“Real World” Australian Experience of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) in Adults with Severe Aplastic Anaemia.

Acquired Severe Aplastic Anaemia (SAA) is a rare bone marrow failure syndrome, for which allogeneic haematopoietic stem cell transplant (HSCT) is a proven curative therapy. Despite excellent outcomes for matched sibling SAA recipients in terms of engraftment and survival, HSCT remains highly challenging in older matched-unrelated-donor (MUD) recipients, due to increased non-relapse mortality (NRM) from causes such as graft versus host disease (GVHD), organ failure and infection. We sought to evaluate our local HSCT outcomes for SAA, determine factors that predict for inferior outcomes, and benchmark local outcomes against international cohorts. To define outcomes for sibling and MUD HSCT in adults ≥17 years of age with SAA at a single Australian institution between 2002 and 2018 and compare these outcomes to internationally published cohorts. The primary outcome was 1-year overall survival (OS). Secondary outcomes included the incidences of engraftment, response, secondary graft failure, GVHD, and moderate to severe organ dysfunction. All 21 patients comprising 10 sibling and 11 MUD HSCTs, with a median age of 30 (range 17-64), received bone marrow grafts. At a median follow up of 3.5 years, 17 (81%) of 21 patients remained alive and in remission from SAA. 1-year OS, non-relapse mortality (NRM), and GVHD incidence were 85%, 15%, and 48% respectively. Two patients died prior to engraftment at Day+27 and Day+33. When comparing sibling and MUD HSCT recipients, incidences of survival, engraftment and post-HSCT complications were similar; however, MUD HSCT survivors experienced a higher incidence of chronic GVHD (67% vs. 11%; p=0.04). Age >40 years, AKI by Day+28, infection by Day+100 and deviation from intended GVHD prophylaxis predicted for worse OS. Our outcomes following HSCT for SAA are comparable to international cohorts with age >40 years, early onset infection, AKI and deviation from intended GVHD prophylaxis protocol negatively impacting OS. Further research is warranted to optimise MUD HSCT conditioning and GVHD prophylaxis protocols for SAA, particularly in older patients.

Download Full-text

Outcome of Severe Aplastic Anemia Post Allogenic Stem Cell Transplant with Mycophenolate and Calcineurin Inhibitor for Graft Versus Host Disease Prophylaxis

Blood ◽

10.1182/blood-2021-144995 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4879-4879

Author(s):

Omar Albanyan ◽

Hyejeong Jang ◽

Seongho Kim ◽

Andrew Kin ◽

Asif Alavi ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Conditioning Regimen ◽

Unrelated Donor ◽

Cell Transplant ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Gvhd Prophylaxis ◽

Grade Ii ◽

Matched Donor

Abstract Introduction: Severe aplastic anemia (SAA) is a rare hematopoietic stem cell disorder characterized by hypocellular marrow and pancytopenia. Multiple factors play an important role in treatment approach include age, comorbidities, degree of pancytopenia and availability of stem cell donor to either immunosuppression irrespective (IST) or allogenic hematopoietic stem cell transplant (alloSCT). The use of nonmyeloablative conditioning regimen has improved the outcomes, however the choice for post-transplant GVHD prophylaxis remain a topic of debate. The use of mycophenolate mofetil (MMF) has been used as an alternative for methotrexate (MTX) as has shown to be associated with lower incidence of mucositis and shorter time to engraftment. Methods: We retrospectively evaluated consecutive adult patients with SAA who underwent alloSCT at Karmanoc Cancer Institute. All patients received fludarabine, cyclophosphamide and antithymocyte globulin for conditioning regimen with calcineurin inhibitors (CNI) and MMF for GVHD prophylaxis. MMF was started at day -3 at 15 mg/kg three times daily and stopped at day +30 in the absence of active GVHD. The primary objectives were to estimate cumulative incidence of acute (aGVHD) and chronic GVHD (cGVHD) and overall survival (OS). Secondary objectives were to evaluate time to engraftment, days of hospitalization and incidence of mucositis. Results: From January 2005 and May 2019, 33 patients with SAA underwent alloSCT. Patient characteristics are detailed in Table 1. Median age was 36 years (range, 18-71). Twenty-seven patients received bone marrow stem cells (82%) and six patients received peripheral blood stem cells (18%). Thirty patients (91%) received 8/8 HLA matched donor and three patients (9%) received 7/8 HLA matched donor. Sixteen patients (48%) received stem cells from sibling donor and 17 patients (52%) received stem cells from unrelated donor. Thirteen patients (39%) had received IST prior to alloSCT, and 20 patients (61%) received upfront alloSCT. For GVHD prophylaxis all patients received MMF and CNI (tacrolimus=32, and cyclosporine=1). Median time from diagnosis to transplant was 15.8 months for patients who received IST prior to alloSCT and 2 months for patients who received upfront alloSCT. Median time to platelet engraftment was 13.5 days and neutrophil engraftment was 12 days, while one patient experienced graft failure. The median number of days for hospital stay were 25 days. Four patients (11%) developed grade I-II mucositis, no grade III-IV mucositis was observed in the first 30 days and 6 patients had CMV reactivation. The 100-day cumulative incidence rate of grade II-IV aGVHD was 21.2% (95% CI, 9.2 - 36.5), grade III-IV aGVHD was 9.1% (2.3-21.9) and 1-year CIR of cGVHD was 21.2% (95% CI, 9.2-36.5). Comparing patients who received IST prior to alloSCT versus upfront alloSCT, the 100-day CIR of grade II-IV aGVHD was 30.8% (95% CI, 8.2 - 56.5) and 15% (95% CI, 3.6 - 34.0), respectively, (Gray p=0.26) and the 3-year CIR of cGVHD was 39.6% (95% CI, 13.1 - 65.5) and 27.8% (95% CI, 9.2 - 50.3), respectively, (Gray p=0.37). Comparing patients who received alloSCT from related versus unrelated donor, 100-day CIR of II-IV aGVHD was 12.5% (95% CI, 1.9 - 33.6) and 29.4% (95% CI, 10.2 - 51.9), respectively, (Gray p=0.26), and the 3-year CIR of cGVHD was 34.2% (95% CI, 11.4 - 58.9) and 29.4% (95% CI, 10.1 - 52.0), respectively (Gray p=0.90). Median follow up of surviving patient was 5 years (95% CI, 3.1-6.8). Three-year OS was 87% (95% CI, 75.7- 99.9) and median OS was not reached. Six patients died by the time of the analysis, one patient died from graft failure (86 days after transplant from 8/8 HLA MUD), two patients died due infectious complications (808 days and 1637 days after transplant), three patients died due to multiorgan failure (215, 297 and 1097 days after transplant). Conclusion: Our data with use of CNI and MMF for GVHD prophylaxis for SAA following alloSCT with nonmyeloablative conditioning regimen showed that the rate of mucositis was low, engraftment time was rapid, and hospitalization was short, while OS, rates of acute and chronic GVDH were comparable to previously published rates with CNI and MTX-based GVHD prophylaxis. Figure 1 Figure 1. Disclosures Modi: Genentech: Research Funding; Seagen: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Membership on an entity's Board of Directors or advisory committees. Deol: Kite, a Gilead Company: Consultancy.

Download Full-text

Higher Rate of Thrombotic Thrombocytopenic Pupura (TTP) Associated with Graft Versus Host Disease (GVHD) and Unrelated Donor Bone Marrow Transplantation (BMT).

Blood ◽

10.1182/blood.v106.11.1111.1111 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1111-1111

Author(s):

B. Oran ◽

A. Aleman ◽

E. J. Shpall ◽

C. Hosing ◽

M. Korbling ◽

...

Keyword(s):

Risk Factors ◽

Bone Marrow ◽

Stem Cell ◽

Median Time ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Hematopoietic Stem ◽

Allogeneic Hsct ◽

Lymphoid Malignancies ◽

Gvhd Prophylaxis

Abstract TTP is one of the complications of allogeneic hematopoietic stem cell transplantation (HSCT). In contrast to idiopathic cases, post-transplantation TTP may not be associated with severe von Willebrand factor-cleaving protease deficiency but rather a diffuse endothelial injury. Our aim was to define incidence, risk factors and mortality of TTP following allogeneic HSCT. 1312 patients with lymphoid malignancies (n=605), myeloid malignancies (n=688) or aplastic anemia (AA, n=18) who were treated with ablative preparative regimens (n=614) or reduced intensity regimens (n=697) followed by HSCT from an HLA matched related (MRD, n=694) or unrelated donor (MUD; n=461) and 1–3 antigen mismatched related (MMR, n=99) or unrelated donor (MMUD, n=57) between December 1997 and December 2004 were studied. Patients with prior allogeneic HSCT or graft failure were excluded. GVHD prophylaxis was tacrolimus-based in 1276 (97.3%) and cyclosporine based in 15 (1.1%) patients. Twenty patients did not receive GVHD prophylaxis per protocol. Anti-thymocyte-globulin (ATG) was added in 350 patients. Stem cell sources were bone marrow (n=626), peripheral blood (n=635) or cord blood (n=50). The following variables were evaluated: age, gender, primary diagnosis, disease status before HSCT, intensity of preparative regimen, stem cell source and acute GVHD(aGVHD) grade ≥2 (time dependent variable). Of the 1312 patients with a median follow-up from transplantation of 11.4 months (range, 5 days-7.2 years), 77 developed TTP (6%). The actuarial risk of developing TTP was 6.5% at 1 year. The median time of the onset of TTP was 67 days post HSCT (range, 11–1812) with 27 cases (35%) presenting after day 100. Female gender, lymphoid malignancies, unrelated or antigen mismatched related donor and aGVHD grade ≥2 were found to be independent risk factors. (Table1). Among the patients who had aGVHD grade≥2, the median time of interval between the onsets of two events was 25 days (range, 2–335 days). All patients were treated with therapeutic plasma exchange (PE). Of the 77 patients only 1 died of TTP (intracranial hemorrhage). The overall one-year survival after TTP was 29% and the most common cause of death were acute or chronic GVHD (n=35, 55%) and primary disease progression (n=10, 16%). Stem cell donors other than MRD, lymphoid malignancies and aGVHD≥2 have been established as risk factors associated with development of TTP and therapeutic PE has been shown to decrease TTP related mortality. Risk factors for TTP after allogeneic HSCT Variables sample size events HR 95% CI p Male 793 33 1.0 Female 518 44 2.2 1.3–3.6 0.002 Myleoid malignancy 688 33 1.0 Lymphoid malignancy 605 42 1.9 1.1–3.3 0.03 AA 18 2 1.3 0.2–8.0 0.75 MRD 694 28 1.0 MUD 461 40 2.9 1.6–5.1 <0.001 MMR 99 7 2.4 0.9–6.0 0.06 MMUD 57 2 1.7 0.4–7.6 0.5 aGVHD ≥2 370 39 3.3 2.0–5.5 <0.001

Download Full-text

KIT Blockade Is Sufficient to Sustain Donor Hematopoietic Stem Cell Engraftment in Fanconi Anemia Mice

Blood ◽

10.1182/blood.v126.23.1206.1206 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1206-1206

Author(s):

Shanmuganathan Chandrakasan ◽

Rajeswari Jayavaradhan ◽

Ernst John ◽

Archana Shrestha ◽

Phillip Dexheimer ◽

...

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Hematopoietic Stem Cell ◽

Fanconi Anemia ◽

Conflicts Of Interest ◽

Bone Marrow Failure ◽

Conditioning Regimen ◽

Cell Transplant ◽

Hematopoietic Stem ◽

Increased Risk

Abstract Background: Fanconi anemia (FA) is the most common cause of inherited bone marrow failure (BMF). Currently, the only curative option for the BMF in FA is an allogenic hematopoietic stem cell transplant (HSCT). However, due to the underlying DNA repair defect, FA patients poorly tolerate alkylating chemotherapy or irradiation based conditioning, which is necessary for donor engraftment. However, this results in significant short and long term morbidity/mortality and augments the inherent increased risk of malignancies in FA patients. To overcome the adverse effects associated with alkylating conditioning agents, alternate experimental approaches exploiting the inherent hematopoietic stem cell (HSC) defect in FA are of utmost clinical necessity. Objective: To develop a safe KIT blocking antibody (KIT-Ab) based HSCT conditioning regimen for FA that does not involve chemotherapy or irradiation. Method: High purity KIT-Ab was made from the ACK2 hybridoma and its specificity to KIT binding was validated using mast cell assay. Baseline peripheral blood cells and the bone marrow hematopoietic stem and progenitor cell (HSPC) compartment (Lin-Kit+Sca+ and Lin-Kit+Sca+CD150+CD48- cells) of FANCA-/- and FANCD2-/- murine models were analyzed. Mechanistic studies using sorted FA bone marrow HSPC were performed ex vivo. This was followed by definitive primary and secondary transplants experiments following injection of KIT-Ab. Results: Several features of FA hematopoietic stem/progenitor cells (HSPC) suggested their susceptibility to KIT-Ab blockade-mediated killing: (a) Expression of KIT was significantly lower in FANCA-/- HSPC, while expression of its ligand was higher in bone marrow stroma; (b) Moreover, genes associated with apoptosis/senescence, stress and inflammatory signaling that were upregulated in WT-HSPC following KIT-Ab blockade, were upregulated in FANCA-/- HSPC at baseline; (c) Furthermore, FANCA-/- HSPC demonstrated increased susceptibility to KIT-Ab mediated apoptosis and had a reduced proliferative capacity. In-vivo studies following ACK2 injection showed a marked reduction of colony-forming units (CFU-C) from both FANCA-/- and FANCD2-/- mice one week following injection, when compared to WT mice (48% and 76% decrease in CFU-C, respectively). Based on these findings, we evaluated the role of ACK2 as a sole HSCT conditioning regimen in FANCA-/- and FANCD2-/- mice. Indeed, definitive HSCT in both FANCA-/- and FANCD2-/- mice using KIT-Ab based conditioning resulted in donor HSC engraftment with multi-lineage chimerism, which progressively increased to 22-24% by 4-months, and was sustained in secondary transplants. Overall, we show that KIT-blockade alone is an adequate non-genotoxic HSPC-targeted conditioning in FA mice, and its clinical translation could circumvent the extensive transplant-related morbidity/mortality in this disease. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Matched Unrelated Allogeneic Stem Cell Transplantation for Patients with Congenital Amegakaryocytic Thrombocytopenia: Texas Children`s Hospital Experience

Blood ◽

10.1182/blood.v126.23.5529.5529 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5529-5529

Author(s):

Saleh Bhar ◽

Khaled Yassine ◽

Caridad Martinez ◽

Ghadir S. Sasa ◽

Swati Naik ◽

...

Keyword(s):

Stem Cell ◽

Collaborative Research ◽

Bone Marrow Failure ◽

Compound Heterozygous ◽

Unrelated Donor ◽

Cell Transplant ◽

Close Monitoring ◽

Hematopoietic Stem ◽

Increased Risk ◽

Unrelated Donors

Abstract Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare inherited bone marrow failure syndrome (IBMFS) characterized by decreased or absent numbers of megakaryocytes and is not associated with congenital malformations. It is an autosomal recessive disorder with mutations in the thrombopoietin receptor c-MPL, presenting at birth with severe isolated thrombocytopenia. Given the increased risk of life threatening hemorrhage, close monitoring and supportive care with regular platelet transfusions is usually required. The severity of the MPL mutation may predict the clinical course of children with CAMT. Null mutations may rapidly progress to pancytopenia and aplastic anemia, while more modest functional loss of receptor function cause a transient increase in platelet count to > 50,000/µL during the first year of life with later progression to pancytopenia. Moreover, like other IBMFSs, CAMT has been referred to as a cancer predisposition syndrome. Allogeneic hematopoietic stem cell transplant (HSCT) offers the only curative option. We present our institutional experience of three patients with CAMT who underwent matched unrelated HSCT early in the course of the disease when their presenting problem was isolated thrombocytopenia without pancytopenia, marrow failure or clonal evolution. We have used a fully ablative regimen with busulfan 1 mg/kg/dose for 16 doses (days -9, -8, -7, and -6), cyclophosphamide 50 mg/kg/dose for 4 doses (days -5, -4, -3, and -2) and alemtuzumab 3 mg/day (weight-based dosage) for 4 doses (days -5, -4, -3, and -2). Cyclosporine and mini methotrexate (on days +1, +3, +6 and +11) were given for GVHD prophylaxis. The first two patients were siblings with persistent thrombocytopenia at birth, the first of whom had compound heterozygous mutations (c.256dupC and c.391+5 G>C) in the MPL gene. Both parents were carriers and the second sibling was diagnosed prenatally with the same mutations. No other phenotypic abnormalities were noted and testing for Fanconi anemia was negative. The siblings were transplanted with matched unrelated donors at 12 months and 14 months respectively. Our third patient was diagnosed prenatally with germinal matrix hemorrhage and vetriculomegaly. He was noted to have thrombocytopenia after birth. He was treated initially for presumed neonatal alloimmune thrombocytopenia. Sequencing of the MPL gene revealed two compound heterozygous missense mutations (R257C and R102P). The patient was transplanted with a matched unrelated donor at the age of 11 months. All patients tolerated the transplant with minimal toxicity, durable engraftment, and no acute or chronic GVHD. The first two siblings are approximately 4 years and 2 years post HSCT and the third patient is past day 100. Previous reports of HSCT for CAMT that used matched unrelated donors recorded poor outcomes, with a high rate of graft failure. Although our current study is small in size, the results suggest that a HSCT following a fully ablative regimen containing alemtuzumab and performed early in the course of the disease may produce better outcomes, and will avoid the complications associated with marrow failure and clonal abnormalities. Disclosures Allen: Roche: Consultancy, Other: unpaid; NovImmune: Consultancy, Other: unpaid. Heslop:Celgene: Other: Collaborative research agreement; Cell Medica: Other: Licensing Agreement. Brenner:Celgene: Other: Collaborative Research Agreement; Cell Medica: Other: Licensing Agreement; Bluebird Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Hematopoeitic Stem Cell Transplant in Aplastic Anemia: Is It Time to Revise the Treatment Alogirthm

Blood ◽

10.1182/blood.v128.22.2395.2395 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2395-2395

Author(s):

Ashish O. Gupta ◽

Steven L Shein ◽

Jignesh D Dalal

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Aplastic Anemia ◽

Graft Failure ◽

Inpatient Admission ◽

Unknown Etiology ◽

Unrelated Donor ◽

Cell Transplant ◽

Hematopoietic Stem ◽

Increasing Trend

Abstract Background: Aplastic anemia (AA) is a rare bone marrow failure (BMF) syndrome of unknown etiology characterized by hypocellular bone marrow and severe persistent pancytopenia. Pediatric AA is more common in adolescent age group with better outcomes as compared to adults. Current treatment modalities include immunosuppressive therapy (IST) or matched related bone marrow transplant, when possible. There is a high risk of disease relapse with IST and clonal evolution into myelodysplastic syndrome. There is limited pediatric data on outcomes with different treatment options. Methods: Retrospective database analysis of Pediatric Health Information Systems (PHIS) database was performed to evaluate healthcare outcomes of pediatric patients (age less than 21 years) with AA from January 1, 2006 to December 31, 2015. PHIS is an administrative quality-controlled database from 43 not-for-profit children's hospitals. ICD-9 code 284.9 was used to identify patients with acquired AA. Appropriate procedure and pharmacy billing codes were used to obtain information regarding transplants and various drugs used. SAS based statistical software was used to perform analysis. Results: A total of 5127 inpatient admissions were noted for AA during the study period. An overall increasing trend of transplant was observed from 2006-2015 (Figure 1). Almost equal inpatient admission rate was noted in males and females, with a slightly higher rate amongst males who underwent transplant (55% vs 45%). Inpatient admission was more common amongst whites in both transplant (n=407, 8%) and non-transplant groups (n=4717, 92%; Table 1). Overall inpatient mortality was about 2% with a similar mortality in those who underwent transplant (5%). Cyclosporine (n= 1785, 38%) and steroids were most common immunosuppressive drugs used in non-transplant group. In the transplant group (Table 2), graft failure (20%) was the most common complication, while Cyclophosphamide (77%), Fludarabine (53%) and anti-thymocyte globulin (31%) based conditioning was most commonly used. Transplant itself was an independent risk factor for mortality (p=0.04) along with graft failure (p=0.02). Steroids (92%) and Cyclosporine (73%) were the most common immunosuppression used. Conclusion: Hematopoietic stem cell transplants have good outcomes in pediatric AA patients. With an increasing trend of HSCT in these patients, successful outcomes with other transplant options such as match unrelated donor transplants should be considered. Treatment algorithm for Pediatric AA needs to be revised to include other transplant sources. Disclosures No relevant conflicts of interest to declare.

Download Full-text