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

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.

Download Full-text

A Fludarabine Based Conditioning Regimen Associated with A Good Survival Following HLA Identical Sibling/Family Donor Transplants in Patients with Aplastic Anemia.

Blood ◽

10.1182/blood.v114.22.1194.1194 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1194-1194 ◽

Cited By ~ 1

Author(s):

Mammen Chandy ◽

Biju George ◽

Vikram Mathews ◽

Shashikant Apte ◽

Velu Nair ◽

...

Keyword(s):

Overall Survival ◽

Aplastic Anemia ◽

Graft Failure ◽

Acute Gvhd ◽

Risk Group ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Transplant Recipients ◽

Primary Graft Failure ◽

Family Donor

Abstract Abstract 1194 Poster Board I-216 Between January 2001 and June 2009, 120 patients with aplastic anemia underwent HLA identical sibling or family donor transplants using a combination of Fludarabine 150-180 mg/m2 over 5 days and Cyclophosphamide 120 mg/kg over 2 days as the conditioning regimen. Antithymocyte globulin (ATG) 10 mg/kg x 4 days in addition was used in 34 patients. Graft versus host disease (GVHD) prophylaxis consisted of Cyclosporine with low dose Methotrexate. Graft source included peripheral blood stem cells (PBSC) in 108 and G-CSF stimulated bone marrow in 12. Seventy patients (58.3%) were considered as high risk (presence of fever/infection at time of HSCT or >20 transfusions prior to HSCT or failed previous immunosuppressive therapy). There were 79 males and 41 females with a median age of 22 years (range: 2 - 51) including 36 children (age <15 years). PBSC was used in 108 while BM was the graft source in 12. The median cell dose infused was 7.1 × 108 MNC/Kg for PBSC (range: 1.9 – 19.6) and 4.9 × 108 TNC/Kg for bone marrow (range: 2.1 to 9.9). One hundred and thirteen patients (94.1%) engrafted while 2 (1.6%) had primary graft failure and 5 expired within the first 2 weeks due to infection. The median time to neutrophil engraftment (ANC > 0.5 × 109/L) was 12 days (range: 7-19) while platelet engraftment (Platelet count > 20 × 109/L) occurred at a median of 13 days (range: 0 -30). Acute GVHD occurred in 38 patients (33.3%) with grade III-IV GVHD in 13.1%. Acute GVHD was not significantly lower in patients where ATG was used in conditioning (21.8% with ATG vs 38.2% without ATG; p = 0.129). Nine patients (7.5%) had veno-occlusive disease of the liver while 11 (9.1%) had hemorrhagic cystitis; all responded well to supportive therapy. Bacterial infections were documented in 28% of transplant recipients while fungal infections (both probable and definite) occurred in 23%. CMV reactivation was seen in <5%. Chronic GVHD occurred in 32.6% of evaluable transplant recipients and was limited in a majority of patients. At a median follow up of 30 months (range: 1 – 105), 88 patients (73.3%) are alive and well. Causes of death included sepsis in 19, acute GVHD in 7, chronic GVHD in 4, primary graft failure in 1 and road traffic accident in 1 patient. The overall survival was similar among children (75%) and adults (72.6%). The overall survival was significantly lower in the high risk group (60%) compared to the low risk group (92%; p = 0.0001). Conclusion: A combination of fludarabine and cyclophosphamide as conditioning for aplastic anemia is associated with good engraftment, a very low incidence of primary or secondary graft failure and good overall survival. Toxicity is low but acute and chronic GVHD remain significant problems. Sepsis continues to remain the major cause of death in these patients. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Allogeneic Transplant In Children with Severe Aplastic Anemia – Excellent Outcomes with the Use of a Fludarabine Based Conditioning Regimen

Blood ◽

10.1182/blood.v116.21.3519.3519 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3519-3519

Author(s):

Biju George ◽

Vikram Mathews ◽

Auro Viswabandhya ◽

Aby Abraham ◽

Lakshmi M Kavitha ◽

...

Keyword(s):

Bone Marrow ◽

Aplastic Anemia ◽

Median Time ◽

Graft Versus Host Disease ◽

Graft Failure ◽

Antithymocyte Globulin ◽

Conditioning Regimen ◽

Allogeneic Transplant ◽

Graft Versus Host ◽

Primary Graft Failure

Abstract Abstract 3519 There is limited data on the use of fludarabine based conditioning regimen in children with aplastic anemia though these regimens are increasingly being used in developing countries. Thirty four children (aged < 15 years) including 21 males and 13 females with a median age of 8 years (range: 2–15) underwent allogeneic transplant (HSCT) at our centre between 2004 and 2010 using HLA identical sibling or family donors. The median time from diagnosis to HSCT was 5 months (range: 2–96) and the median number of transfusions prior to HSCT was 10 (range: 3– 64). Five patients (14.7%) had failed treatment with Antithymocyte globulin (ATG) and 4 (11.4%) had an intracranial bleed in the 3 months prior to HSCT. Conditioning regimen consisted of Fludarabine 150 mg/m2 over 5 days and Cyclophosphamide 120 mg/kg over 2 days. Antithymocyte globulin (ATGAM) [10 mg/kg/day for 4 days] was used in 9 patients. Graft source consisted of either bone marrow [9 patients] or G-CSF stimulated peripheral blood stem cells (PBSC)[25 patients]. Graft versus host disease (GVHD) prophylaxis consisted of Cyclosporine and short course methotrexate. The median cell doses infused were 4.9 × 108 TNC/Kg for bone marrow and 8.5 × 108 MNC/Kg for PBSC. Thirty patients (88.2%) engrafted while 2 (5.8%) had primary graft failure. Two children died on Day 0 and Day +5 respectively due to infection. The median time to neutrophil engraftment was 14 days (range: 8–19) while the median time to platelet engraftment was 12 days (range: 7–24). Two patients (5.8%) developed veno-occlusive disease (VOD) of the liver while none developed hemorrhagic cystitis. Acute graft versus host disease (GVHD) was seen in 7 patients (23.3%) and was grade 1–2 in all patients. Chronic GVHD was seen in 31% of patients who could be evaluated and was limited in nature in a majority of patients. Of the 2 patients with primary graft failure, one was rescued with a second transplant while the second expired due to fungal pneumonia. The Day 100 mortality was 14.1%. Secondary graft failure was seen in 1 patient but was rescued with a second transplant using the same donor. At a median follow up of 30 months (range: 1 –67), 29 patients are alive for a 3 year OS of 85.1%. Fludarabine based conditioning regimens are associated with favorable outcomes in Indian children with aplastic anemia. These results are superior to an OS of 37% with the use of ATG and Cyclosporine in a similar population (George B et al PHO March 2010). Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Outcome of Alternative Donor Transplantation for Severe Aplastic Anemia Can Be Comparable to Outcome with Matched Related Donors.

Blood ◽

10.1182/blood.v106.11.2052.2052 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2052-2052

Author(s):

Alana A. Kennedy-Nasser ◽

Kathryn Leung ◽

Steven Gottschalk ◽

Dean A. Lee ◽

George Carrum ◽

...

Keyword(s):

Bone Marrow ◽

Overall Survival ◽

Aplastic Anemia ◽

Pediatric Patients ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Severe Aplastic Anemia ◽

Unrelated Donor ◽

Alternative Donor

Abstract Matched related donor (MRD) bone marrow transplantation is the treatment of choice for pediatric patients with severe aplastic anemia; however, only 25% of patients will have an HLA-identical sibling. Alternative donor transplants may be an option for these patients, but such therapies have been associated with greater incidences of graft failures and graft-versus-host disease (GVHD). We retrospectively analyzed 32 pediatric patients who have undergone either bone marrow or peripheral blood stem cell transplant for severe aplastic anemia at our institution from April 1997 to April 2005. These patients had a total of 34 transplants. One patient had a MRD transplant followed by a matched unrelated donor (MUD) transplant eight years later, while another patient had a HLA-mismatched unrelated donor (MMUD) transplant followed by a transplant from a haplo-identical parent. Of the remaining 30 patients, 12 received MRD transplants, whereas 18 patients received alternative donor transplants - 11 MUD, 3 haplo-identical donors, and 4 MMUD. The median age at transplant was 9 years (range 1.5 to 18.4 yrs). All patients who received alternative donor transplants had previously failed therapy, including antithymocyte globulin (ATG) and cyclosporine. For MRD transplants, the conditioning regimen most often utilized cyclophosphamide 50 mg/kg x 4 days and ATG 30 mg/kg x 3 days. For alternative donor transplants, the conditioning regimen most often utilized cyclophosphamide 50 mg/kg x 4 days, Campath 3–10 mg x 4 days (dependent upon patient’s weight) or ATG 30 mg/kg x 3 days, and TBI (single fraction 200 cGy for MUD; two fractions 200 cGy for MMUD). Alternative donor recipients who received ATG in their preparative regimen were transplanted between December 1997 and March 2001 (n=9), whereas patients who received Campath were treated between November 2001 and April 2005 (n=11). GVHD prophylaxis was either FK506 or cyclosporine +/− mini-methotrexate. The overall survival for MRD patients was 91.7% versus 80% for alternative donor patients at a median follow-up of 47 months (range 3 to 100 months). Of the 32 patients, there were 5 deaths: pulmonary failure with extensive, chronic GVHD (n=1); poor graft function with infection (n=1); and infection (n=3). For patients receiving alternative donor transplants, the overall survival for the Campath group was 81.8% vs. 77.8% in the ATG group. None of the Campath patients developed extensive, chronic GVHD compared to 3/9 ATG patients. In conclusion, alternative donor transplantation using Campath or ATG in the preparatory regimens can establish donor engraftment and offers a curative therapy for pediatric severe aplastic anemia patients with survival similar to that of patients receiving matched sibling transplants. Although follow-up is shorter, Campath may be associated with a reduced incidence of extensive, chronic GVHD and further investigation is warranted.

Download Full-text

Bone Marrow Transplant Activity - A Country Report from Pakistan.

Blood ◽

10.1182/blood.v110.11.5038.5038 ◽

2007 ◽

Vol 110 (11) ◽

pp. 5038-5038

Author(s):

Khalil Ullah ◽

Tahir S. Shamsi ◽

Salman N. Adil

Keyword(s):

Bone Marrow ◽

Overall Survival ◽

Bone Marrow Transplant ◽

Graft Failure ◽

Marrow Transplant ◽

Histopathological Analysis ◽

Country Report ◽

Post Transplant ◽

Transplant Centre ◽

Related Mortality

Abstract Bone Marrow transplant activity started in 1999 in Pakistan when Bismillah Taqee Institute of Health Sciences & Blood Diseases Centre started functioning in the southern port city of Karachi, Pakistan. Two years later in year 2001 Armed Forces Bone Marrow Transplant Centre started functioning in the northern part of country, Rawalpindi, Pakistan. In 2004 another transplant centre, started in Aga Khan University Hospital, Karachi, Pakistan. Since the establishment of these transplant centers a total of 349 allogeneic transplants have been carried out for various hematological disorders. The major indications included aplastic anaemia (n=166), β-Thalassaemia major (n=76), chronic myeloid leukaemia (n=57), acute leukaemias (n=37) and misc disorders including MDS, Fanconi anaemia and others (n=13). A total of 22 autologous transplants in lymphomas and multiple myeloma have also been carried out. Since this number is very small, only data of allogeneic transplants is being presented here. Major post transplant complications encountered were neutropenic fever in 92.6% patients with 27% culture positivity (412/1571). Infective complications included bacterial infections (both gram+ive and gram-ive) in 194 patients (56%), fungal infection in 32 patients (10%), CMV infection in 15 patients (5%), herpes infection in 16 patients (5%), tuberculosis in 9 patients (3%) and PCP in 1 patient (0.28%) and malaria in 1 patient (0.28%). So post transplant infections were confirmed in 76.6% (268/349) patients on the basis of clinical assessment, microbiological, virological and histopathological analysis. Non infective post transplant complication included aGvHD (grade II-IV) in 80 patients (23%), cGvHD 46 patients (13.1%), VOD liver in 25 patients (7.2%), haemorrhagic cystitis in 27 patients (7.7%), ARF in 13 patients (3.7%), primary graft failure in 5 patients(1.4%), graft rejection in 17 patients (4.9%) and relapse in 14 patients (4%). Transplant related mortality was observed in 93 patients (26.6%). Infective & non infective causes of mortality included septicemia in 15 patients (4.3%), CMV in 8 patients (2.3%), fungal infections in 8 patients (2.3%), tuberculosis in 2 patient (0.6%). herpes encephalitis in 1 patient (0.3%) VOD in 8 patients (2.3%), aGvHD in 12 patients (3.4%), cGvHD in 7 patients (2.0%), ARF in 8 patients (2.3%) and intracranial haemorrhage in 3 patients (0.9%). Graft related mortality due to graft failure and relapse was observed in 6 patients (1.7%) and 14 patients (4%) respectively. Unrelated accidental death in 1 patient (0.3%). Overall survival was observed in 256 patients (73.3%) and DFS in 250 patients (71.6%). The OS and DFS was 72.7% and 70.9% in BTIHS & BDC patients, whereas OS & DFS was 72.8% and 70.7% respectively in AFBMTC patients. The OS & DFS was 82.6% at AKUH. Disease wise overall survival in aplastic anemia, β-Thalassaemia, CML and acute leukemia was 78.3%, 76.3%, 63.1% and 59.5% respectively.

Download Full-text

National, Retrospective, Multi-Centre Comparison of Alemtuzumab- Versus ATG-Based Conditioning Regimens in Hematopoietic Stem Cell Transplantation for Aplastic Anemia: A Study From the British Society for Blood and Marrow Transplantation (BSBMT) (CTCR 09-03)

Blood ◽

10.1182/blood.v118.21.52.52 ◽

2011 ◽

Vol 118 (21) ◽

pp. 52-52

Author(s):

Judith C. W. Marsh ◽

Rachel M Pearce ◽

Mickey B Koh ◽

Daniel Tang ◽

ZiYi Lim ◽

...

Keyword(s):

Overall Survival ◽

Aplastic Anemia ◽

Median Time ◽

Research Funding ◽

Graft Failure ◽

Low Dose ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Conditioning Regimens

Abstract Abstract 52 Background: The ideal conditioning regimen for HSCT in AA is one that achieves engraftment, absence of GVHD and minimal toxicity. Standard conditioning for young patients undergoing matched sibling donor (MSD) HSCT for AA is cyclophosphamide (CY) 200mg/kg and ATG as T-cell depletion (TCD), with ciclosporin (CSA) and methotrexate (MTX) as post graft immunosuppression. For patients who are > 30–40years old receiving MSD HSCT a fludarabine (FLUD)-based regimen with low dose CY (1200mg/m2) and ATG is commonly used. For unrelated donor (UD) HSCT, in Europe, a similar FLUD-based regimen with low dose CY and ATG is commonly used, with addition of low dose TBI (2Gy) for older patients. Long term survival for MSD HSCT is 80–90%, but only 50% for patients aged > 50 years. For UD HSCT, survival is around 75–80%. Chronic GVHD remains a problem, in 30–40% of MSD and up to 50% of UD HSCT. A recent retrospective study of 50 patients transplanted with Alemtuzumab instead of ATG, with CY (1200mg/m2), FLUD, and CSA alone as post graft immunosuppression, showed overall survival at 2 years was 95% for MSD and 83% for UD HCT and only two patients (4%) developed chronic GVHD. Patients: We analyzed data from 159 patients with acquired AA transplanted in the UK, who received either Alemtuzumab or ATG pre-transplant, as part of the conditioning for a first allograft. Patients who received their graft between 1999 and 2009 and had a minimum follow-up of 6months were included in this study. Median age was 20yr (range 1– 67) and M: F ratio was 86: 73. MSD HSCT was performed in 88 (55%) patients, UD HSCT in 65 (41%) including 2 mis-matched, and 6 patients were transplanted from other related donors of which 3 were mis-matched. Source of stem cells was BM in 108 (68%), PB in 39 (25%), BM+PB in 8 (5%) and cord blood in 4 (2%) patients. Conditioning was with Alemtuzumab in 103 (65%) and ATG in 55 (35%), and one patient had received both. CY +/− FLUD was used in 148 and FLUD +/− Melphalan in 11 patients, with addition of TBI in 11 (7%) patients. Median time from diagnosis to HSCT was 6 months (range 0.5–300). Results: Of 159 patients, 137 (86%) are alive at a median follow up of 3.3yr (range 3 months – 10.4 yr). Twenty two patients have died from the following causes of death (not mutually exclusive): infection (n = 15, 68%), GVHD (n = 6, 27%), multi-organ failure (n = 4), lymphoproliferative disorder (n = 1), relapse of breast cancer (n = 1) and one unknown. For all patients, the 1 yr, 5 yr and 10 yr overall survival (OS) were 89% (95% C.I. = 83–93%), 85% (78–90%) and 85% (78–90%), respectively. There was no difference in the 1 yr OS in relation to the method of TCD (Alemtuzumab 91% (84–95%) versus ATG 84% (71–91%), p = 0.1578). Graft failure was observed in 15 (9%) patients. Median time to neutrophil engraftment, defined as ANC > 0.5 × 109/l on first of 3 consecutive days, was 20 days (range 10–89) and platelet engraftment, defined as platelet count > 20 × 109/l on first of 3 consecutive days and no platelet transfusions 7 days prior, was 21 days (range 0–275). Chimerism was full donor in 70 (46%), mixed in 41 (27%), not performed in 37 (24%) and unknown or not evaluable in 2 patients. Acute GVHD grade I-II occurred in 35 (25%) evaluable patients, grade III-IV in 8 (6%). Chronic GVHD was seen in 23 (16%) evaluable patients, limited in 14, extensive in 6 and unknown in 3. Conclusions: From this national study, we report excellent outcomes for HSCT in SAA during the last decade. There was a trend, not significant, for better survival with Alemtuzumab instead of ATG in the conditioning regimen. This is the first reported study comparing outcomes after Alemtuzumab versus ATG based conditioning regimens for SAA. Further analyses, comparing graft failure, acute and chronic GVHD, probability of survival and event - free survival, and patient-related, disease-related and treatment related variables, between Alemtuzumab and ATG-based conditioning regimens, are currently in progress. Disclosures: Marsh: Genzyme: Research Funding. Off Label Use: ATG used as part of conditioning regimen for HSCT in aplastic anaemia. Alemtuzumab used as part of the conditioning regimen for HSCT in aplastic anemia. Pagliuca:Genzyme: Speakers Bureau. Mufti:Celgene: Consultancy, Research Funding.

Download Full-text

Risk Factors for Graft Failure and Mortality after HLA-Matched Sibling Donor Transplant for Severe Aplastic Anemia in Brazil.

Blood ◽

10.1182/blood.v110.11.622.622 ◽

2007 ◽

Vol 110 (11) ◽

pp. 622-622 ◽

Cited By ~ 1

Author(s):

Ricardo Pasquini ◽

Jeanette Carreras ◽

Mei-Jie Zhang ◽

Marco A. Bitencourt ◽

Jefferson Ruiz ◽

...

Keyword(s):

Bone Marrow ◽

Overall Survival ◽

Blood Transfusion ◽

Aplastic Anemia ◽

Graft Failure ◽

Conditioning Regimen ◽

Severe Aplastic Anemia ◽

Failure Rates ◽

Platelet Recovery ◽

Matched Sibling

Abstract Higher rates of graft failure observed after conventional cyclophosphamide (Cy) at 200mg/kg and HLA-matched sibling bone marrow transplant (BMT) for severe aplastic anemia (SAA) in South America prompted the use of a different conditioning regimen: busulfan (Bu) at 12 mg/kg plus Cy at 120 mg/kg. This change was instituted to provide greater immunosuppression for heavily transfused patients (>15 blood transfusion units pre-BMT). We report transplant outcomes in 269 SAA patients who received their HLA-matched BMT at a single center in Brazil between 1990 and 2003. Median age at transplant was 19 years (range 2 – 45). Median time from diagnosis to transplant was 3 months; 78% were transplanted ≤ 6 months from diagnosis, 11%, 7–24 months and 11% > 24 months. 128 patients received Cy alone, 2, Cy plus anti-thymocyte globulin and 139, Bu plus Cy. Eighty-one patients (62%) who received Cy conditioning also received ≤15 blood transfusion units and 49 (38%) received >15 blood transfusion units pre- BMT; all patients who received Bu plus Cy conditioning received >15 blood transfusion units. All patients received T-cell replete bone marrow grafts and almost all patients received cyclosporine and short course methotrexate for graft-versus-host disease prophylaxis. Median follow-up of surviving patients after Cy is 9 years and after Bu plus Cy, 6 years. This reflects the change in practice after 1994, when Bu plus Cy was favored for patients who received >15 blood transfusion units pre-BMT. Most patients achieved neutrophil recovery; the day-60 probabilities of recovery were 95% and 86% after Cy conditioning (≤15 and >15 blood transfusion units, respectively) and 92% after Bu plus Cy. Corresponding day-100 probabilities of platelet recovery were 95%, 86% and 87%. Thirty-nine patients subsequently lost their graft; failure rates were similar after Bu plus Cy and Cy conditioning in patients who received ≤15 blood transfusion units (13% vs. 17%; RR 0.97, p=0.924). Though failure rates were higher (10 of 42, 24%) after Cy conditioning in patients who received >15 blood transfusion units this did not attain statistical significance when compared to those who received Bu plus Cy (16 of 128, 13%, p=0.077). This may be explained by limited numbers of patients in the heavily transfused Cy group. Younger age (≤10 years) was the only factor that was associated with higher rates of secondary graft failure (RR 2.91, p=0.001). As expected, the 8-year probability of overall survival was highest (87%) after Cy conditioning in patients who received ≤15 blood transfusion units. Mortality rates were higher after Bu plus Cy conditioning (RR 3.18, p<0.001) and Cy conditioning in patients who received > 15 blood transfusion units (RR 4.66, p<0.001). The corresponding 8-year probabilities of overall survival were 67% and 51% (p=0.059). The data suggest secondary graft failure rates are similar after Bu plus Cy conditioning in patients who received >15 blood transfusion units compared to those who received Cy conditioning and fewer transfusions. Though survival rates are generally lower in patients who receive >15 blood transfusion units, the use of Bu plus Cy appears to confer a survival advantage. Patients with SAA should be referred for transplantation as soon as the diagnosis is confirmed to avoid excess blood transfusion pre-BMT.

Download Full-text

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

Blood ◽

10.1182/blood-2019-126321 ◽

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.

Download Full-text

HLA-Matched Related Donor Hematopoietic Cell Transplantation in Patients with Fanconi Anemia Conditioned with a Combination of Cyclophosphamide and Fludarabine : A Study on Behalf of the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC)

Blood ◽

10.1182/blood.v124.21.4391.4391 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4391-4391 ◽

Cited By ~ 1

Author(s):

Lina Benajiba ◽

Clementine Salvado ◽

Jean-Hugues Dalle ◽

Charlotte Jubert ◽

Claire Galambrun ◽

...

Keyword(s):

Bone Marrow ◽

Overall Survival ◽

Graft Failure ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

French Society ◽

Cell Therapies ◽

Related Donor ◽

Grade 3

Abstract Background. Fanconi anemia (FA) is a rare, phenotypically heterogeneous, inherited disorder clinically characterized by congenital abnormalities, progressive bone marrow failure (BMF) and a predisposition to develop malignancies. Hematopoietic stem cell transplantation (HSCT) is the only curative option for FA patients. However, finding the best conditioning regimen is still challenging for clinicians. To reduce toxicities, we used progressively lower doses of cyclophosphamide (CY) for conditioning through non-irradiation based regimens. A reduced conditioning regimen based on CY 60mg/kg alone was proposed by Bomfim et al (BBMT, 2007). Survival rates were excellent but some patients experienced primary (n=1) or late (n=4) graft failure (11% of the patients). Mucositis was a major problem as 25 patients (60%) presented grade 3 / 4 mucositis. The rate of Chronic graft versus host disease (GvHD) was 29%. We hypothesized that tapering the dose of CY to 40mg/Kg and adding fludarabine (FLU) at 90mg/m2 might improve engraftment, decrease GvHD rates and eventually improve overall toxicity in FA patients transplanted with HLA matched siblings. Method. In 2004, the French reference centre for aplastic anemia and the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC) recommended to use FLU 90mg/m2 (30mg/m2 days -4, -3, -2) and CY 40mg/kg (10mg/kg days -5, -4, -3, -2) for FA patients transplanted from matched family donor. Indication for transplantation was based on hematological complications (transfusions and/or infections). FA patients with morphologic signs of clonal evolution (myelodysplastic syndrome or acute myeloid leukemia) were excluded. All patients in France who received a first Allo-HSCT for FA from a matched related donor between October 2004 and January 2013 using this approach were analyzed (n=20). Clinical data were prospectively collected using ProMISe (Project Manager Internet Server), an internet-based data registry system shared by all SFGM-TC centres. All patients received uromitexan. Ciclosporin A and micophenolate mofetil were used as GVHD prophylaxis. Six patients received an in vivo T cell depletion using antithymocyte globuline because of local policy at their centre. The guidelines were approved by Saint-Louis hospital ethical committee. Results. The median age at transplant was 9 years (range: 6-19). Stem cell source was bone marrow in 16 cases and matched related cord blood in the remaining transplants. None of the patients received peripheral blood stem cells. All patients had severe or moderate BMF (median hemoglobin: 8.9g/dl, median platelets: 31 103/ul, median neutrophils: 0.88 103/ul) at time of transplant. Two patients had chromosomal abnormalities (47,XX,i(1)(q10)[10]/48,idem,+8[3] and 47,XX,+der(1;3)(q10;q10)[14]/46,XX[6]); however, none of them developed overt myelodysplasia/leukemia before transplant. Patients belonged to complementation groups FANC-A (n=17) and FANC-G (n=2). Transplantation was performed within a median of 30 months from FA diagnosis (range: 7-143). A median of 3.8. 108 nucleated marrow cells were infused (range: 0,65-8,97). Within a median follow up of 2 years (range: 0.2-7.4), overall survival was 95% (figure 1). Only one patient with an atypical form of FA associated with severe immunodeficiency prior to transplant died subsequently due to uncontrolled cerebral toxoplasmosis. Engraftment rate was 100% with a median time to neutrophils and platelets recovery of 16.5 (11-28) and 15 (4-29) days, respectively. No grade 3/4 regimen related toxicity was observed and only 1 patient experienced mucositis (grade 2) using this conditioning regimen. Total acute GvHD grade 3 / 4 was only observed in 3 patients (15%) and chronic GvHD was extensive in 2 patients (10%) and limited in 3 patients (15%). Median alive patients karnofsky scored 100% (range 90 – 100%). No secondary malignancy was observed in our cohort so far. Conclusion. The combination of low dose CY (40mg/Kg) plus FLU (90mg/m2) in HLA-matched donor HSCT in patients with FA resulted in an excellent engraftment rate (100%) with no secondary graft failure, low rates of acute and chronic GvHD, low rates of regimen related toxicity, eventually resulting in an excellent overall survival (95% at 2 years). A longer follow-up in this cohort is needed to confirm such excellent results long-term, namely the continued absence of secondary cancer. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Transplantation for Congenital Sideroblastic Anaemia Is Feasible and Offers Outcomes Comparable to Other Transfusion Dependent Anaemias. a Joint Retrospective Study of the Paediatric Diseases and Severe Aplastic Anaemia Working Parties (PDWP/SAAWP) of EBMT

Blood ◽

10.1182/blood-2020-142397 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 45-47

Author(s):

Josu de la Fuente ◽

Dirk-Jan Eikema ◽

Paul Bosman ◽

Robert F Wynn ◽

Miguel Díaz ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Research Funding ◽

Graft Failure ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Response To Treatment ◽

Variable Response ◽

Advisory Committees ◽

Grade Ii

Congenital sideroblastic anaemias (CSA) are a rare group of disorders characterized by the presence of pathologic iron deposits within the mitochondria of erythroid precursors (ring sideroblasts) in the bone marrow due to heterogenous germline mutations leading to defects in mitochondrial heme synthesis, iron-sulfur (Fe-S) cluster biogenesis, or protein synthesis. Patients present with anaemia and relative reticulocytopenia, and systemic iron overload secondary to chronic ineffective erythropoiesis, leading to end-organ damage. The disease is heterogenous underlying the genetic variability and the variable response to treatment. Although a number of CSA patients have received a bone marrow transplant, the outcomes and toxicities are not known. This status makes it very difficult to understand the role of BMT in the management of CSA. A search in the EBMT database identified 28 patients receiving a HSCT for CSA between 1998 to 2018 by 24 participating centres. The median year of transplantation was 2014 (IQR 2004-2016). The distribution was equal between males (n=14) and females (n=14). The median age at transplantation was 7 years of age (3-10 years). Fifteen patients had a sibling HSCT (88%), one a family matched donor HSCT (6%) and one an unrelated matched (6%), the type of transplant being unknown in others (n=11). The source of stem cells was bone marrow in 20 cases (74%), peripheral blood in 4 cases (15%), cord blood in 2 (7%) and combined bone marrow and cord in one (4%). Five cases had a Bu/Cy based conditioning regimen, 4 had Bu/fludarabine based regimen and three fludarabine/treosulfan based conditioning with the rest having a variety of approaches. Eighty-six percent of cases had serotherapy with ATG or alemtuzumab. The median follow-up was 31.6 months (95% CI, 12.2-74.1%). The overall survival at 12 and 24 months was 88% (76-100) and 82% (66-99), respectively (figure 1). The median neutrophil engraftment was 18 (15-21) days and platelet engraftment >20 x 109/L was 29 (20-51) days, with a graft failure incidence of 7% (0-17) at 12 months. Two patients suffered from VOD. There were four deaths, three of which were related to transplant complications. The event free survival (survival without graft failure, relapse and second transplant) at 12 and 24 months was 85% (72-99) (figure 2). Six patients developed acute GvHD grade II and one case grade III; giving a grade II/III incidence of 28% (10-46). There was one case of limited and one of chronic GvHD, giving an incidence of 11% (0-26%) at 12 months and 24 months. In conclusion, whilst HSCT for CSA is a rare occurrence, these data demonstrate that HSCT for this condition is feasible and the outcomes are in keeping with those obtained for transplantation for transfusion dependent anaemias during the same time-period. Disclosures Handgretinger: Amgen: Honoraria. Moraleda:Gilead: Consultancy, Other: Travel Expenses; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Other: Travel Expenses; Sandoz: Consultancy, Other: Travel Expenses; Takeda: Consultancy, Other: Travel Expenses. Risitano:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jazz: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Samsung: Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; RA pharma: Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Achillion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Speakers Bureau. Peffault De Latour:Amgen: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Apellis: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Download Full-text

Early Immune Reconstitution after Haplo-Identical Hematopoietic Stem Cell Transplantation (HCT) with Post-Transplant Cyclophosphamide (PTCY) Does Not Improve Overall Survival Compared to Matched Unrelated Donor HCT Recipients Receiving Thymoglobulin Prophylaxis (ATG)

Blood ◽

10.1182/blood-2019-131954 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5676-5676

Author(s):

Yasser Khaled ◽

Joshua Boss ◽

Poojitha Valasareddy ◽

Arnel Pallera ◽

Robert Johnson ◽

...

Keyword(s):

Cell Proliferation ◽

Overall Survival ◽

T Cell ◽

Graft Failure ◽

Immune Reconstitution ◽

T Cell Proliferation ◽

First Year ◽

Post Transplant ◽

Allogeneic Hct ◽

Primary Graft Failure

Recent retrospective studies demonstrated similar overall survival (OS) and relapse rate after allogeneic HCT using matched unrelated or haplo-identical donors. However, differences in graft versus host disease (GVHD) prevention protocols using ATG or PTCY may have influenced the results. In addition, there is little knowledge about immune reconstitution after PTCY compared to ATG. We examined the outcomes of 73 consecutive patients who received allogeneic HCT from 5/2015 to 4/2019 (39 Haplo, 34 MUD). Patient's Characteristics shown in table-1. The two groups matched except for donor age, CD34 dose infused and race. Conditioning regimens shown in table-1. MUD recipients received GVHD prophylaxis with Tacrolimus/ Mycophenolate (Tacro/MMF) in addition to ATG (24 Patients) or PTCY (10 Patients) while Haploidentical patient received Tacro/MMF with PTCY. A panel of immune reconstitution markers collected at day 100 post- transplant for CD3, CD4, CD8, Activated T cell ( HLA- DR3+ CD3+)and NK cells ( CD56+) was obtained for 29 MUD and 28 Haploidentical recipients. We observed pronounced proliferation and recovery in all T cell subsets in Haploidentical patients compared to MUD patients at day 100 as shown in Fig-1. This robust T cell recovery in Haploidentical transplant patients with PTCY was statistically significant for CD3, CD4 and CD8. When Immune reconstitution for Haploidentical patients compared to MUD patients who received PTCY, it maintained its robust effect on T cell proliferation (Fig-2) although it did not reach statistical significance. The overall survival at one-year with median duration of follow up of 22.6 months was 61.5% and 82.3% for Haploidentical and MUD recipients respectively; P=0.14. There were 15 deaths during the first year in the Haploidentical patients (3 = relapse, 5 = severe cytokine release syndrome (CRS), 1=Veno-occlusive disease, 3= infection, 2=GVHD and 1 = primary graft failure). In contrast there were only six deaths in MUD patients (2= relapse, 3= GVHD and 1= infection). There was no deaths in MUD PTCY patients in the first year. There was no primary graft failure in either arm, however secondary graft failure occurred in 2 Haploidentical and 1 MUD patients. Median time to engraftment was 18 days for Haploidentical (range, 12-57) and 11.6 days for MUD (range, 10-18). Acute GVHD grade 2-4 developed in 35% in MUD and 23% in Haploidentical patients. Conclusions: We found robust early immune recovery after Haploidentical HCT compared to MUD HCT. The degree of HLA mismatch with Haploidentical HCT and antigen presentation may have contributed to pronounced T cell proliferation as the same effects was not observed in MUD HCT with PTCY. Despite the early recovery of T cells after Haploidentical HCT the overall survival did not exceed the overall survival with MUD HCT. Severe CRS contributed to the increased mortality seen in Haploidentical HCT patients. Further strategies are needed to decrease treatment related mortality with Haploidentical HCT. Disclosures No relevant conflicts of interest to declare.

Download Full-text