scholarly journals Reversing Clonal Hematopoiesis and Associated Atherosclerotic Disease By Targeted Antibody-Drug-Conjugate (ADC) Conditioning and Transplant

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 34-35
Author(s):  
Karin Gustafsson ◽  
Catherine S Rhee ◽  
Elizabeth W Scadden ◽  
Vanessa Frodermann ◽  
Rahul Palchaudhuri ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Peripheral Blood ◽  
Publicly Traded ◽  
Antibody Drug Conjugate ◽  
Hematopoietic Stem ◽  
Clonal Hematopoiesis ◽  
The Past ◽  
Antibody Drug

Cardiovascular disease (CVD) is the leading cause of death worldwide. Recently, age-related clonal hematopoiesis (CH) has been recognized as a risk factor for CVD of comparable magnitude to smoking, hypertension and hypercholesteremia. While these other risk factors can be mitigated by pharmacological intervention or lifestyle changes, there are no such strategies in place for CH. As CH is initiated by mutations in hematopoietic stem cells (HSCs), a hematopoietic stem cell transplantat (HSCT) could serve as a curative therapy. However, stem cell transplantation is associated with significant toxicity due in part from current conditioning regimens. There is also no evidence that depletion of the disease-driving clones impacts established atherosclerosis. We developed an antibody drug conjugate (ADC) targeting murine CD45. In the context of stem cell transplantation, the CD45-ADC efficiently depletes endogenous HSCs as well as mature leukocytes while enabling rapid engraftment of an infused stem cell graft. In addition, the CD45-ADCs are not based on broad-acting genotoxic agents that lead to long-lasting health risks. We decided to test if CD45-ADC and HSCT could halt atherosclerosis progression through elimination Tet2 knockout HSCs and their disease propagating myeloid progeny. To model CH associated atherosclerosis, LDLR knockout mice were transplanted with 20% CFP labeled wild-type (WT) or Tet2 knockout bone marrow. A single dose of isotype- or CD45-ADC was delivered after 6 weeks of atherosclerosis development and was followed by an infusion of WT CD45.1 bone marrow. As has been reported before, we observed in the isotype-ADC treated animals that Tet2 deficiency leads to a competitive advantage over WT cells. Tet2 knockout cells contributed to peripheral blood chimerism at successively increasing levels and mice harboring the knockout graft showed a significant expansion of their HSC population. Despite their obvious advantage, Tet2 deficient HSC were as efficiently depleted as their WT counterparts upon CD45-ADC and HSCT. Peripheral blood and bone marrow chimerism were similar in WT and Tet2 knockout hosts and the expanded HSC pool was successfully curbed 6 weeks following the intervention. More importantly, CD45-ADC also depleted cells in the atherosclerotic plaques as efficiently as in blood in both WT and Tet2 mutant recipients. This resulted in a significant reduction of myeloid cell infiltration in CD45-ADC conditioned and transplanted knockout hosts and ultimately lead to drastically reduced plaque size in these animals. In conclusion, these data demonstrate that CD45-ADC and HSCT efficiently replaces the disease driving myeloid cells in the atherosclerosis plaques leading to an overall reduction in disease burden. CD45-ADC and transplantation may thus offer a novel therapy for CH and its associated morbidities. Disclosures Palchaudhuri: Magenta Therapeutics: Current Employment. Hyzy:Magenta Therapeutics: Current Employment, Current equity holder in publicly-traded company. Proctor:Magenta Therapeutics: Current Employment. Gillard:Magenta Therapeutics: Current Employment. Boitano:Magenta Therapeutics: Ended employment in the past 24 months, Patents & Royalties. Cooke:Magenta Therapeutics: Ended employment in the past 24 months. Scadden:Magenta Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Development of an allele-specific minimal residual disease assay for patients with juvenile myelomonocytic leukemia

Blood ◽  
2008 ◽  
Vol 111 (3) ◽  
pp. 1124-1127 ◽  
Author(s):  
Sophie Archambeault ◽  
Nikki J. Flores ◽  
Ayami Yoshimi ◽  
Christian P. Kratz ◽  
Miriam Reising ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Peripheral Blood ◽  
Residual Disease ◽  
Juvenile Myelomonocytic Leukemia ◽  
Hematopoietic Stem ◽  
Allele Specific ◽  
Myelomonocytic Leukemia

AbstractJuvenile myelomonocytic leukemia is an aggressive and frequently lethal myeloproliferative disorder of childhood. Somatic mutations in NRAS, KRAS, or PTPN11 occur in 60% of cases. Monitoring disease status is difficult because of the lack of characteristic leukemic blasts at diagnosis. We designed a fluorescently based, allele-specific polymerase chain reaction assay called TaqMAMA to detect the most common RAS or PTPN11 mutations. We analyzed peripheral blood and/or bone marrow of 25 patients for levels of mutant alleles over time. Analysis of pre–hematopoietic stem-cell transplantation, samples revealed a broad distribution of the quantity of the mutant alleles. After hematopoietic stem-cell transplantation, the level of the mutant allele rose rapidly in patients who relapsed and correlated well with falling donor chimerism. Simultaneously analyzed peripheral blood and bone marrow samples demonstrate that blood can be monitored for residual disease. Importantly, these assays provide a sensitive strategy to evaluate molecular responses to new therapeutic strategies.

Haplo-Identical Allogeneic Stem Cell Transplantation Using GCSF-Mobilized Marrow Plus Blood Stem Cells from Parent Donors for Children with High-Risk Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5084-5084
Author(s):  
Quanyi Lu ◽  
Xiaoqing Niu ◽  
Peng Zhang ◽  
Delong Liu
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Peripheral Blood ◽  
Peripheral Blood Stem Cells ◽  
Hematopoietic Stem ◽  
Blood Stem Cells

Abstract Increasing number of patients in China have difficulty of finding sibling donors due to limited number of siblings. We therefore explored the feasibility using haploidentical parent donors for allogeneic hematopoietic stem cell transplantation. Eight leukemia patients were studied in our hospital. These included 2 CML-BC, 2 MDS-RAEB, 3 relapsed ALL and 1 relapsed AML. The median age was 12 (7–17). GCSF- mobilized bone marrow and peripheral blood stem cells were collected from parents (1 to 3 locus mismatched). The conditioning regimen consisted of fludarabine (30mg/m2/d x5), bulsulfan (4mg/kg/d x3) and cyclophosphamide (50mg/kg/d x2). Cyclosporin A, mycophenolate mofetil, methotrexate, and ATG were used for GVHD prophylaxis. The total number of CD34+ cell in the grafts ranged between 5–10 x 106/kg. The median follow- up was 13 months (6–24). One patient failed to engraft, the other 7 patients achieved full donor chimerism at day 28. The incidence of acute GVHD (grade II-IV) was 57.1% (4 of 7). The incidence of chronic GVHD of limited stage occurred in the same 4 patients. One patient died of lung complication at 17th month, another patient with CML-BC relapsed 10 months after transplantation. The rest 6 patients are alive without disease. These results suggested that parents could be considered as stem cell donors in the absence of alternative donors for young patients with high-risk diseases. GCSF-primed bone marrow plus peripheral blood stem cells might be beneficial to reduce the risk of GVHD for leukemia children in China. More patients are needed to further study this approach.

Seroprevalence for Toxoplasma Gondii in Allogeneic Hematopoietic Stem Cell Transplantation Recipients

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5459-5459
Author(s):  
Erden Atilla ◽  
Pinar Ataca ◽  
Sevinc Balli ◽  
Baris Isikoglu ◽  
Pervin Topcuoglu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Toxoplasma Gondii ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Peripheral Blood ◽  
Common Source ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Low Rate

Abstract Introduction: Toxoplasmosis is a rare but serious and life-threatening infection following Allogeneic Stem Cell Transplantation (Allo-HSCT). The main cause of toxoplasmosis is the reactivation of latent infection in pre-transplant seropositive patients. In our study, our aim is to present toxoplasma gondii seroprevalence in our center. Patients and Methods: A total of 251 allogeneic stem cell transplant recipient were evaluated retrospectively from 1998 to 2015. During Allo-HSCT preparation procedures all recepients were serologically tested. Donor serology records were not adequate. Toxoplasma gondii-specific IgG and IgM antibodies were determined by Chemiluminescence by ARCHITECT lab analyzers using commercially available kits (Abbott, USA). All patients were followed for reactivation. Results: Toxoplasma IgG positivity was detected in 51 of patients (20.3%). There was no statistically difference detected between related or unrelated transplants. The mean age of the group was 36 (range 14-71). 144 recipients were male (57%). 208 (83%) patients were transplanted for malign hematological diseases. The majority of patients were grafted from full-matched related donors (173, 69%). The most common source of stem cell was peripheral blood in 192 patients (77%) followed by bone-marrow in 51 patients (51%), bone-marrow plus peripheral blood in 7 patients (2.8%) and cord in 1 patient (0.4%). 192 (77%) patients received myeloablative conditioning regimens. All patients received prophylactic twice weekly trimethoprim/sulfamethoxazole (TMP/SMX) (160/800mg PO daily) after engraftment. Two patients had clinical symptoms of toxoplasmosis however they were seronegative in serology. None of the patients developed an active toxoplasmosis after Allo-HSCT. Conclusion: Since less than 30% seropositivity defined as low rate, our institution had low rate seropositivity for Toxoplasma Gondii in Allo-HSCT recipients. Routine use of TMP/SMX prophylaxis and difficulties in diagnosis of toxoplasmosis may lead to low frequency active toxoplasmosis. Disclosures No relevant conflicts of interest to declare.

scholarly journals AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR HIGH-RISK ACUTE LYMPHOBLASTIC LEUKEMIA: NON-RANDOMIZED STUDY WITH A MAXIMUM FOLLOW-UP OF MORE THAN 22 YEARS

2014 ◽  
Vol 6 (1) ◽  
pp. e2014047 ◽  
Author(s):  
Grzegorz Helbig ◽  
Malgorzata Krawczyk-Kulis ◽  
Malgorzata Kopera ◽  
Krystyna Jagoda ◽  
Patrycja Rzepka ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Peripheral Blood ◽  
Lymphoblastic Leukemia ◽  
Hematopoietic Stem

Objective. To evaluate the efficacy and toxicity of autologous hematopoietic stem cell transplantation (AHSCT) for high-risk acute lymphoblastic leukemia (ALL). Material and methods. Overall, 128 high-risk ALL patients at a median age of 26 years (range 18-56 years) at diagnosis received AHSCT between 1991-2008. Induction treatment was anthracycline-based in all patients. Conditioning regimen consisted of CAV (cyclophosphamide, cytarabine, etoposide) in 125 patients whereas 3 subjects received cyclophosphamide and TBI (total body irridation). Bone marrow was stored for 72 hours in 4oC and re-infused 24 hours after conditioning completion. Bone marrow was a source of stem cells in 119 patients, peripheral blood in 2 and 7 subjects received both bone marrow and peripheral blood. Results. With a median follow-up after AHSCT of 1.6 years (range 0.1-22.3 years), the probability of leukemia-free survival (LFS) for the whole group at 10 years was 27% and 23% at 20 years. Transplant-related mortality at 100 days after AHSCT was 3.2%.. There was a strong tendency for better LFS for MRD-negative patients if compared with patients who had positive or unknown MRD status at AHSCT (32% vs 23% and 25%, respectively; p=0.06). There was no difference in LFS between B- and T-lineage ALL as well as between patients transplanted in first complete remission (CR1) and CR2. LFS at 10 years for patients with detectable BCR-ABL at transplant was 20% and this was comparable with subjects with negative and missing BCR-ABL status (26% and 28%; p=0.97). Conclusions. The results of AHSCT for high-risk ALL remains unsatisfactory with low probability of long-term LFS.

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