients, grades III to IV in 2, and extensive chronic GVHD in 8 of 18 evaluable patients. There were 3 patients who died from acute GVHD, infection, and relapse. There are 18 patients alive 12 to 122 months (median, 31 months) after transplantation, and 17 are in remission (1 after a second transplantation). The use of RIC regimens in allogeneic stem cell transplantation results in prolonged survival in intermediate/high-risk MMM patients.

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Stem Cell Transplantation in Children with Infantile Osteopetrosis Is Associated with a High Incidence of VOD, Which Could Be Prevented with Defibrotide.

Blood ◽

10.1182/blood.v108.11.5235.5235 ◽

2006 ◽

Vol 108 (11) ◽

pp. 5235-5235

Author(s):

Selim Corbacioglu ◽

Hoenig Manfred ◽

Georgia Lahr ◽

Susanne Stoehr ◽

Gaurav Berry ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Multiorgan Failure ◽

High Risk Population ◽

Hematopoietic Stem ◽

High Incidence ◽

Osteoclast Function ◽

Very High

Abstract Background: Malignant infantile osteopetrosis (MIOP) is a rare hereditary disorder of osteoclast function, which can be reversed by hematopoietic stem cell transplantation (SCT). In recent studies defibrotide (DF) demonstrated superior efficacy in the treatment of hepatic veno-occlusive disease (VOD). Methods: Twenty children with MIOP were consecutively transplanted in our centre between 1996 and 2005. Eleven of these patients were transplanted between 1996 and 2001 without any VOD prophylaxis. Thereafter nine patients were transplanted between 2001 and 2005 with prophylactic DF from the first day of conditioning until 30 days after SCT because we observed a high incidence of VOD in transplanted patients and explored the prevention of this complication by using DF as a prophylaxis. Results: Patients without DF experienced an overall incidence of VOD of 63.6% (7/11). VOD was severe in three patients and one patient succumbed to VOD related multiorgan failure (MOF). In nine patients consecutively transplanted between 2001 and 2005 only one patient (11.1%) was diagnosed with moderate VOD. Conclusion: SCT in patients with MIOP is associated with a very high risk to develop VOD. Prophylactic DF was implemented in our current transplant protocol and reduced the VOD rate dramatically in this high risk population.

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