A Phase II Study Using Post-Transplant Cyclophosphamide (PTC) As Graft Versus Host Disease (GVHD) Prophylaxis in Patients Undergoing HLA Matched Sibling Donor Stem Cell Transplant (SCT) for Severe Aplastic Anemia (SAA)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4199-4199
Author(s):  
Biju George ◽  
Vikram Mathews ◽  
Kavitha M Lakshmi ◽  
Rayaz Ahmed ◽  
Aby Abraham ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Immunosuppressive Therapy ◽  
Median Time ◽  
Chronic Gvhd ◽  
Cell Transplant ◽  
Post Transplant ◽  
Sibling Donor ◽  
Gvhd Prophylaxis ◽  
Matched Sibling ◽  
Grade Ii

Abstract Abstract 4199 Between September 2010 and June 2012, 15 patients with SAA underwent HLA identical sibling donor SCT using post transplant cyclophosphamide for GVHD prophylaxis. The conditioning regimen consisted of Inj Fludarabine 30 mg/m2/day from day -7 to -2 and Inj Cyclophosphamide 50 mg/kg IV on days -3 and -2. Total Body irradiation (TBI) 200 cGy as single fraction was added on day -1 from December 2011 because of concern regarding graft failure. GVHD prophylaxis consisted of Inj Cyclophosphamide administered at 50 mg/kg/day IV on day +3 and +4 post SCT. G-CSF mobilized peripheral blood stem cells (PBSC) was the graft source. There were 10 males and 5 females with a median age of 25.9 years (range: 8 – 42). The median time from diagnosis to SCT was 7.5 months (range: 2 – 36). All had 6/6 HLA matched sibling donors except 1 who had a 9/10 matched family donor. The median PBSC cell dose infused was 5.4 × 108 MNC/Kg (range: 2.4 – 8.5) and 9.58 × 106CD34/Kg (range: 5.4 – 17.2). Thirteen patients engrafted (86.6%) with a median time to ANC >0.5 × 109/L of 15.4 days (range: 15–17) and Platelet count >20 × 109 of 16.6 days (range: 12–32). Grade II –IV acute GVHD occurred in 3 patients (23%) at 42, 49 and 68 days post SCT. GVHD was grade II in 2 patients and grade IV in 1 patient. Two responded to a combination of cyclosporine and prednisolone while one patient with grade IV GVHD expired with refractory GVHD at median time of 64 days post SCT. Of the 11 evaluable patients, 4 (36.3%) developed chronic GVHD which was limited in all. Two patients who developed de novo chronic GVHD were managed with prednisolone alone. Overall 7 patients (46.6%) have not required any immunosuppression after SCT while 3 have required immunosuppressive therapy for 114, 127 and 225 days respectively At a median follow up of 11 months (range: 1 – 22), 11 (73.3%) are alive and well including 7 patients who did not require any immunosuppressive therapy following SCT. In conclusion, the use of post transplant cyclophosphamide as GVHD prophylaxis following sibling donor transplant for SAA is associated with low rates of GVHD. What makes it more attractive is the fact that 46% did not require any immunosuppression post SCT. Larger studies are required to understand the utility of this prophylaxis in sibling donor transplants for aplastic anemia. This trial is registered in the Clinical Trials Registry India - CTRI/2010/091/001480. Disclosures: No relevant conflicts of interest to declare.

scholarly journals A Calcineurin Inhibitor Free Graft Versus Host Disease (GVHD) Prophylaxis for Patients Undergoing Matched Related (MRD) and Matched Unrelated Donor (MUD) Allogeneic Hematopoietic Cell Transplant (Allo-HCT)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3893-3893
Author(s):  
Madiha Iqbal ◽  
Felipe Andres Mendieta Nieto ◽  
Kaitlyn M Brannick ◽  
Zhuo Li ◽  
Hemant S. Murthy ◽  
...  
Keyword(s):  
Median Time ◽  
Research Funding ◽  
Calcineurin Inhibitor ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Cell Transplant ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Matched Donor

Abstract Introduction Post-transplantation cyclophosphamide (PTCy) and calcineurin inhibitor (CNI) based GVHD prophylaxis has shown lower rates of acute and chronic GVHD when compared with the traditional prophylaxis of calcineurin inhibitor (CNI) and methotrexate (MTX) in matched donor (related and unrelated) allo-HCT. The combination of PTCy with sirolimus as a calcineurin inhibitor-free GVHD prophylaxis has shown promising results with cumulative rates of grade II-IV acute and chronic GVHD in the range of 15-27% and 20-27% respectively in patients undergoing matched and haploidentical allo-HCT. We report a single center, nonrandomized comparison of patients undergoing matched donor allo-HCT receiving PTCy in combination with sirolimus (PTCy/Siro) with those receiving the standard GVHD prophylaxis of tacrolimus and MTX (Tac/MTX). Methods One hundred and sixteen consecutive patients who had undergone a MRD or MUD allo-HCT between January 2018 to January 2021 and received either PTCy with sirolimus or tacrolimus with methotrexate as GVHD prophylaxis regimens were eligible for inclusion. The selection of PTCy with sirolimus or tacrolimus with methotrexate as GVHD prophylaxis regimen was based on physician choice. Primary endpoints were cumulative incidence of acute (grade II to IV) and chronic GVHD. Secondary endpoints were a) neutrophil and platelet engraftment; b) overall survival (OS); c) non-relapse mortality (NRM); d) relapse; e) clinical infections and f) time to immunosuppression (IS) withdrawal. Kaplan-Meier method was used to estimate 1-year and 2-year freedom from long term adverse events, including chronic GVHD, relapse, NRM and OS. All tests were two-sided with alpha level set at 0.05 for statistical significance. Results Out of a total of 116 patients undergoing MRD and MUD allo-HCT, 29 received PTCy/Siro and 87 Tac/MTX. Baseline characteristics were similar between the two arms except patients in PTCy/Siro were younger with median of 48 (range: 24-69) years vs. 61 (range: 20-73) years (p=0.004) in Tac/MTX. There was difference in primary indication for allo-HCT between the two arms with non-hodgkin lymphoma (NHL) being the most common in PTCy/Siro and acute myeloid leukemia (AML) in the Tac/MTX group. Patients receiving PTCy/Siro had a significantly higher median CD3 day 100 chimerism at 100 (90-100) vs. 90 (40-100) % (<0.001) and a significantly shorter median time to IS withdrawal at 138 (37-312) vs 232(66-1120) days for patients receiving Tac/MTX. There was no difference between the two arms for length of hospital stay and time to neutrophil engraftment, but PTCy/Siro had a significantly longer median time for platelet engraftment at 17.5 (12-74) vs.14 (11-38) days (p= 0.001). No significant difference was observed between the two arms for incidence of grade II to IV acute GVHD, grade III to IV acute GVHD, steroid refractory acute GVHD or clinical infections (Table 1). After a median follow up of 1.1 (range: 0-1.8) years, patients receiving PTCy/Siro were significantly less likely to have chronic GVHD with 2-year freedom from GVHD of 75% (95%CI: 58-98%) vs 20% (95%CI 10-40%), p=0.005 (Figure 1). There was no difference between the two arms for OS, disease relapse or non-relapse mortality (Table 2). Conclusion In this study, the combination of PTCy/Siro is associated with a significantly lower risk of chronic GVHD when compared against the traditional GVHD prophylaxis of CNI and methotrexate, despite significantly earlier IS withdrawal. Other long-term outcomes of interest remained comparable between the two arms. Chronic GVHD contributes to significant morbidity and mortality in patients undergoing allo-HCT. Newer strategies to limit the impact of chronic GVHD are needed. The results of our study warrant validation in a large, multicenter, randomized prospective trial. Figure 1 Figure 1. Disclosures Murthy: CRISPR Therapeutics: Research Funding. Foran: gamida: Honoraria; takeda: Research Funding; novartis: Honoraria; trillium: Research Funding; boehringer ingelheim: Research Funding; OncLive: Honoraria; abbvie: Research Funding; certara: Honoraria; sanofi aventis: Honoraria; syros: Honoraria; taiho: Honoraria; revolution medicine: Honoraria; bms: Honoraria; servier: Honoraria; pfizer: Honoraria; actinium: Research Funding; aptose: Research Funding; kura: Research Funding; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding.

scholarly journals Comparable Outcomes between Unrelated Donor (8/8 or 7/8 matched) and Haploidentical Donor for Allogeneic Stem Cell Transplantation in Adult Patients with Severe Aplastic Anemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4619-4619
Author(s):  
Jee Yon Shin ◽  
Sung-Soo Park ◽  
Gi June Min ◽  
Silvia Park ◽  
Sung-Eun Lee ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Advisory Committees ◽  
Sibling Donor ◽  
Alternative Donor ◽  
Matched Sibling ◽  
Grade Ii

Background Either allogeneic hematopoietic stem cell transplantation (SCT) from HLA-matched sibling donor or immunosuppressive therapy (IST) has been recommended as one of the standard treatments for severe aplastic anemia (SAA). Regarding only 30% of chance finding HLA‐matched sibling donor, SCT from an alternative donor including unrelated (URD) or haplo-identical related donor (HAPLO) is considered to be a treatment option after failure to IST in patients who lack of a HLA-matched sibling donor. The aim of this study was to compare the outcomes of URD SCT and HAPLO SCT for SAA patients. Method Consecutive 152 adult patients with SAA who received first SCT between March 2002 and May 2018 were included: 73 of HLA-well-matched (8/8) URD (WM-URD), 34 of HLA-mismatched URD (MM-URD), and 45 of HAPLO. With the intention to have a follow-up period at least 1 year, data were analyzed at May 2019. A conditioning regimen with total body irradiation (TBI) and cyclophosphamide was used for URD-SCT, whereas that with TBI and fludarabine was administered for HAPLO-SCT (Lee et al, BBMT 2011;17:101, Park et al, BBMT 2017;23:1498, Lee et al, Am J Hematol 2018;93:1368). The combination of tacrolimus and methotrexate were used as graft-versus-host disease (GVHD) prophylaxis. Results The median follow-up was 53.4 (range, 0.2-174.1) months. The median age of URD and HAPLO cohort was 30 (range 18-59) and 34 (range 18-59) years, respectively. Except for one and three patients who failed respective a neutrophil and platelet engraftment, other patients achieved neutrophil and platelet engraftments with median 11 and 15 days for WM-URD, 13 and 16.5 days for MM-URD, and 12 and 14 days for HAPLO, respectively. The five-years overall survival (OS), failure-free survival (FFS), and cumulative incidences (CIs) of graft-failure and transplant-related mortality were similar among three groups: 88.3%, 85.5%, 2.7%, and 11.7% for WM-URD; 81.7%, 81.7%, 0%, and 18.3% for MM-URD, and 86.3%, 84.1%, 6.7%, and 9.2% for HAPLO. The 180-days CI of grade II-IV acute GVHD in WM-URD, MM-URD and HAPLO were 35.6%, 52.9%, and 28.9%, respectively; and moderate to severe chronic GVHD were 28.7%, 38.7% and 11.8% in respective cohort. The CI of grade II-IV acute GVHD and moderate to severe chronic GVHD were significantly higher in MM-URD than those in HAPLO (both, p=0.026). ATG is the only factor affecting both grade II-IV acute GVHD (Hazard ratio 0.511, p=0.01) and moderate to severe chronic GVHD (Hazard ratio 0.378, p=0.003) in multivariate analysis. Other complications including CMV DNAemia, hemorrhagic cystitis, invasive fungal disease, secondary malignancy, and sinusoidal obstruction syndrome were similar among three groups. Survival outcomes of a subgroup of ≥ 2 allele MM-URD (n=16) extracted form MM-URD were inferior that of other donor types (n=136): 75.0% vs. 86.9% (p=0.163) for 5-year OS and 75.0% vs. 84.7% (p=0.272) for 5-year FFS. Conclusion This study shows that there were no significant differences between alternative donor sources in the absence of suitable matched sibling donor. Host/donor features and urgency of transplant should drive physician towards the best choice among alternative donor sources for SAA patients treated with SCT. However, selection of ≥ 2 allele MM-URD should not be recommended due to high incidence of GVHD and inferior outcomes. Figure Disclosures Kim: Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Amgen: Honoraria; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; BL & H: Research Funding; Otsuka: Honoraria. Lee:Alexion: Consultancy, Honoraria, Research Funding; Achillion: Research Funding.

scholarly journals Post-Transplant Cyclophosphamide and Thymoglobulin, a Graft-Versus-Host Disease Prophylaxis in Matched Sibling Donor Peripheral Blood Stem Cell Transplantations

2020 ◽  
Vol 29 ◽  
pp. 096368972096590
Author(s):  
Chutima Kunacheewa ◽  
Weerapat Owattanapanish ◽  
Chutirat Jirabanditsakul ◽  
Surapol Issaragrisil
Keyword(s):  
Stem Cell ◽  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Chronic Gvhd ◽  
Survival Rates ◽  
Free Survival ◽  
Graft Versus Host ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Matched Sibling

Post-transplant cyclophosphamide (PTCy) has been explored in several types of stem cell transplantations (SCTs) and it proved highly effective in controlling graft-versus-host disease (GvHD) without aggravating relapsed disease. However, PTCy alone has resulted in inferior outcomes in matched sibling donor (MSD) employing peripheral blood (PB) SCTs. We hypothesized that adding thymoglobulin to PTCy would be able to control GvHD effectively. We retrospectively compared the use of standard GvHD prophylaxis encompassing a combination of PTCy and thymoglobulin (ATG) in patients with myeloid malignancies in a myeloablative conditioning MSD PBSCT. Forty-two patients underwent PBSCT using either methotrexate and cyclosporine (MTX/CSA, 21 patients) or PTCy and ATG (21 patients) as a GvHD prophylaxis. With median follow-ups of 71 months, the 1-year GvHD-free, relapse-free survival rates and chronic GvHD-free survival rate of the standard and PTCy/ATG groups were similar: 24% versus 37% ( P = 0.251) and 29% versus 43% ( P = 0.095), respectively. When focusing on chronic GvHD we observed that 17/35 patients (48.6%) suffered from this, 5/18 (27.8%) treated with MTX/CSA had extensive chronic GvHD, but 0/17 PTCy/ATG did. Twenty-one patients required additional GvHD treatment; 7/21 in the PTCy/ATG received only corticosteroid, while 8/14 MTX/CSA required at least 2 drugs. The 5-year overall survival rates were 52% and 52% ( P = 0.859), and the 5-year disease-free survival rates were 52% and 52% ( P = 0.862) for the MTX/CSA and PTCy/ATG groups, respectively. We conclude that PTCy in combination with ATG without immunosuppression of a calcineurin inhibitor can effectively control GvHD.

scholarly journals Encouraging Outcomes in African-American Patients with Use of Post-Transplant Cyclophosphamide after HLA Mismatched Hematopoietic Stem Cell Transplant

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3228-3228
Author(s):  
David H. Aggen ◽  
Kendra Mellert ◽  
Divaya Bhutani ◽  
Lois Ayash ◽  
Lawrence G. Lum ◽  
...  
Keyword(s):  
Overall Survival ◽  
African American ◽  
Chronic Gvhd ◽  
Allogeneic Transplantation ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Unrelated Donors ◽  
Equity Ownership

Abstract An inherent difficulty in performing allogeneic transplantation in patients (pts) of African American (AA) descent is finding suitably matched 8/8 unrelated donors. In addition for complicated reasons studies have shown that AA have an inferior survival compared to suitable matched patients from different ethnic groups undergoing allogeneic transplantation. Post transplant cyclophosphamide (PTCy) administered on day + 3 and +4 given in combination with tacrolimus and mycophenolate mofetil (MMF) allows for the safe use of more mismatched transplants, including haploidentical transplants. This has created a new approach for patients who lack suitable donors and may allow more AA pts to proceed to transplant. At our institution, we have used PTCy as graft-versus-host-disease (GVHD) prophylaxis in patients undergoing reduced intensity conditioning (RIC) hematopoietic stem cell transplant (HSCT) from mismatched related and unrelated donors, and this group consisted largely of high-risk AA pts. We retrospectively reviewed 16 pts who underwent HLA mismatched HSCT (5/10 to 8/10 HLA matches) at our institution between July 2012 and 2015. All patients received RIC HSCT with PTCy (days +3 and +4) along with tacrolimus and MMF for GVHD prophylaxis. Patients did not routinely receive growth factor support. Primary endpoints included time to neutrophil and platelet engraftment, length of hospital stay, and rates of acute and chronic GVHD. Secondary outcomes included time to relapse, transplant related mortality, and overall survival. Table 1 shows the demographics of the 16 patients who were transplanted. The median age of the patients was 57 years (range: 25-72). Ten pts were of AA descent. Fifteen donors were haploidentical family donors; 6 were 5/10 matches, 4 were 6/10 matches, and 5 were 7/10 matches. One patient received a 8/10 unrelated donor transplant. Five patients had failed previous transplants which included 3 allogeneic and 2 autologous HSCT. Based on published risk stratification (Armand et al. Blood, 2012) of the remaining 11 pts, 7 pts were high risk and 4 were intermediate risk. Neutrophil engraftment (first of 3 days when ANC was ³500 cells/mm3) occurred a median of 19 days post transplant (range:12-22 days); Platelet engraftment (³20,000/µL without platelet transfusion) occurred a median of 21.5 days post-transplant (range: 14-37 days). Median length of hospitalization was 26 days (range: 22-81 days). Two pts failed to engraft after first HSCT. One of these pts had high levels of anti-HLA antibodies directed against her donor. Both pts went on to a second haploidentical transplant and engrafted their neutrophil counts at 13 days and 21 days; respectively. Grade II acute GVHD occurred in 6/16 patients. No patient developed grade III-IV aGVHD. Chronic GVHD was observed in 8/16 patients with severe chronic GVHD seen in one patient. With a median follow up of 160 days (range: 89-778 days) the Kaplan-Meier estimates of overall survival at one year were 81.3% for all transplanted pts (Figure 1) and 80% for the AA pts (Figure 2). Three pts died; 1 patient from an invasive fungal infection and 2 pts from relapse. One additional patient relapsed but continues on treatment. Our experience suggests that the use of PTCy permits HLA mismatched transplantation, with overall survival of > 80% and acceptable rates of acute and chronic GVHD. Moreover, the severity of acute GVHD in patients who received PTCy post-transplant was limited, with no reported acute grade III-IV GVHD. In addition, the early outcomes of HLA mismatched transplantation in 10 African-American patients, a population that is often underrepresented in the donor registry, suggests that this approach may preferentially benefit AA pts from an expanded donor pool derived from utilization of partially HLA-matched donors. Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures Lum: Karyopharm Therapeutics Inc: Equity Ownership; Transtarget.Inc: Equity Ownership. Deol:Bristol meyer squibb: Research Funding.

A phase II trial 90y-ibritumomab tiuxetan in combination with reduced intensity regimen of fludarabine (flu) and melphalan (mel) followed by allo-HCT in patients with refractory B-cell lymphoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6545-6545 ◽  
Author(s):  
Auayporn Nademanee ◽  
Andrew Antony Raubitschek ◽  
Ni-Chun Tsai ◽  
Jennifer Simpson ◽  
Neil Martin Kogut ◽  
...  
Keyword(s):  
Disease Control ◽  
B Cell ◽  
Median Time ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
B Cell Lymphoma ◽  
Disease Status ◽  
Gvhd Prophylaxis ◽  
Transformed Lymphoma ◽  
Grade Ii

6545 Background: RIC allo-HCT has reduced transplant-related mortality (TRM) in patients with relapsed NHL. However, relapses do occur despite potential graft vs. lymphoma (GVL) effect. We hypothesized that adding Zevalin to Flu/Mel may improve disease control and reduce relapse post allo-HCT. Methods: Patients received In- Zevalin on day -21 followed by 90Y- Zevalin 0.4mCi/kg on day -14, flu 25 mg/m2 daily on days -9 to -5 and mel 140 mg/m2 on day -4. Rituximab (R) level was measured on Day -22 and -15 and if the level was ≥ 10 μg/ml, R was not given prior to In-Zevalin or 90Y- Zevalin to enhance biodistribution. Tacrolimus and sirolimus was used for GVHD prophylaxis. Between 10/2007 and 11/2011, 31 were treated. Median age 55 (range 27-67), median regimen =3 (range 2-8). Median time from diagnosis to HCT was 20 mo (range 5-105). Histology: DLBCL (including transformed lymphoma)=14 (45%), MCL=7 (23%), FL=5 (16%) and SLL/CLL=5 (16%). Disease status at HCT: 1CR=7, Relapse=9, ≥2CR=5, primary refractory =10. Fifteen had chemoresistant and 19 had FDG PET+ at HCT. Donors: sib=13, URD=18. Results: All patients engrafted with the median time to ANC ≥500 and platelet ≥ 20,000 was 14 (range 10-28) and 13.5 days (range 11-28), respectively. There were 10 deaths from disease progression (2) infection (5) GVHD (1) and multi-organ failure (2). TRM at day +100 and at 1 yr was 6.5% and 17%, Five with DLBCL relapsed between 3-7 mos. Grade II-IV acute GVHD was 65%, Grade III-IV was 16%, chronic GVHD was 65%. Fifteen became PET- at day +100 while 4 remained PET+ and relapsed. Twenty-one are alive at a median followup of 24 mos (range 2-46). The 2 yrs OS and PFS was 65% (95% CI, 51-75%) and 57% (95% CI, 46-67%), respectively. Univariate analysis identified disease status predict for OS and PFS while histology predict for PFS. Conclusions: This study demonstrates the feasibility of adding Zevalin to flu/mel in the allo-HCT setting for B-cell NHL and suggest that this approach could be used to provide early disease control before GVL effect takes place. Innovative approaches should be explored in DLBCL.

Improved Post-Transplant Outcomes in Hematologic Malignancy Patients Undergoing Non-Myeloablative Hematopoietic Stem Cell Transplant (NMHSCT) Using a 400 cGy Total Body Irradiation (TBI) Dose with Fludarabine.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3674-3674
Author(s):  
Ronald M. Sobecks ◽  
Karl S. Theil ◽  
Lisa Rybicki ◽  
Roger Macklis ◽  
Brad Pohlman ◽  
...  
Keyword(s):  
T Cell ◽  
Median Time ◽  
Graft Rejection ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Cell Transplant ◽  
Disease Relapse ◽  
Post Transplant ◽  
Transplant Outcomes ◽  
Preparative Regimen

Abstract Fludarabine and TBI (200 cGy) is a common NMHSCT preparative regimen. However, this regimen resulted in a 14% graft rejection rate and 42% incidence of disease relapse at our institution. We hypothesized that escalation of the TBI dose to 400 cGy may improve post-transplant outcomes. From 12/10/03 to 4/19/05, 17 patients (pts) with hematologic malignancies underwent NMHSCT using a preparative regimen of fludarabine 30 mg/m2/d IV on days −5, −4 and −3 and TBI 200 cGy on days −1 and 0 (total dose 400 cGy). Immunosuppressant therapy consisted of cyclosporine and mycophenolate for matched sibling donor pts (n = 10) or Tacrolimus and mycophenolate for matched unrelated donor pts (MUD) (n = 7), which was started day −1 and discontinued day +56 in the absence of GVHD. Diagnoses included 4 NHL, 3 AML, 2 MDS, 2 myelofibrosis (MFB), 1 Hodgkin lymphoma (HL), 1 ALL, 1 multiple myeloma (MM), 1 CLL, 1 chronic myeloproliferative disorder (CMD) and 1 bilineal acute leukemia (BAL). Only 2 (12%) pts were in complete remission at the time of transplant (both AML). The median time from diagnosis to transplant was 11 months (range, 3–246 months). All transplants were performed as an outpatient, but 16 (94%) pts required hospitalization and the most common reason was for fever (9 pts– 56%). The median CD34+ and CD3+ cell doses infused were 4.92 x 106/kg and 4.44 x 108/kg, respectively. The median time to absolute neutrophil count recovery of ≥500/μL was 10 days (range, 8–13 days) while time to platelet recovery ≥20K/μL was 12 days (range, 11–16 days). T-cell (CD3+) chimerism was monitored by short tandem repeat analysis and complete donor chimerism (CDC) was defined as ≥ 95% donor DNA in CD3+ T-cells. CDC was achieved in 14 (82%) pts at a median of 28 days (range, 21–130 days), whereas, in our prior analysis with pts receiving 200 cGy TBI, 75% of pts achieved durable CDC at a median of 77 days (range, 14–310 days). Ten (59%) pts developed acute GVHD at a median of 61 days (range, 13–85 days) with 4 grade I, 4 grade II, 1 grade III, and 1 grade IV. Chronic GVHD developed in 5 (29%) pts at a median of 10 months (range, 3–13 months) and only 1 (6%) developed extensive chronic GVHD. Responses included 4 CR (1 NHL, 1 AML, 1 CLL, 1 MFB), 4 PR (2 NHL, 1 HL, 1 MM), 2 stable disease (1 CMD, 1 NHL), and 3 not evaluable (2 MDS, 1 MFB). Graft rejection occurred in only 1 AML patient with a MUD and HLA-B and -Cw disparities. Three (18%) pts (1 ALL, 1 AML, 1 BAL) had disease relapse at a median of 6 months post-transplant (range, 2–12 months). The Kaplan-Meier method reported a median relapse-free survival of 11.6 months. Seven pts died, 3 within 100 days of NMHSCT; estimated median survival was 12.7 months. Causes of death included 2 acute GVHD, 1 chronic GVHD, 1 relapse, 1 sepsis, 1 ARDS, 1 cardiac arrest. We conclude that escalation of the TBI dose to 400 cGy in combination with fludarabine for NMHSCT is an effective approach which when compared to the 200 cGy regimen has resutled in less graft rejection (6% vs. 14%, respectively) and a lower relapse rate (18% vs. 42%, respectively). The more rapid achievement of T-cell CDC may be responsible for these differences. Further investigation and follow-up with this regimen is warranted.

A Matched Controlled Analysis of Post-Transplant Cyclophosphamide (CY) Versus Tacrolimus and Mini-Dose Methotrexate in Matched Sibling and Unrelated Donor Transplant Recipients Receiving Reduced-Intensity Conditioning: Post-Transplant CY Is Associated with Higher Rates of Acute Gvhd

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4200-4200 ◽  
Author(s):  
Amin M. Alousi ◽  
Rima M Saliba ◽  
Julianne Chen ◽  
Borje S Andersson ◽  
Issa Khouri ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Disease Status ◽  
Control Group ◽  
Unrelated Donor ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Unrelated Donors ◽  
Matched Sibling ◽  
And Control

Abstract Abstract 4200 Graft-vs.-Host Disease (GVHD) remains a common complication following matched sibling and unrelated donor hematopoietic cell transplantation (HCT). Standard GVHD prophylaxis calls for prolonged immune suppression, typically with a calcineurin-inhibitor. Recently, post-transplant cyclophosphamide (CY) has been studied as sole prophylaxis in matched related and unrelated bone marrow (BM) transplant recipients following an ablative conditioning regimen with busulfan (Bu) and CY and demonstrated comparable rates of acute GVHD and lower rates of chronic GVHD as traditional GVHD prophylaxis regimens. We recently conducted a phase II study of post-transplant CY following a reduced-intensity conditioning (RIC) regimen of Busulfan (Bu) and Fludaribine (Flu) in matched related and unrelated donor transplants and performed a matched-control analysis comparing their results with patients who received traditional GVHD prophylaxis with tacrolimus and mini-dose methotrexate (MTX) during the same time period. Forty-nine (49) patients were enrolled onto this study. They received Flu at a dose of 40mg/m2 over 1hour followed by intravenous Bu over 3 hours targeting a daily AUC of 4,000 microMol-min on days –6 to –3. Recipients of unrelated transplants received ATG on days –3 to –1 (total dose 4 mg/kg). CY was given as sole GVHD prophylaxis at a dose of 50 mg/kg on days +3 and +4. During the same period of time, 133 patients received a RIC regimen with intravenous Bu/Flu or Flu and melphalan (Mel) and received GVHD prophylaxis with tacrolimus plus mini-dose MTX (10mg/m2 on day +1, 5mg/m2on days +3, +6, +11). Unrelated donor transplants also received ATG. A computer generated algorithm was used to identify a comparable control group from our departmental database matching, in order of priority, on age, diagnosis, disease status, donor (matched-related versus unrelated) and graft source (PB versus BM). Matched controls (control group) were successfully identified for 37 study patients (Post-Cy group). Results: The median age for the Post- CY group and control group was 61 (range, 39–72) and 62 years (range, 37–72). Eight-one (81) % of patients in both groups had AML or MDS, 3% had ALL and 16% had NHL or CLL. Fifty-nine (59) % of patients in both groups had unrelated donors and received ATG in the conditioning. Disease status for the Post-CY and control groups respectively were CR1: 14 and 14%, CR2: 8 and 11%, >CR2: 38 and 32% and Primary Induction Failure / Untreated: 40 and 32%. Seventy (70) % of the post-CY group received BM versus 48% of the control group, whereas sex mismatching (Male donor for Female patient) occurred in 22% of the post-Cy and 8% of the control group. The cumulative incidence of grade II-IV acute GVHD and chronic GVHD in the post-CY and control groups were: 46% versus 19% (Hazard Ratio (HR): 2.8, 95% CI, 1.1–6.7; p=0.02) and 14% versus 21% (HR: 0.8, 95% CI, 0.2–2.6, p=0.7). Grades III/IV acute GVHD occurred in 14% (95% CI, 6–32) of the patients in the post-CY group whereas there were no cases of grade III/IV in the control group (p=0.02). Overall, progression-free and non-relapse mortality at 2-years are shown in the table below. Conclusion: Post-transplant CY following RIC is associated with higher rates of acute GVHD, with resultant trends for higher non-relapse mortality and lower overall survival when compared to tacrolimus and mini-dose MTX. The use of post-transplant CY as a sole GVHD prophylaxis regimen should be avoided following RIC transplant in matched-related and unrelated donors. Disclosures: Off Label Use: azacitidine: off-label use as maintenance therapy following allogeneic stem cell transplant for MDS/AML.

scholarly journals Worse outcome and more chronic GVHD with peripheral blood progenitor cells than bone marrow in HLA-matched sibling donor transplants for young patients with severe acquired aplastic anemia

Blood ◽  
2007 ◽  
Vol 110 (4) ◽  
pp. 1397-1400 ◽  
Author(s):  
Hubert Schrezenmeier ◽  
Jakob R. Passweg ◽  
Judith C. W. Marsh ◽  
Andrea Bacigalupo ◽  
Christopher N. Bredeson ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Peripheral Blood ◽  
Chronic Gvhd ◽  
Young Patients ◽  
Graft Versus Host ◽  
Sibling Donor ◽  
Peripheral Blood Progenitor Cells ◽  
Matched Sibling ◽  
Overall Mortality

AbstractWe analyzed the outcome of 692 patients with severe aplastic anemia (SAA) receiving transplants from HLA-matched siblings. A total of 134 grafts were peripheral blood progenitor cell (PBPC) grafts, and 558 were bone marrow (BM) grafts. Rates of hematopoietic recovery and grades 2 to 4 chronic graft-versus-host disease (GVHD) were similar after PBPC and BM transplantations regardless of age at transplantation. In patients older than 20 years, chronic GVHD and overall mortality rates were similar after PBPC and BM transplantations. In patients younger than 20 years, rates of chronic GVHD (relative risk [RR] 2.82; P = .002) and overall mortality (RR 2.04; P = .024) were higher after transplantation of PBPCs than after transplantation of BM. In younger patients, the 5-year probabilities of overall survival were 73% and 85% after PBPC and BM transplantations, respectively. Corresponding probabilities for older patients were 52% and 64%. These data indicate that BM grafts are preferred to PBPC grafts in young patients undergoing HLA-matched sibling donor transplantation for SAA.

scholarly journals Unrelated Cord Blood Transplantation and Post-Transplant Cyclophosphamide (PT-CY)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3332-3332
Author(s):  
Patrizia Chiusolo ◽  
Andrea Bacigalupo ◽  
Simona Sica ◽  
Sabrina Giammarco ◽  
Elisabetta Metafuni ◽  
...  
Keyword(s):  
Cord Blood ◽  
Median Time ◽  
Cord Blood Transplantation ◽  
Chronic Gvhd ◽  
High Dose ◽  
Unrelated Donor ◽  
Immune Recovery ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Unrelated Cord Blood

Background .There has been a decrease in the use of unrelated cord blood transplants (UCBT) in the past years: this is probably due to slow hematologic and immune recovery, resulting in a relatively high non relapse mortality (NRM). The addition of anti-thymocyte globulin (ATG) in the conditioning prevents graft versus host disease (GvHD) but makes immune recovery very slow. In addition there is a growing competition of unmanipulated haploidentical transplants. Aim of the study. We have opened a pilot study to test whether high dose post-transplant cyclophosphamide (PT-CY) would prevent GvHD but still allow for robust immune and hematologic recovery . Methods. We have grafted 10 patients with an unrelated CB unit and PT-CY. The conditioning regimen was thiotepa (10 mg/kg), busulfan 9.6 mg/kg and fludarabine 150 mg/m^2 (TBF). GvHD prophylaxis was cyclosporin (CSA) starting day 0 (3 mg/kg/day(i.v.), mycophenolate (MMF) 30 mg/kg starting day +1 (p.o) , and PT-CY 30 mg/kg days +3 and +5. The median patients' age was 58 (43-66), and the median weight was 75 kg (54-85) the diagnosis was AML in 8 patients, Ph'+ALL in one and RAEB in one patient; 6 patients were in remission and 4 had active disease. CB units. The HLA matching of the CB unit was 5/8 antigens/alleles (A,B,C,DRB1) in six patients, 4/8 in two and 2/8 in one. The median nucleated cell dose was 3.1x10^7/kg (range 1.8- 4.5). The ABO was mismatched in all 10 patients. Hematologic recovery: median time to neutrophils 0.5x10^9/l was day 23 days (range 17-27) and the median time to a platelet count of 20x10^9/L was 38 days (range 34-40). The median counts on day +50 were as follows: Hb 9,1 gr/dL (range 8.7-11.1), Neutrophils 2,3 x10e9/L (range 1-5), PLTs 56 x10e9/L (10-90). One patient failed to engraft and received a second transplant from an unrelated donor, which was successful. No patient developed pure red cell aplasia despite 9/10 being ABO major mismatched. CD4 recovery : the median CD4 count on day +50 was 74 /cmm (range 67-116) and on day +100 it was 111/cmm(range 100-136). CMV pre-emptive therapy occurred in 3/6 evaluable patients Outcome: two patients with advanced disease, died early of infections, within day +20. GvHD was seen in 1 patient as a transient rash. No patient was treated for GvHD. No patient developed chronic GvHD. No patient relapsed. Eight patients survive in remission, with a median follow up of 6 months, and a projected one year actuarial survival of 80%. Readmissions were extremely rare. Conclusions. These first 10 patients suggest that UCBT followed by PT-CY, CSA, MMF, as GvHD prophylaxis is feasible and leads to encouraging hematologic and immunologic recovery. We were particularly impressed with the lack of GvHD, the absence of relapses and the good quality of life. Figure Disclosures No relevant conflicts of interest to declare.

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