scholarly journals Reduced Intensity Conditioning for Haploidentical Bone Marrow Transplantation in Patients with Symptomatic Sickle Cell Disease: BMT CTN Protocol 1507

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 802-802
Author(s):  
Adetola A. Kassim ◽  
Mark C. Walters ◽  
Mary Eapen ◽  
Brianne Allison ◽  
Adam M. Mendizabal ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Graft Rejection ◽  
Conditioning Regimen ◽  
Rejection Rate ◽  
Marrow Transplant ◽  
Cell Disease ◽  
Event Free Survival ◽  
Learning Collaborative ◽  
Free Survival ◽  
Post Transplant

Background: Hematopoietic cell transplantation (HCT) has curative potential in sickle cell disease (SCD). A reduced intensity haploidentical bone marrow transplant (haplo-BMT) platform piloted by investigators at Johns Hopkins, addressed key barriers in HCT for SCD, donor availability and toxicity, but had a graft rejection rate of 43%. (Blood. 2012;120(22):4285-4291). Subsequently, a Vanderbilt University Medical Center supported multi-institution learning collaborative with London, France and United States was developed in 2013 with the objective of reducing this graft rejection rate. Evolution of this haplo-BMT platform with the addition of only thiotepa, resulted in a reduction in the graft rejection rate to 7% (1 of 15), an event free survival (EFS) of 93% (14 of 15), > 95% stable donor engraftment at 6 months and 100% overall survival (Biol Blood Marrow Transplant. 2019 Jun;25(6):1197-1209). Based on the preliminary data from the learning collaborative, we initiated an NIH sponsored BMT CTN, dual-strata, phase II, multi-center prospective clinical trial, (clinicaltrials.gov # NCT03263559) to estimate event free survival (EFS) at 2 years in children with neurological morbidity and adults with severe SCD. Study Design and Methods: Eligibility: Patients are stratified into 2 groups: (1) children with SCD (Hb SS or Sβ+ Thalassemia) between 5.00 - 14.99 years of age with central nervous system (CNS) disease (stroke, elevated transcranial Doppler (TCD) with evidence of intracranial vasculopathy; silent cerebral infarction) and (2) adults with severe SCD (Hb SS, SC, Sβ° thalassemia, Sβ+ Thalassemia, SD, S-OArab), between 15.00 - 45.99 years of age who have had a stroke, recurrent ACS, recurrent vaso-occlusive pain episodes, chronic transfusions to prevent sickle complications and tricuspid valve regurgitant jet velocity (TRJV) ≥2.7 m/sec. Participants must have an HLA haploidentical first degree relative donor with 2, 3, or 4 (out of 8) HLA-mismatches who is willing and able to donate bone marrow. Those with an HLA-matched sibling are excluded. Primary objective is to estimate EFS at 2 years after haplo-BMT in patients with SCD enrolled in each stratum. Secondary objectives include determining the effect of haplo-BMT on clinical and laboratory manifestations of SCD by 2 years post-transplant and determining the incidence of other transplant-related outcomes. A key secondary analysis will be central adjudication of CNS progression in children and adults with evidence of previous CNS injury. Treatment Description: Preconditioning with hydroxyurea 30mg/kg daily (Day -70 to Day -10). The conditioning regimen includes: Thymoglobulin (rATG) (0.5mg/kg on Day -9, 2mg/kg on Day -8, Day -7), Thiotepa 10mg/kg on Day -7, Fludarabine (30mg/m2 on Day -6 to Day -2), Cyclophosphamide 14.5mg/kg on Day -6 and Day -5, and TBI 200cGy on Day -1. Day 0 is the day of infusion with non T-cell depleted bone marrow. Cyclophosphamide 50 mg/kg and Mesna 40mg/kg is given on Days +3 and +4, and GVHD prophylaxis (sirolimus and mycophenolate mofetil) begin on Day +5 (Figure). Study Accrual and Endpoints: The target sample size is 40 patients enrolled and treated in each stratum; if the stopping rule for graft failure is triggered within the first 12 evaluable participants in either stratum using the 200cGy dose of TBI and the DSMB and sponsor approve the pre-defined switch in conditioning regimen, then accrual for that strata will restart under the modified conditioning regimen with 400 cGy TBI. The estimated accrual period is 4 years. The rate of overall mortality by Day 180 after starting hydroxyurea therapy pre-transplant, acute grade III-IV GVHD at 100 days, and severe chronic GVHD at 18 months post-transplant will be monitored by a sequential probability ratio test (SPRT) for censored exponential data for each of these. Graft failure at 100 days post-transplant will be monitored by using a SPRT for binary data. Conclusion: This NIH sponsored BMTCTN phase II trial of HLA-haploidentical HCT is active at 30 BMT CTN sites. This study will determine if a modulated conditioning regimen has adequate donor engraftment, with acceptable risks of transplant-related morbidity and mortality to support a future comparative clinical trial in SCD. Figure Disclosures Walters: AllCells, Inc: Consultancy; TruCode: Consultancy; Editas Medicine: Consultancy. Brodsky:Achillion: Research Funding; Alexion: Membership on an entity's Board of Directors or advisory committees, Other: Grant funding.

scholarly journals A Novel TBI Free Conditioning Protocol for Haploidentical Transplant in Acquired Aplastic Anemia: (FluCAB-Prime)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 12-13
Author(s):  
Raheel Iftikhar ◽  
Qamar Un Nisa Chaudhry ◽  
Syed Kamran Mahmood ◽  
Tariq Ghafoor ◽  
Nighat Shahbaz ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Aplastic Anemia ◽  
Graft Failure ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Marrow Transplant ◽  
Free Survival ◽  
Post Transplant ◽  
Primary Graft Failure

Introduction Allogeneic hematopoietic stem cell transplant (HSCT) is the standard treatment for patients younger than 40 years with Severe and Very Severe Aplastic Anemia (AA) who have a Matched Related Donor (MRD). For patients lacking a MRD, treatment options include immunosuppressive therapy (IST), matched unrelated donor (MUD) or alternate donor (haploidentical/cord blood) transplant. Pakistan has a population of around 23 million but there is no donor registry for MUD transplants and horse antithyomcyte globulin (hATG) is not available. Over past decade, results of haploidentical transplants have improved remarkably with use of post-transplant cyclophosphamide. However, most of these protocols incorporate total body irradiation (TBI) to improve engraftment and reduce graft failure. TBI is not available in most of the transplant centres across Pakistan. We have developed a novel TBI free conditioning regimen (NCT03955601) for haploidentical HSCT in acquired AA patients lacking a MRD. Materials and Methods We conducted a prospective, single centre, interventional trial (NCT03955601) using novel TBI free conditioning at AF bone marrow transplant centre (AFBMTC)/ National institute of blood and marrow transplant (NIBMT) for patients with acquired severe and very severe AA. Between July 2018 and March 2020, a total of 10 patients received related haploidentical transplant.Study inclusion criteria was diagnosis of severe and very severe AA, patients of both genders, age 2-60 years, Karnofsky performance status>70%. Exclusion criteria was presence of donor specific antibodies (DSA), inherited bone marrow failure syndrome, prior HSCT and severe sepsis. Conditioning regimen used was Fludarabine (Flu) 30 mg/m2 IV daily from day -7 to -3, Cyclophosphamide (Cy) 14.5 mg/kg IV daily on day -6 and -5 , rabbit Antithymocyte globulin (rATG) 5 mg /kg/day from day -6 to day-3; Busulphan (Bu) IV 3.2 mg per kg/day in 04 divided doses on day -3 and day-2, Granulocyte Colony Stimulating factor (GCSF) primed Bone marrow harvest (BMH) and/or PBSC graft on day 0 and day +1 respectively. Graft versus host disease (GVHD) prophylaxis used was post-transplant cyclophosphamide (PTCy) administered at a dose of 50mg/kg/day given daily on days +3 and +5 post-transplant, cyclosporine (CsA) from day +5 and mycophenolate mofetil (MMF) from day+5 to +35. Primary outcome measure was overall survival (OS) while secondary outcome measures included graft failure, treatment related mortality (TRM), disease free survival (DFS), GVHD free relapse free survival (GRFS), acute and chronic GVHD. Results: Ten patients were transplanted, 5 (50%) female and 5 (50%) male (table 1). Median age was 15.5 years (range 5-41 years). Median duration from diagnosis to transplant was 14 months (range 4-51 months). One patient received ATG prior to transplant. Median number of red cell concentrate (RCC) transfusions before transplant were 27 (8-90) and platelet transfusions 100(6-150). Median donor age was 23 years (10-41 years). Donor-recipient major ABO mismatch was present in 2(20%) while four (40%) had minor ABO mismatch. Primed bone marrow harvest (BMH) was used in 3(30%) while primed BM+PBSC was given in 7(70%) patients. Median CD34 dose given was 8 x 106/kg (range 5.1-16). Seven patients (70%) achieved sustained neutrophil engraftment. One patient had primary graft failure, one patient secondary graft failure at day 35 due to Cytomegalovirus infection and one patient (currently day +118) is having poor graft function. Acute skin GVHD stage-2 developed in 1 patient which settled with topical steroids. None of the patient developed chronic GVHD. Cytomegalovirus reactivation was documented in 8 (80%) patients. All donors and recipients were CMV seropositive pre-transplant. One patient (female, 20 years) had primary graft failure and died on day +31 with sepsis and multiorgan dysfunction syndrome (MODS). One patient (female, 14 years) had secondary graft failure due to CMV infection and died on day +44 with intracranial hemorrhage. Conditioning regimen was well tolerated without any treatment related morbidly and mortality. Median follow-up of study was 13 months (range 4-22 months). Overall survival of study cohort is 80%, DFS 70% and GRFS 70%. Conclusion: Our study shows that for countries lacking TBI, use of FluCAB-Prime protocol is feasible and is associated with low rates of acute and chronic GVHD. Disclosures No relevant conflicts of interest to declare.

Results of a Multicenter Pilot Investigation of Bone Marrow Transplantation in Adults with Sickle Cell Disease (STRIDE)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 543-543 ◽  
Author(s):  
Lakshmanan Krishnamurti ◽  
Keith M. Sullivan ◽  
Naynesh R. Kamani ◽  
Edmund K Waller ◽  
Allistair Abraham ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Sickle Cell Disease ◽  
Graft Failure ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Cell Disease ◽  
Event Free Survival ◽  
Eligibility Criteria ◽  
Free Survival ◽  
Reduced Toxicity

Abstract Background: Hematopoietic cell transplantation (HCT) for sickle cell disease (SCD) is potentially curative, yet applied sparingly in adults due in part to limited donor availability and to concerns about safety. We conducted a multicenter pilot clinical trial to determine ways to broaden the availability of this therapy. Objective: To determine the feasibility, efficacy, and safety of a reduced toxicity transplant conditioning regimen in adults with severe SCD receiving related and unrelated donor HCT. Methods: Patients between 16-40 years of age were enrolled between October 2012 and June 2015 at 8 participating transplant centers. Eligibility criteria included stroke; recurrent episodes of acute chest syndrome (ACS) or sickle pain in the past 2 years; 8 or more RBC transfusions/year; or a tricuspid valve regurgitant jet velocity ³2.7 m/sec. Patients received unmodified bone marrow from a human leukocyte antigen (HLA)-matched sibling or an unrelated donor matched for 8 of 8 HLA loci. Patients were prepared for HCT with Busulfan from day -8 to -5 (13.2 mg/kg), Fludarabine from day -7 to -3 (150 mg/m2) and Thymoglobulin from day -5 to -2 (6 mg/kg). GVHD prophylaxis consisted of cyclosporine or tacrolimus with methotrexate. Outcomes and Measures: The primary endpoint was event-free survival 1 year after HCT, with events defined as graft failure, disease recurrence, or death. The Kaplan-Meier probabilities of event-free and overall survival were determined. Donor chimerism, transplant-related toxicities and clinical and laboratory measures of SCD were secondary endpoints obtained 1 year after HCT. Serious adverse events were monitored after transplantation. Results: Twenty-two patients (13 were female) who ranged in age from 17-36 (median 22) years were enrolled. Seventeen patients received a sibling and 5 an unrelated donor HCT. An eligibility review committee confirmed subject eligibility. Enrolled subjects had stroke (2 pts), ACS (3 pts), painful crises (14 pts), RBC transfusions (6 pts) and/or tricuspid valve regurgitant jet velocity (5 pts); 8 subjects satisfied eligibility criteria for more than 1 category. There were 6 severe adverse events after transplantation in 4 patients including one death from intra-cranial hemorrhage related to posterior reversible encephalopathy syndrome. None of the patients had graft failure or SCD recurrence after HCT. Currently, 21 of 22 patients survive with stable engraftment of donor cells at a median 9.7 months (range, 1-31) after HCT. The overall and event-free survival probabilities are both 95% (90% CI 76%; 99%, Figure 1) at 12-months after HCT. Two patients developed grade I skin acute GVHD and three patients developed chronic GVHD. Full donor myeloid chimerism was observed after HCT. The median donor T-cell and RBC chimerism at 28, 100 and 180 days after HCT was 55.5% and 100%, 80% and 100%, and 87.5% and 100%, respectively. Conclusions: We report excellent outcomes after HLA-matched HCT in adults with SCD using a reduced toxicity-conditioning regimen performed in a multi-center setting. We observed very low rates of graft rejection and GVHD in this pilot study. We speculate that these outcomes, if sustained long-term after HCT, will be superior to survival in adults with SCD who receive standard supportive care. If confirmed in a larger comparative trial, this approach would broaden the availability and application of transplantation for adults with severe SCD. Figure 1. Figure 1. Disclosures Walters: ViaCord and AllCells, Inc: Other: Medical director.

scholarly journals Treatment of Familial Hemophagocytic Lymphohistiocytosis With Bone Marrow Transplantation From HLA Genetically Nonidentical Donors

Blood ◽  
1997 ◽  
Vol 90 (12) ◽  
pp. 4743-4748 ◽  
Author(s):  
Nada Jabado ◽  
Elizabeth R. de Graeff-Meeder ◽  
Marina Cavazzana-Calvo ◽  
Elie Haddad ◽  
Françoise Le Deist ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Graft Rejection ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Marrow Transplantation ◽  
Conditioning Regimen ◽  
Free Survival ◽  
Familial Hemophagocytic Lymphohistiocytosis ◽  
Disease Free

Abstract Familial hemophagocytic lymphohistiocytosis (FHL) is a rare genetic disorder associated with the onset early in life of overwhelming activation of T lymphocytes and macrophages invariably leading to death. Allogeneic bone marrow transplantation (BMT) from an HLA-identical related donor is the treatment of choice in patients with this disease. However, fewer than 20% of patients have a disease-free HLA-identical sibling. BMT from HLA-nonidentical related donors has previously met with poor results, with graft rejection a major obstacle in all cases. We describe BMTs from HLA-nonidentical related donors (n = 13) and from a matched unrelated donor (n = 1) performed in two centers in 14 consecutive cases of FHL. Remission of disease was achieved before BMT in 10 patients. Marrow was T-cell–depleted to minimize graft-versus-host disease (GVHD). Antiadhesion antibodies specific for the α chain of the leukocyte function–associated antigen-1 (LFA-1, CD11a) and the CD2 molecules were infused pre-BMT and post-BMT to help prevent graft rejection, in addition to a conditioning regimen of busulfan (BU), cyclophosphamide (CP), and etoposide (VP16) or antithymocyte globulin (ATG). Sustained engraftment was obtained in 11 of 17 transplants (3 patients had 2 transplants) and disease-free survival in 9 patients with a follow-up period of 8 to 69 months (mean, 33). Acute GVHD greater than stage I was not observed, and 1 patient had mild cutaneous chronic GVHD that resolved. Toxicity due to the BMT procedure was low. Results obtained using this protocol are promising in terms of engraftment and event-free survival within the limitations of the small sample. We conclude that an immunologic approach in terms of drugs used to obtain disease remission and a conditioning regimen that includes antiadhesion molecules in T-cell–depleted BMT from HLA genetically nonidentical donors is an alternative treatment that warrants further study in FHL patients who lack a suitable HLA genetically identical donor.

scholarly journals Tortoise and hare win for SCD

Blood ◽  
2007 ◽  
Vol 110 (7) ◽  
pp. 2223-2224
Author(s):  
John F. Tisdale
Keyword(s):  
Stem Cell ◽  
Conditioning Regimen ◽  
Standard Of Care ◽  
Long Term Results ◽  
Cell Disease ◽  
Event Free Survival ◽  
Free Survival ◽  
Matched Donor ◽  
Over Time

Bernaudin and colleagues report, in this issue of Blood, the long-term results of the largest study of related myeloablative stem-cell transplantation for sickle cell disease (SCD). Their results show that slow, steady improvements over time, along with the addition of rabbit anti–thymocyte globulin (ATG) to the conditioning regimen, combine to produce an event-free survival (EFS) of 95.3%. They argue that for children with a suitable sibling-matched donor, myeloablative transplantation should be considered the standard of care in those at high risk for stroke.

scholarly journals Graves’ Disease After Hematopoietic Allogeneic Bone Marrow Transplant in a Patient With Sickle Cell Disease

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A930-A931
Author(s):  
Majid Alameri
Keyword(s):  
Bone Marrow ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Marrow Transplant ◽  
Graves Disease ◽  
Allogeneic Bone ◽  
Cell Disease ◽  
Free T4 ◽  
Post Transplant

Abstract Endocrinopathies are among the most recognized late complications post hematopoietic stem cell transplant (HSCT). Dysfunctions of hormonal axes including the hypothalamus, pituitary, gonads, thyroid and adrenals reported. Moreover, thyroid dysfunctions including thyroiditis, hypothyroidism and hyperthyroidism has been reported to develop 8-32 months after HSCT. We report a 27-year-old male with sickle cell disease diagnosed at age of 5. He had multiple painful vasoocclusive sickle crises treated with blood transfusions, folic acid and rituximab. At age of 21, he presented with sudden right sided weakness and slurred speech. Further investigations, including magnetic resonance imaging of brain revealed occlusion of the left middle cerebral artery resulting in ischemic infarction. Subsequently, he had multiple red blood cell exchange transfusions on regular basis. He remained with residual weakness and slurred speech after rehabilitation. Bone marrow transplant was recommended as a curative treatment for his sickle cell disease by haematology team. A year later, he underwent a geno-identical allogeneic bone marrow transplantation harvested from his brother. He remained well for 22 months post-transplant without any evidence of graft versus host disease. 23 months post-transplant, he presented with loose motions, 2 kg wight loss and fine tremors. He was referred to endocrine department for further workup. Physical examination revealed a small smooth goitre. He had discrete exophthalmos of his left eye without any signs of active inflammation. Thyroid function tests confirmed diagnosis of Graves’ disease with TSH<0.01 milli IU/L, Free T4=23.9 pmol/L, and TSH receptor antibodies of 3.79 IU/ml. Ophthalmological consultation suggested 6 months of selenium supplementation (200 mcg/day) with regular follow up. There has been no family history of autoimmune diseases or thyroid disorders. He started carbimazole (CMZ) 30 mg daily. His symptoms improved within 8 weeks, with normalization of Free T4 and Free T3 (TSH remained suppressed). 18 months later, he remained asymptomatic on carbimazole. He had recurrence of hyperthyroidism symptoms after 4 weeks trail of stopping carbimazole with elevation of Free T4 and Free T3. Carbimazole was restarted and he has been offered other treatment modalities of Graves’ disease. He elected to undergo total thyroidectomy. His sickle cell and blood counts remained stable during follow up period. Conclusion: Transplanted patients carries a life-long risk for developing endocrinopathies post initial transplant therapy. Acknowledging the wide spectrum of post-transplant endocrinopathies, an individualized case based periodic screening can be helpful to improve health outcomes of such patients. Because of the usual late presentation of such endocrine complications, transplanted patients might need life-long endocrine follow-up.

Targeting Busulfan to Concentration Steady State of 600–700 ng/Ml Is Associated with Robust Engraftment and Decreased Toxicity in Patients with Sickle Cell Disease Receiving An HLA Identical Donor Transplant

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1966-1966
Author(s):  
Jennifer Domm ◽  
Elizabeth Yang ◽  
Richard Ho ◽  
Adetola a Kassim ◽  
Haydar Frangoul
Keyword(s):  
Bone Marrow ◽  
Steady State ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Graft Versus Host Disease ◽  
Immune Suppression ◽  
Graft Rejection ◽  
Cell Disease ◽  
Graft Versus Host ◽  
Post Transplant

Abstract Abstract 1966 Sickle cell disease is a chronic illness with significant morbidity and mortality. The most frequent adverse events are painful vaso-occlusive crises (VOC) that often require hospitalization. VOC are recurrent and unpredictable and associated with higher mortality. Adults frequently suffer from the consequences of cumulative organ damage. The life expectancy of patients with sickle cell disease is still in the 40s by the most recent evaluation. The only curative therapy is allogeneic hematopoietic stem cell transplant. The major complication related to transplant includes transplant related mortality and graft rejection. We used the previously described regimen of busulfan, cyclophosphamide and ATG. Concentration steady state (CSS) of busulfan <600 ng/ml has been associated wth graft rejection and a CSS >900 ng/ml is associated with increased risk of regimen related toxicity. We targeted busulfan to a CSS of 600–700 ng/ml in an attempt to decrease regimen related toxicity and achieve donor engraftment. Between 2004 and 2011 14 patients underwent allogeneic bone marrow transplant from HLA identical siblings. Preparative regimen consisted of intravenous busulfan 0.8–1 mg/kg/dose for 16 doses, cyclophosphamide of 50 mg /kg daily for 4 doses, and equine ATG 30 mg/kg daily for 3 doses. Busulfan levels were measured after the first dose busulfan and subsequent doses were adjusted to provide a total exposure of concentration steady state of 600–700 ng/ml. Graft versus host disease prophylaxis was with cyclosporine starting on day −3 and short course methotrexate. Indications for transplantation included stoke or abnormal transcranial doppler (n=2), acute chest syndrome (n=1), renal disease (n=1), history of vaso-occlusive crisis in (n=10) and availability of HLA identical donor. The median age at time of transplant was 6.1 years (range 1.2–19 years). All patients received anti-seizure prophylaxis and antihypertensive therapy until all immune suppression was discontinued. All patients received a bone marrow graft from HLA identical siblings. The median busulfan steady state exposure was 648 ng/ml (range 607–670). Only 3 patients (21%) developed mucositis requiring parentral nutrition and none of the patients developed sinusoidal obstructive syndrome post transplant. All patient achieved neutrophil and platelet engraftment at a median of 18 and 22 days respectively. Grade II acute graft versus host disease developed in 2 patients (14%) and none of the 13 evaluable patients developed chronic GVHD (one patient is <100 days from transplant). Median donor engraftment is 100% (range 85–100) and all patients have achieved a hemoglobin profile identical to their donor's. None of the patients experienced sickle cell related complications post transplant. With a median follow up of 600 days (range 70–2644), the event free and overall survival are both 100%. All patients who are beyond one year post transplant are off all immune suppression. We conclude that targeting of busulfan between 600 and 700 ng/ml in combination with cyclophosphamide and ATG can result in excellent and sustained engraftment with low risk of toxicity in young patients with sickle cell disease. Disclosures: No relevant conflicts of interest to declare.

Post-Transplantation Cyclophosphamide (PT-CY) After Myeloablative Conditioning Regimen (MAC) In Unmanipulated Haploidentical Bone Marrow Transplantation (hBMT) Is Highly Effective As Gvhd Prophylaxis and Disease Free Survival In Pediatric and Adult Patients With High Risk Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4576-4576
Author(s):  
Maria Domenica Simone ◽  
Anna Proia ◽  
Alessandro Severino ◽  
Alison Shardlow ◽  
Novella Natale ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Conditioning Regimen ◽  
Marrow Transplant ◽  
Adult Patients ◽  
High Rate ◽  
Myeloablative Conditioning ◽  
Free Survival ◽  
Gvhd Prophylaxis ◽  
Disease Free

Introduction BMT from HLA haploidentical family members (hBMT), using either T-cell depleted or T-cell replete grafts, is increasingly employed in patients who urgently need (but lack) a donor. After the promising results in hBMT obtained by the Baltimore group (Luznik et al., Biol Blood Marrow Transplant 2008, Blood 2010) introducing post-transplant high-dose cyclophosphamide (PT-CY) following a non-myeloablative conditioning regimen, the Genoa group (Raiola et al., Biol Blood Marrow Transplant 2013) has shown, in the haploidentical setting that a myeloablative conditioning (MAC) with PT-CY (on day +3 and +5), cyclosporine from day zero and mycophenolate mofetil (MMF) from day +1, is associated with a high rate of engraftment, acceptable TRM and GVHD, and induces durable remission with low incidence of relapse in a high proportion of patients with high-risk hematologic malignancies. We now report a series of 13 heavly pretreated high-risk leukemia patients who underwent a MAC protocol consisted of TBF regimen: Thiotepa (10 mg/kg), Busulfan (9,6 mg/kg) and Fludarabine (150 mg/mq). As graft versus host disease (GVHD) prophylaxis, 2 patients received a 5 drugs combination (ATG-Fresenius, CSA, MTX, MMF and Basiliximab) and stem cells source was G-CSF-primed haploidentical bone marrow (hBM) cells (Di Bartolomeo et al., Blood 2013). In 11 patients stem cells source was non-primed unmanipulated hBM cells, and GVHD prophylaxis consisted of PT-CY (50mg/kg) iv on day +3 and +4, CSA 2.5 mg/kg/day and MMF 45 mg/kg/day from day +4. Results From 2008 to 2013, 11 adult patients (M/F=8/3; median age 40 years, range 23 to 62) and 2 pediatric patients (M/F=1/1, age 4 and 7 years) with high risk ALL (1 pediatric; 2 adult), AML (1 pediatric; 8 adults) and one Richter evolution of CLL, underwent T replete hBMT. At time of transplant 10 patients were in CR (CR1=9, CR2=1), 1 in a good PR and 2 had refractory disease. Grafts contained a median of 5.68 x 108/kg nucleated BM cells (range 0.7-62.1), 2.14x106/kg CD34+ cells (range 0.55-7.09) and 34.7x106/kg CD3+ cells (range 16-93.4). 12 patients are evaluable for engraftment. This occurred in 100% for neutrophils and 93% for platelets, with a median time to neutrophil recovery (> 0.5 x 109/L) of 22.5 days (range, 13-40) and to platelet recovery (> 20.0 x 109/L) of 27.5 days (range, 17-49). All patients had full donor chimerism by day +30. Non relapse mortality (NRM) was 23%: 2 pt died for sepsis (one before engraftment), 1 for aGVHD. 4 patients had grade I and 3 grade II aGvHD, respectively. Only one patient had a grade III, and another had grade IV fatal GVHD. 3 patients had only limited chronic GvHD. Up to now, only 3 patients have relapsed and of these 2 have died. 8 patients (61.5%) are currently surviving, 7 of them are disease-free with median follow-up time of 165 days (range 32-896 days) from transplant. Conclusion Our preliminary results confirm that haplo-BMT following a MAC regimen, is a feasible treatment in pediatric and adult patients, and that PT-CY is highly effective as GVHD prophylaxis, producing a high rate of stable engraftment with encouraging non relapse mortality and relapse-free survival. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Outcomes of Non-Myeloablative HLA-Haploidentical Bone Marrow Transplant with Thiotepa and Post-Transplant Cyclophosphamide in Children and Adults with Severe Sickle Cell Disease, a Phase II Trial: Vanderbilt Global Haploidentical Transplant Learning Collaborative (VGC2)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 8-9
Author(s):  
Adetola A. Kassim ◽  
Josu de la Fuente ◽  
Ali Debsan Alahmari ◽  
Michael J. Eckrich ◽  
Rabi Hanna ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Sickle Cell ◽  
Graft Rejection ◽  
Research Funding ◽  
Graft Failure ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Stopping Rules ◽  
Global Learning ◽  
Learning Collaborative

Introduction: HLA-Haploidentical bone marrow transplant (haplo-BMT) is a curative approach for individuals with severe sickle cell disease (SCD) who lack an HLA-identical sibling donor. Haplo-BMT expands the donor pool among adults and children with SCD to &gt; 90% and is a less toxic treatment option than myeloablative matched related donor transplant, gene therapy or gene editing. In 2013, our research team developed a multi-institution learning collaborative with the main objective of optimizing haplo-BMT. In a Phase II clinical trial, to improve engraftment rates, we augmented the original Hopkins haplo-BMT protocol (Bolaños-Meade et al. Blood 2012) with thiotepa (10 mg/kg). The trial was conducted at 3 sites and showed durable engraftment in 93% (14/15) of participants (including 2 with previous graft rejection), and a 100% overall survival after a median follow-up of 13.3 months (de la Fuente et al. BBMT 2019). We present results of extension of this ongoing trial comprising additional sites and participants. Material and methods: The trial was approved by the Institutional Review Board (IRB) at each participating site and opened in October 2013 (ClinicalTrials.gov identifier NCT01850108). The global learning collaborative includes 22 sites, in 10 countries, meets weekly via conference calls for sharing of SCD Haplo-BMT knowledge and patient related questions. Each site has a standalone institutionally IRB protocol, with similar eligibility criteria, and data sharing agreement with Vanderbilt University Medical Center. The agreements for aggregate REDCap data sharing and DSMB assessment of the outcomes with stopping rules. Common conditioning regimen included: rabbit ATG 4.5 mg/kg, thiotepa (10 mg/kg), fludarabine 150 mg/m2, cyclophosphamide 29 mg/kg and TBI 2Gy. GVHD prophylaxis included posttransplant cyclophosphamide (PTCy) 100 mg/kg, mycophenolate mofetil and sirolimus. Bone marrow mobilized with filgrastim (5-10 μg/kg/d x5 days) was initially used, 27% (11/41), but later stopped at several sites. Primary graft failure was defined as &lt;5% donor myeloid chimerism or &lt; 5% donor cells by whole blood chimerism by day +42 posttransplant. Secondary graft rejection was defined &lt;5% donor myeloid chimerism or &lt; 5% donor cells by whole blood chimerism with prior documentation of &gt; 5% donor (myeloid) cells by day +42. The primary endpoint was 1-year EFS. Primary or secondary graft rejection, stroke, and death were considered events. Safety stopping rules were implemented, independent of age, using graft failure, death, grade III or IV acute GVHD or moderate or severe chronic GVHD. Results: We enrolled 41 consecutive participants from 8/14/2014 - 6/30/2020. Participant genotype included 39 patients with HbSS, 1 patient each with HbSC and Sβ0 thalassemia. Median age was 16.9 years (range 1.3 to 43), and 51% (21/41) of participants were &lt;18 years of age. Donors included siblings (14/41, 34%), parents (27/41, 61%), and 88% (36/41) had sickle cell trait. Median TNC dose was 5.8 x 108 /kg (4.2, 8.0), and median CD34+ and CD3+ cell doses were 3.9 x 106/kg (2.6, 6.1) and 32.3 x 108/kg (27.1, 50.8), respectively. A total of 93% of participants engrafted. Median times to neutrophil (&gt; 500/mcL) and platelet (&gt;50 x 109/L) counts were 20 days (17.0, 24.2) and 32 days (27.0, 36.8) respectively. Incidence of grades III-IV acute and moderate chronic GVHD were 9.7% (4/41) and 12.1% (5/41), respectively. No participant had severe GVHD. Among durably engrafted participants, 81.8% (27/33) were off immunosuppression at 1-year posttransplant. Kaplan-Meier probabilities of EFS and OS were 75.5% (95% CI 61.3%, 92.9%) and 87.9% (95% CI 75.5%, 100.0%) at one year, respectively (Figure). Mortality was 7.3% (3/41). Graft failure was 12% (5/41; 3-primary and 2-secondary). All graft failures were in participants &lt;18 years of age, and all had autologous reconstitution (Table). Conclusion: Our novel global learning collaborative effort for haplo-BMT for SCD is a scalable and efficient approach to sharing knowledge and implementing curative therapy for SCD. Importantly all haplo-BMT candidate had donors. An unexpected outcome in this trial, not likely to occur by chance, is that all graft rejections occurred in young participants (&lt; 18 years), and all older participants (&gt; 18 years) engrafted. The trial will add new stopping rules by age strata (&lt;18, &gt; or = to 18 years) and will modify the conditioning regimen in pediatric stratum. Disclosures Black: HRSA: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Micelle BioPharma: Research Funding; NHLBI: Research Funding. DeBaun:Novartis: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics (GBT): Membership on an entity's Board of Directors or advisory committees.

The Addition of Rituximab to High Dose Sequential Chemotherapy (HDS) Programs with Autologous Transplantation Significantly Improves the Outcome of Patients with Refractory or Relapsed B-Cell Non Hogkin’s Lymphoma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2084-2084
Author(s):  
Sergio Cortelazzo ◽  
Andrea Rossi ◽  
Emanuela Carlotti ◽  
Piera Viero ◽  
Alessandro Rambaldi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Complete Remission ◽  
Peripheral Blood ◽  
Response Rate ◽  
Autologous Transplantation ◽  
Conditioning Regimen ◽  
Event Free Survival ◽  
Free Survival

Abstract The aim of the present study was to evaluate retrospectively the clinical outcome of 2 consecutive cohorts of relapsed/refractory NHL patients treated with HDS chemotherapy with and without Rituximab and autologous peripheral blood stem cell (PBSC) transplantation. A total of 110 relapsed or refractory NHL patients with different histology (SLL n= 4, FL n=24, Low grade-transformed n=31, DLBCL n=51) entered this analysis. From October 1992 up to November 2004, patients were treated with the original HDS program (n= 33, HDS: cyclophosphamide 7 gr/sqm, methotrexate 8 gr/sqm, etoposide 2 gr/sqm) (Gianni AM et al.: N.Engl.J.Med., 1997) or a modified version (n= 15) in which methotrexate was replaced by HD-Ara-C (2 g/sqm every 12 hours for 6 days). Because the addition of Rituximab could improve the antitumor activity and the response rate before transplantation, from June 1999, Rituximab (375 mg /sqm) was given twice after HD-CTX and twice after HD-Ara-C. Following the HDS chemotherapy program, a BEAM (carmustine BCNU, 300 mg/sqm; etoposide, 200 mg/sqm; Ara-C, 4000 mg/sqm; L-PAM 140 mg/sqm) conditioning regimen with autologous PBSC transplantation was planned. By quantitative PCR analysis of BCL2/IgH chimeric gene, a molecular evaluation of minimal residual disease was performed before transplantation and during follow up on bone marrow or peripheral blood obtained from 21 patients. At enrollment, 69 patients (63%) were high risk being primary refractory (39), early relapsed (7) after first line treatment or relapsed more than twice (23). Moreover, an IPI >1 was documented in 62 patients (56%) and a bone marrow infiltration in 42 (38%). Sixteen patients (15%) had received 2 or 3 lines of conventional chemotherapy and 29 (26%) involved field Radiotherapy. At the end of HDS chemotherapy, before the conditioning regimen, the Response Rate was 82% with 76 patients achieving complete remission (CR, 69%) and 14 patients partial remission (PR, 13%). After autologous transplantation, 76 patients remained in CR (69%), 5 in PR (5%), 25 (23%) showed no response or progressive disease. Four patients (3%) died during treatment. Ninety-four patients (85%) could complete the planned program and underwent autologous transplantation and a median number of 6.3 x 10^6 cells CD34+/Kg was transplanted. After transplantation, 24 patients relapsed, 1 patient developed secondary MDS and 1 patient died because of a secondary GI tract solid tumor. With a median follow-up of 28 months (range 3–146), the 5-year estimate overall survival (OS) and event-free survival (EFS) of the whole group of patients is 48% and 39%, respectively. However, the EFS of patients not receiving Rituximab was 27% as compared to 55% registered in the R-HDS program (p= 0.005). The Cox multivariate analysis confirmed an improved OS (p=0.0000) and EFS (0.001) for patients treated with R-HDS. The achievement of a durable molecular remission was achieved in 11 out of 21 analyzed and was strongly associated with the R-HDS program. In conclusion: the response rate of relapsed or refractory NHL after HDS chemotherapy is high and more than 70% of patients can undergo conditioning regimen and autologous transplantation being in complete remission. The addition of Rituximab to HDS chemotherapy allows the collection of tumor free PBSC in most patients and significantly correlates with an improved Event Free Survival and Overall Survival.

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