Sustained Graft-Versus-Lymphoma Effect among Patients (pts) with Mantle Cell Lymphoma (MCL) Given Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation (HCT).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2147-2147 ◽  
Author(s):  
Mohamed L. Sorror ◽  
Barry Storer ◽  
Brenda M. Sandmaier ◽  
Michael Maris ◽  
Thomas Chauncey ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Progression Free Survival ◽  
Median Number ◽  
Therapeutic Modality ◽  
High Dose ◽  
Duration Of Treatment ◽  
Autologous Hct

Abstract We previously reported 2-year overall survival (OS) of 65% among 33 pts with MCL given nonmyeloablative HCT (Blood2004; 104: 3535). Here, we update our results on the initial 33 pts with median follow up of 63 months and report on 20 additional pts with emphasis on: long-term disease control and resolution of chronic GVHD. Pts were conditioned with 2Gy TBI with or without fludarabine (90 mg/m2). Median age for all pts was 56 (range 33–75) years and median number of prior regimens was 4. Forty percent of pts had failed high-dose autologous HCT and an additional 11% had planned autologous HCT before allograft (4 pts had refractory disease and 2 were in PR). Comorbidity scores of ≥3 were found among 40% of pts. Forty percent of pts were not in CR/PR at HCT and 26% and 21% had marrow infiltration and lymph node size ≥5 cm, respectively. Donors were related (n=28) or unrelated (n=25). After HCT, incidences of grades II, III, and IV acute GVHD were 25%, 13%, and 9% respectively, and chronic extensive GVHD was 53%. Complete (CR) and partial remissions (PR) were seen in 71% and 3% of pts with measurable disease at HCT, respectively. Estimated 5-year rates of non-relapse mortality (NRM), progression/relapse, OS, and progression-free survival (PFS) were 27%, 22%, 58%, and 52%, respectively (Table 1). Among 19 pts in CR at HCT, 11 are alive and in CR, 7 died in CR, and one relapsed (now in CR after Rituximab and donor lymphocyte infusion). Among 13 in PR at HCT, 10 achieved CR and are alive, one died in PR, and 2 died from relapse. Among 21 pts with refractory/relapsed disease at HCT, 12 achieved CR and are alive, 2 have stable disease and are alive, and 7 relapsed (2 are alive in CR and PR after further treatment). At 5-years, 44% and 14% were alive without or with chronic GVHD requiring immunosuppression (Figure); and median duration of treatment for chronic GVHD was 33 months. Outcomes were comparable among related and unrelated recipients. Relapse rates were 47% vs. 14% among pts with vs. without LN size of ≥5 cm (p=0.02) and NRM was 41% vs.17% (p=0.05) among pts with HCT-CI scores of ≥3 vs. 0–2, respectively. Nonmyeloablative HCT is a potentially curative therapeutic modality for pts with advanced MCL, including patients who were chemotherapy-refractory, with a median PFS beyond 5 years. Sustained remissions and continuing resolution of chronic GVHD were observed with extended follow up. Pts with bulky LN might benefit from further debulking strategies before HCT. Table: Outcomes by donor type Donor Related (n = 28) Unrelated (n = 25) % % Grades III–IV non-hematological toxicities 39/18 38/26 Acute GVHD, grades II/ III/ IV 22/14/7 28/12/12 Chronic GVHD 50 55 CR 73 67 5-year NRM 26 28 5-year Progression/relapse 22 21 5-year PFS 53 51 5-year OS 59 56 5-year Pts alive with chronic GVHD requiring immunosuppression 14 7 Figure Figure

Outcomes of Allogeneic Hematopoietic Cell Transplantation (HCT) after Non-Myeloablative Conditioning in Relapsed Diffuse Large B-Cell Lymphoma (DLBCL).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3037-3037
Author(s):  
Andrew R. Rezvani ◽  
L. Norasetthada ◽  
T. Gooley ◽  
Mohamed Sorror ◽  
Stephen J. Forman ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Early Death ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
High Dose ◽  
Myeloablative Conditioning ◽  
Allogeneic Hct ◽  
Autologous Hct

Abstract BACKGROUND: We report on outcomes after non-myeloablative allogeneic HCT in patients (pts) with relapsed DLBCL. PATIENTS: Thirty-two pts with relapsed DLBCL were treated at 11 centers with allogeneic HCT from related (n=21) and unrelated (n=11) donors following non-myeloablative conditioning with 2 Gy total body irradiation, with or without fludarabine. Median age was 51.8 years. Twenty-four pts (75%) had undergone prior high-dose therapy (HDT) with autologous HCT: 18 (56%) had failed HDT, and 6 (19%) underwent planned tandem autologous/allogeneic HCT. The remaining 8 pts (25%) were medically ineligible for HDT. Twenty-three pts (72%) had chemosensitive disease at HCT, while 9 (28%) were chemorefractory. Disease status at HCT was complete response (CR, 14/32, 44%), partial response (PR, 9/32, 28%), or relapsed/refractory (9/32, 28%). RESULTS: All patients engrafted. Cumulative incidences of acute GVHD grades II-IV, acute GVHD grades III-IV, and chronic GVHD were 53%, 19%, and 47%, respectively. Median follow-up of surviving patients was 45 months. Of pts with measurable disease at HCT (n=18), responses were seen in 7/18 (39%), with 6 CR’s and 1 PR. Nine of these eighteen pts progressed, and 2/18 were not evaluable due to early death from non-relapse causes. Of pts in CR at HCT, 10/14 (71%) remained in CR while 4/14 (29%) progressed. Three-year estimated overall (OS) and progression-free survival (PFS) were 45% and 35%, respectively. Three-year cumulative incidences of relapse and non-relapse mortality were 41% and 25%, respectively (see Fig. 1). In multivariate models, chemosensitive disease and receipt of >4 lines of chemotherapy prior to HCT were associated with better overall survival. Pts with chemosensitive disease at HCT had 3-year OS and PFS of 56% and 43%, respectively, while those with chemorefractory disease had 3-year OS/PFS of 11% (see Fig. 2). Prior failed or tandem autologous HCT did not have a significant effect on outcome. CONCLUSION: Non-myeloablative allogeneic HCT can produce sustained disease responses in pts with chemosensitive relapsed DLBCL. Patients with relapsed DLBCL who have failed or are ineligible for autologous HCT lack effective therapeutic options. Non-myeloablative allogeneic HCT is a promising treatment for such patients. Figure Figure Figure Figure

Tandem Auto-Allo in Acute Myeloid Leukemia (AML) Patients in First Complete Remission (CR).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3355-3355
Author(s):  
Luca Castagna ◽  
Sabine Furst ◽  
Thomas Prébet ◽  
Jean El Cheikh ◽  
Aude Charbonnier ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cause Of Death ◽  
Relapse Rate ◽  
Acute Gvhd ◽  
Prognostic Score ◽  
Chronic Gvhd ◽  
Median Number ◽  
Prognostic Scores ◽  
High Dose

Abstract Abstract 3355 Poster Board III-243 Background. High and intermediate risk AML can benefit by allogeneic stem cell transplantation in first CR. The use of reduced intensity conditioning regimens (ALLO-RIC) decreases the toxicity even if the relapse rate is more pronounced. To contrast the high relapse rate we hypothyzed that if a better quality of remission could be achieved, the relapse incidence could be lowered. Patients and methods. From 2001 to 2008, 31 AML patients in first CR received a tandem auto-allo program. The median number of white blood cell was 3 × 10e9/l (range 0.9-235), 13% of patients have extramedullary localisations. In 13% AML was secondary to previous CT treatment. Cytogenetic was abnormal in 36% of pts. After one or two induction chemotherapies (CT), all but two patients received a consolidation course with high-dose cytarabine (HD-ARAC) CT, followed by autologous stem cell harvest. Then, HD melphalan (HD-PAM 140 mg/m2) followed by autologous stem cells reinfusion was administered, followed by ALLO-RIC. RIC consisted of fludarabine plus (2 Gy) TBI (3 pts) or fludarabine, oral or intravenous busulfan (8 mg/kg) in two days, and anti thymocyte globulin (2.5 or 5 mg/kg). Graft versus host disease (GVHD) prophylaxis was cyclosporine (CyA) plus mycofenolate mofetil (3 pts) or CyA alone (28 pts). Donors were all but one HLA identical sibling. The median number of allogeneic CD34+ and CD3+ cells was 6.1 × 10e6/Kg (range 1.9-11) and 315 (range 166-609). Prognostic scores (HCT-CI, PAM, EBMT) were retrospectively calculated for each patient. All pts have a performance status ≥ 90%. Results. The median follow-up was from diagnosis and ALLO-RIC 40 and 34 months, respectively. The median time between last CT and HD-PAM was 51 days (range 30-77) and HD-PAM and ALLO-RIC was 69 days (55-176). Treatment related mortality after HD-PAM was null. Prognostic scores were: HCT-CI score 0-2= 53% (16 pts), ≥3= 47% (14 pts), 1 pt not evaluable; PAM score 9-16= 30% (10 pts), 17-23= 67% (19 pts), 24-30= 3% (1 pt); EBMT score 1= 9% (3 pts), 2= 78% (24 pts), 3= 13% (4 pts). At last follow-up, 42% of pts (n= 13) died: 5 due to disease relapse and 8 because of toxicity. Grade II-IV acute GVHD and chronic GVHD incidence were respectively 26% and 65% (extensive 84%). GVHD was the cause of death in seven pts. Six pts (19%) reactived CMV, without disease, and 1 pt not survived to an interstitial pneumonitis. The 5-year overall survival (OS), relapse free survival (RFS), and 1-year TRM were 60%, 60%, and 15%, respectively. In multivariate analysis, prognostic scores did not influence TRM and OS. Conclusions. This report showed that i) tandem auto-allo is feasible in AML pts; ii) acute GVHD incidence is not increased iii) prognostic score did not impact on TRM and survival; iv) the TRM is quite low with GVHD as main cause of death. A retrospective comparison with a cohort of pts not receiving HD-PAM is on going. Disclosures: No relevant conflicts of interest to declare.

Allogeneic Hematopoietic Cell Transplantation (HCT) with Nonmyeloablative Conditioning after Failed Myeloablative HCT: Factors Affecting Outcomes.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1143-1143 ◽  
Author(s):  
Frederic Baron ◽  
R. Storb ◽  
B. Storer ◽  
D. Maloney ◽  
M. Maris ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Multivariate Analyses ◽  
Chronic Gvhd ◽  
Progression Free Survival ◽  
Hodgkin Disease ◽  
High Dose ◽  
Factors Associated ◽  
Increased Risk ◽  
Overall Mortality

Abstract We describe data from 147 consecutive patients (median age, 46; range, 9–73 yrs) who had failed myeloablative conventional autologous (n=135), allogeneic (n=10), or syngeneic (n = 2) HCT, and were given HLA-matched related (MRD) (n=62) or unrelated (URD) (n=85) HCT after conditioning with 2 Gy TBI with or without 90 mg/m2 of fludarabine with the aim of identifying predictive factors for HCT outcomes. Postgrafting immunosuppression consisted of cyclosporine (CSP) and mycophenolate mofetil (MMF). Median times between failed HCT and nonmyeloablative HCT were 22 (range, 3–128) months for MRD recipients and 25 (range, 4–222) months for URD recipients, respectively. Median follow-up for surviving patients was 27 (range, 7–66) months. Comorbidities at HCT were scored according to the HCT-specific comorbidity index (HCT-CI, Sorror et al. Blood 2005). Sustained engraftment was achieved in 141 patients, while 6 (5 URD and 1 MRD) rejected their grafts 13 to 1123 days after HCT. Median donor T-cell chimerism levels on days 28, 56, 84, 180 and 365 after HCT were 95%, 97%, 97%, 99% and 100%, respectively. Grades II, III and IV acute GVHD were seen in 36%, 15%, and 5% of MRD recipients, and 48%, 8%, and 7% of URD recipients, respectively. Extensive chronic GVHD occurred in 47% of MRD recipients and 57% of URD recipients. Three-yr probabilities of nonrelapse mortality (NRM), relapse, progression-free survival (PFS) and overall survival (OS) were 31%, 48%, 22% and 32% in MRD recipients and 34%, 37%, 29% and 42% in URD recipients, respectively. The best outcomes were observed in patients with non-Hodgkin lymphoma (NHL), while patients with multiple myeloma and Hodgkin disease had poor outcomes due to high incidences of relapse/progression (Table 1). Pre-transplant factors associated with better PFS in multivariate analyses were chemosensitive malignancy (CR/PR) (P=0.0009), absence of comorbidity (HCT-CI score 0) (P=0.02), and URD (P=0.03). Pre-transplant factors associated with better OS in multivariate analyses were chemosensitive malignancy (CR/PR) at HCT (P=0.02), and absence of comorbidity (HCT-CI score 0) at HCT (P=0.008). In time-dependent analyses, grade II-IV acute GVHD was associated with increased NRM (HR=2.56, P=0.008), and a trend for increased risk of overall mortality (HR 1.53, P=0.07), while chronic GVHD was associated with a lower risk of relapse (HR 0.47, P=0.05) and no increase in overall mortality (HR 0.84, P=0.53). In conclusion, encouraging outcomes could be achieved with nonmyeloablative conditioning in selected patients having failed high-dose HCT, particularly in patients with NHL. Results with URD were as least as good than those with MRD, suggesting that this approach should not be restricted to patients with a MRD. Table 1: Survival according to diagnosis OS @ 3 yrs PFS @ 3 yrs NHL-MCL (n=14) 64% 57% NHL-Indolent (n=12) 56% 56% NHL-Aggressive (n=24) 40% 36% Hodgkin Disease (n=35) 33% 9% CML/AML/MDS (n=35) 31% 27% Multiple myleoma (n=22) 26% 0% Other (n=5) 27% 30%

Single Center Retrospective Comparison of Gvhd Preventive Regimens after Cy/Flu Minimal Intensity Allotransplantation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5874-5874
Author(s):  
Praveen Ranganath ◽  
Michael J. Robertson ◽  
Rafat Abonour ◽  
Jennifer E. Schwartz ◽  
Sherif Farag ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Single Agent ◽  
Progression Free Survival ◽  
Allogeneic Transplantation ◽  
Peripheral Blood Mononuclear ◽  
Minimal Intensity

Abstract Graft-versus-host disease (GVHD) remains the 2nd leading cause of mortality—after relapse/progression following allogeneic hematopoietic cell transplantation for the treatment of hematological malignancies. The incidence of clinically significant GVHD ranges from 10 to 80% and accounts for approximately 10-20% transplant related mortality. The combination calcineurin inhibitor and methotrexate is widely used as a GVHD preventive following myeloablative conditioning; however, there is no standard prophylaxis regimen for Cy/Flu minimal intensity nonablative transplants. The objective of the current study is to compare outcomes in patients treated at a single institution with identical conditioning regimens and supportive methods but different GVHD preventive regimens. Outcomes on 134 patients who underwent nonmyeloablative transplant between May 2000 and Nov 2011 were retrospectively analyzed. The primary endpoint was incidence and severity of acute GVHD (aGVHD). Secondary endpoints included incidence and severity of chronic GVHD (cGVHD), incidence of relapse, overall survival (OS), progression-free survival (PFS) and causes of death. Median follow-up was 49 months; the median age at transplant was 56 years, 66% of patient were not in remission at time of transplant (predominately myelodysplasia). Donors were peripheral blood mononuclear cell (PBMC, n=133) or bone marrow (n=1) HLA matched related or partially matched (9/10) donors. GVHD preventive regimens included the following: (1) single agent cyclosporine (CsA); (2) combination CsA/mycophenolate mofetil (MMF); (3) CsA+ basiliximab after ANC > 500/mm3; (4) CsA + basiliximab post-transplant, pre-engraftment; (5) sirolimus + tacrolimus. The incidence of grade III-IV acute GVHD was lower in patients who received sirolimus/tacrolimus than patients in the cyclosporine group (25% and 32%, respectively; p = .062). There was a significantly higher proportion of patients in the cyclosporine group who had clinical extensive chronic GVHD (62% vs. 25%, p = .008). The incidence of relapse trended higher in the sirolimus/tacrolimus group compared to CsA alone or CsA/MMF (50% vs. 28% vs. 30%, respectively, p= .519). There was a trend towards slightly better OS and PFS with the cyclosporine-based prophylaxis, but follow-up was longer with these regimens. Sirolimus/tacrolimus provides potent GVHD prophylaxis for nonmyeloablative Cy/Flu allogeneic transplantation; however, may be associated with higher relapse/progression rates. Larger numbers and/or comprehensive analyses of multicenter registry data might help further delineate differences in clinical outcomes between these regimens. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

scholarly journals Shortened Immunosuppression Following Peripheral Blood (PB) Haploidentical (haplo) Transplantation with Post-Transplant Cyclophosphamide (PTCy) Is Associated with Tolerable Rates of Graft-Vs-Host Disease (GVHD)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3320-3320
Author(s):  
Amy E. DeZern ◽  
Marianna Zahurak ◽  
Javier Bolanos-Meade ◽  
Richard J. Jones
Keyword(s):  
Graft Failure ◽  
Acute Gvhd ◽  
Risk Index ◽  
Chronic Gvhd ◽  
Prospective Trial ◽  
Stopping Rules ◽  
High Dose ◽  
Gvhd Prophylaxis ◽  
Grade 3

With PTCy as GVHD prophylaxis, nonmyeloablative (NMA) HLA- haplo and HLA-matched blood or marrow (BMT) have comparable outcomes. Previous reports showed that discontinuation of immunosuppression (IST) as early as day 60 after infusion of bone marrow (BM) haplo allograft with PTCy is feasible. However, there are certain diseases in which PB may be favored over BM grafts to augment engraftment rates; however, given the higher rates of GVHD with PB, excessive GVHD becomes a concern with early discontinuation of IST. We present a completed, prospective single-center trial of stopping IST at days 90 and 60 after NMA haplo PB. (NCT02556931) From 12/2015-7/2018, 117 evaluable patients (pts) with hematologic malignancies associated with higher rates of graft failure with PTCy (MDS, MPN, overlap syndromes, 2o AML, AML with MRD, MM, and CLL) received NMA PB allografts on trial. Haplo donors were preferred, but in patients lacking suitable haplo relatives, unrelated donors were employed with 6 in each IST cohort. The primary objective was to evaluate the safety and feasibility of reduced‐duration IST (from Day 5 through Day 90 in cohort 1 and through Day 60 in cohort 2.) Transplant inclusion criteria were standard and the conditioning included Cy (14.5 mg/kg IV D -6 and -5), fludarabine (D -6 to -2), TBI (200 cGy D -1) and T-cell replete PB. GVHD prophylaxis consisted of high-dose PTCy (50 mg/kg IV D 3 and 4), mycophenolate mofetil (D 5-35) and IST (tacrolimus/sirolimus) from D 5 forward. Priot to transplantation, pts were assigned to stop IST early if eligible, as defined by having ≥ 5% donor T cells at ~D 56 onward, no relapse, and no grade 2-4 acute or significant chronic GVHD. If ineligible to discontinue IST early, it continued through D 180. Monitoring rules declared reduced IST feasible if ≥ 33% of pts stopped IST early as planned. Safety stopping rules for early IST cessation were based on ≥ 5% graft failure, ≥ 5% NRM, ≥ 50% relapse, and ≥ 10% combined grade 3-4 acute GVHD and severe chronic GVHD, measured from the IST stop date to ~D 180. Historical data from 55 haplo transplants for MDS, CLL, and MPNs at our center using the same regimen and PB grafts informed safety calculations. Of the 117 pts (median age 64 years, range 24-78), the most common diagnoses were MDS (33%), AML (with MRD or arising from antecedent disorder) (31%), MPNs (21%) myeloma (10%), and CLL (6%). By refined Disease Risk Index, 13% were low risk, 69% intermediate and 18% high. Shortened IST was feasible in 75 pts (64%) overall. Ineligibility for shortened IST was due most commonly to GVHD (17 pts), followed by early relapse (11 pts), NRM (7 pts), patient/ physician preference (4 pts) or graft failure (3 pts). Of the 57 patients in the D90 cohort (median follow up 35 mos), 33 (58%) stopped IST early as planned. Of the 60 patients in the D60 cohort (median follow up 20 mos), 42 (70%) stopped IST early as planned. The graft failure rate was 2.6%. NRM was very similar in the two arms, 12% at both 12 and 18 months in the D90 cohort and 10% and 13% at 12 and 18 months in the D60 cohort. Relapse in D90 cohort is 40% at 18 months compared to 33% at 18 months in the D60 cohort. Figure 1 shows cumulative incidence (CI) of acute grade 2-4 and grade 3-4 GVHD. Although the CI of grade 1-2 GVHD may be slightly higher in day 60 cohort, it is only 40% at D180. Severe chronic GVHD was 12% (D90) and 11% (D60) at 540 days. One year OS is 75% and 78% for the D90 and D60 cohorts, respectively. At 12 months PFS is 54% in the D90 group and 67% in the D60. At 12 months, the GRFS is 33% in the D90 group, and 38% in the D60 group. (Figure 2) These data suggest that reduced-duration IST in pts receiving NMA haplo PB with PTCy is feasible and carries an acceptable safety profile. Risks of acute GVHD, chronic GVHD, graft failure and NRM appear similar to historical outcomes with IST until D180 and between the two cohorts. When comparing the D90 and D60 arms, grade 3-4, severe chronic GVHD, GRFS, OS and PFS were similar. Although a larger, prospective trial would be needed to uncover potential small differences in outcomes based on IST duration, these data show that similar to our findings with BM, many PB pts (64% in this trial) can discontinue IST as early as D60 without undue toxicity. The favorable toxicity profile of the PTCy platform, coupled with the feasibility and safety of early IST cessation, provides an ideal setting to incorporate novel post-transplantation approaches for relapse reduction. Figure 1 Disclosures DeZern: Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. Bolanos-Meade:Incyte Corporation: Other: DSMB fees.

A Novel Reduced Intensity Conditioning Can Induce a High Incidence of Sustained Donor Engraftment After Double Unit Cord Blood Transplantation (CBT) without Anti-Thymocyte Globulin

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2351-2351
Author(s):  
Doris M Ponce ◽  
Craig Sauter ◽  
Marissa Lubin ◽  
Anne Marie Gonzales ◽  
Glenn Heller ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Gvhd ◽  
Progression Free Survival ◽  
High Dose ◽  
Free Survival ◽  
Prior Therapy ◽  
Cd34 Cells ◽  
High Incidence ◽  
Related Mortality

Abstract Abstract 2351 CBT can be curative for patients with high-risk hematologic malignancies. However, patients of older age, those with extensive prior therapy, or significant co-morbidities may not tolerate high-dose myeloablative conditioning. Reduced intensity (RI) or non-myeloablative (NMA) conditioning has been successfully used in CBT, especially in patients with lymphomas. However, patients with myeloid malignancies without extensive prior therapy have an increased risk of graft rejection following NMA CBT. Further, the addition of anti-thymocyte globulin (ATG) to enhance engraftment increases the risk of serious infections and Epstein-Barr virus post-transplant lymphoproliferative disease, and could increase the risk of relapse. Therefore, we investigated the efficacy and safety of a novel ATG-free RI conditioning prior to double unit CBT in patients with acute leukemias and myelodysplasia with the hypothesis that this regimen can induce a high incidence of sustained donor engraftment. Conditioning consisted of cyclophosphamide 50 mg/kg (day -6), fludarabine 30 mg/m2/day × 5 (days -6 to -2), thiotepa 5 mg/kg/day × 2 (days -5 and -4), and total body irradiation 200 cGy × 2 (days -2 and -1). All patients received cyclosporine-A and mycophenolate mofetil for graft-versus-host disease (GVHD) prophylaxis. Between 10/01/07-04/30/10, 20 patients were transplanted. The median age was 56 years (range 18–69). Thirteen (65%) had AML (9 CR1, 4 CR2), 4 (20%) had ALL (3 CR1, 1 CR3), and 3 (15%) had MDS (with one patient also having follicular lymphoma). The majority had high-risk disease. Indications for RI conditioning were the risk factors for transplant-related mortality (TRM) with high-dose conditioning of age ≥50 years, and/or extensive prior therapy, and/or significant co-morbidities. Thirteen patients had only 1 of these risk factors, whereas 7 had ≥2 risk factors. Units were predominantly 4–5/6 HLA-matched to the recipient (one 6/6, twenty-four 5/6, fifteen 4/6). The median infused cell doses of the larger units were 2.7 × 107 total nucleated cells/kg (range 1.46–5.56) and 0.95 × 105 CD34+ cells/kg (range 0.35–3.32), and 1.89 × 107/kg total nucleated cells/kg (range 1.42–2.47) and 0.59 × 105/kg CD34+ cells/kg (range 0.18–1.52) for the smaller units, respectively. The cumulative incidence of sustained donor engraftment at day 45 was 95% (95%CI: 81–100). The single patient with graft failure was 100% donor in the day 21 bone marrow, but died early post-transplant of multi-organ failure without count recovery. The median time to neutrophil recovery ≥0.5 × 109/l was 25 days (range 13–43). The median total donor chimerism in the day 21 bone marrow was 94% (both units combined, range 71–100), and sustained engraftment was accounted for by one unit in 18/19 engrafting patients. The incidence of grade II-IV acute GVHD at day 100 was 55% (95%CI: 32–78), and 46% (95%CI: 21–71) of patients have had late acute GVHD requiring ongoing therapy or chronic GVHD to date. The incidence of day 100 transplant-related mortality (TRM) was 20% (95%CI: 2–38). Notably, none of the 13 patients with only one risk factor died of transplant-related causes. By contrast, 5/7 (71%) patients with ≥2 risk factors died of TRM by day 100 (p=0.03, Table 1). Two additional patients died of relapse. With a median follow-up of 13 months (range 3–31), 1 year progression-free survival is 74% (95%CI: 55–94) (Figure 1). We demonstrate that this ATG-free RI conditioning is associated with a high incidence of sustained donor engraftment, and acceptable toxicities in older patients without other risk factors. While longer follow-up is needed, progression-free survival is encouraging provided multiple risk factors are not present. This conditioning combined with double unit grafts warrants further investigation, and may also be a promising alternative to high-dose conditioning in younger patients. Table 1. Day 100 TRM according to number of risk factors (age ≥50 years, extensive prior therapy, significant co-morbidities). Risk Factors Day 100 TRM P Value 1 (N = 13) 0/13 (0%) 0.03 ≥2 (N = 7) 5/7 (71%) Figure 1. Progression-Free Survival At 1 Year Figure 1. Progression-Free Survival At 1 Year Disclosures: Giralt: Celgene: Honoraria, Speakers Bureau; Millenium: Honoraria, Speakers Bureau.

Outcomes after Double Umbilical Cord Blood Transplantation in Children: A Survey on Behalf of Eurocord and PDWP-EBMT

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2570-2570
Author(s):  
Federica Giannotti ◽  
Annalisa Ruggeri ◽  
Gerard Michel ◽  
Jean-Hugues Dalle ◽  
Tracey O'Brien ◽  
...  
Keyword(s):  
Single Unit ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Median Number ◽  
Cell Dose ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Grade Iii

Abstract Double UCBT (dUCBT) has been used in adults to reach an acceptable cell dose. For most children a single unit with a total nucleated cell (TNC) dose >3x107/Kg can be easily identified, but that is not always the case for heavier patients (pts). Use of dUCBT might decrease relapse and increase graft-versus-host-disease (GvHD). Data on dUCBT in children are scarce in the literature. A recent randomized study in children has described similar outcomes after double compared to single UCBT. Our study provides an overview of the use of dUCBT in the pediatric population reported to Eurocord. We retrospectively analyzed the outcomes of unrelated dUCBT in 177 children transplanted between 2002 and 2012 in 61 EBMT centres. Analysis was performed separately for pts with malignant (n=139) and non-malignant (NM, n=38) diseases. Among pts with malignancies, 76 had ALL, 40 AML, 6 MDS, 2 CML, 11 NHL, 3 Hodgkin Lymphoma and 1 Multiple Myeloma. Median age at dUCBT was 15 years (1.3-17.9) and median weight was 55 kg (13-97). Disease status at dUCBT was 1st complete remission (CR) (36%), ≥2nd CR (34%) or advanced (25%), and missing in 5% of the pts. In this group, 117pts received a myeloablative conditioning (MAC) and 22 a reduced intensity regimen (RIC). Cyclophosphamide+fludarabine+TBI was administered to 41% of the pts; 55% received ATG in the conditioning. Median number of collected TNC was 5.7x107/kg (3,6-12,8). Considering the unit with the higher number of HLA incompatibilities with the recipient, 56% had 2 mismatches. GvHD prophylaxis was cyclosporine-A (CSA) based in 93% of the pts (58% received CSA + mycofenolate mofetil). Median follow-up was 31 months. Cumulative incidence (CI) of neutrophil (PMN) and platelet (PLT) engraftment was 88% at 60 days and 64% at 180 days after dUCBT, and it was achieved with a median time of 24 and 45 days, respectively. Among the 122 pts with PMN engraftment, 85/94 with available data on chimerism were full donor and, of these, 20% had dual chimerism. CI of acute GvHD grade II-IV and grade III-IV at 100 days was 51% and 26%, respectively; it was significantly higher in pts who did not receive ATG (grade II-IV: 35% vs 67%, p=0.004; grade III-IV: 12% vs 37%, p=0.0075). Chronic GvHD was observed in 24/104 pts at risk (60% extensive; 2-year (yr) CI: 18%). The 2-yr CI of relapse was 31%. In univariate analysis, RIC, advanced stage at transplantation and a collected TNC dose lower than the median, were significantly associated with higher rates of relapse.The 2-yr CI of transplant related mortality (TRM) was 27%. Overall, 73 pts died: 35 of relapse, 15 of infections, 9 of GvHD and 14 of other causes. The 2-yr disease free survival (DFS) and overall survival (OS) were 42% and 45%, respectively. Among pts with NM disorders, 24 had bone marrow failure syndrome (BMFS) (10 Fanconi Anemia, 13 Acquired Aplastic Anemia and 1 other inherited BMFS), 2 hemoglobinopathies, 7 immune deficiencies and 5 metabolic disorders. Median age at dUCBT was 11 years (0.7-17.9) and the median weight was 40 kg (13-70). In this group, 27 pts received a RIC (40% TBI based), 10 a MAC (90% busulfan based), and 1 no conditioning regimen. ATG was administered to 82% of the pts and GvHD prophylaxis was CSA-based in 77%. The median number of collected TNC was 8.4x107/kg (1,2-11,2) and 60% of the grafts had ≥2 HLA mismatches with the recipient. Median follow-up was 39 months. Overall, 28 pts achieved PMN engraftment and 16 PLT engraftment, with a median time of 23 and 61 days, respectively. In univariate analysis, pts with BMFS compared to others had a significantly lower CI of PMN engraftment (58% vs 100%, p=0.002). Among the 10 pts who did not engraft, 3 had autologous reconstitution and 3 had a subsequent allogeneic HSCT. Forteen pts developed acute GvHD grade II-IV and 10/25 pts at risk had chronic GvHD (3 extensive). Overall 21 pts died (17 with BMFS): 9 of infections, 5 of GvHD and 7 of other causes. The 2-yr OS was 42% and it was significantly lower in pts with BMFS compared to those affected by other NM disorders (28% vs 70%, p=0.03). In pts with malignancies, despite a higher incidence of acute GvHD, DFS and OS seem to be comparable to those reported in the literature for single UCBT or HSCT from other alternative stem cell sources. In the NM disorders group, despite the high cell dose, dUCBT did not seem to improve results in pts with BMFS. This survey suggests that dUCBT is feasible in children and should be considered when a single unit with an adequate cell dose is not available. Disclosures No relevant conflicts of interest to declare.

Outpatient Haploidentical Peripheral Blood Stem-Cell Transplantation with Post-Transplant Cyclophosphamide in Children and Adolescents

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4389-4389
Author(s):  
Oscar Gonzalez-Llano ◽  
Elias Eugenio Gonzalez-Lopez ◽  
Ana Carolina Ramirez-Cazares ◽  
Edson Rene Marcos-Ramirez ◽  
Guillermo J. Ruiz-Arguelles ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
High Risk ◽  
Children And Adolescents ◽  
Hematological Malignancies ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
High Dose ◽  
Post Transplant

Abstract Patients with high-risk hematological malignancies have a poor prognosis without a hematopoietic stem cell transplant. An HLA- haploidentical donor is available in 95% of the cases, and post-transplant cyclophosphamide permits the use of T-cell replete grafts in settings were ex-vivo manipulation is not available. The experience with HLA-haploidentical HSCT with PBSC and post-tranplant Cy in the pediatric and adolescent population is limited; we report the following experience. We retrospectively collected data on 25 patients (0 to 21 years old) with hematological malignancies, who underwent ambulatory haploidentical HSCT with post-transplant Cy from November 2011 to November 2014. The different conditioning regimens are described in Table 1. All patients received high-dose Cy(50mg/kg) on days +3 and +4. Cyclosporine A (CYA; 6mg/kg/d per os) and mycophenolate mofetil (MMF; 15mg/kg two times daily per os) were started on day +5. MMF was discontinued on day +35 and tapering of cyclosporin started day +90 in the absence of GVHD. All patients received anti-microbial prophylaxis for bacteria, fungal, herpes infection and Pneumocystis jiroveci according to institutional practices. First chimerism was performed at day +30, and second chimerism at day +100. Primary graft failure was defined when neutrophil counts did not exceed 0.5 x 109/L by day +30. Acute and chronic GVHD were graded according to NIH criteria. Patient, donor and stem-cell harvest characteristics are described in Table 1. All patients had high risk hematological malignancies. There were 5 patients who underwent their first transplant on 1st CR, 4 with ALL with high risk cytogenetics and 1 with AML. All other patients were defined as high risk because they were refractory/relapsed. Twenty-three patients (92%) had neutrophil engraftment after a median 17 (7-24) days. Platelet engraftment was observed in 20 (80%) patients after a median of 14.5 (11-23) days, 3 (12%) patients did not have platelet counts below 20,000/mcL. One patient was catalogued as a primary failure for not achieving neutrophil and platelet engraftment by day +30. One patient died before engraftment at day +10 of septic shock. Four patients (16%) died before day +30. The only patient that did not have a complete chimerism, had a diagnosis of AML and 30% of donor cells by day +30, by day +45 relapse of disease was documented. After a median follow-up of 157 days, 13 patients (52%) remain alive, with an estimated 1-year OS of 52% (95%CI: 30.4 - 65.6%).Nine patients (36%) died of complications (mainly infectious) not related to relapse at a median time of 66 days (10-579 days) from stem cell infusion. Nine patients (36%) relapsed in a median time of 105 days (45-288 days); three of those patients died at days +150, +113 and + 370 from transplant. Estimated 1 year event-free survival is 40.2% (95%CI: 41.3 - 75.8%) (Figures 1 and 2). Patients transplanted on 1st CR had a median follow-up of 664 days with an OS and EFS of 80% (4 patients), which was statistically different from the rest of the population (p=0.03) (Figure 3). Among those who engrafted (n=21), 9 cases (42.9%) had grade 2-4 acute GVHD and 4 cases (19%) of grade 3-4 acute GVHD. Three patients (14.3%) developed chronic GVHD, two had mild skin or liver cGVHD. One patient had severe (NIH stage 3) skin cGVHD, she was alive and with a grade 2 cGVHD until last follow up at day +893. Outpatient procedure, HLA-haploidentical HSCT including PBSC as a stem cell source, and post-transplant T-cell in vivo depletion using high-dose cyclophosphamide is feasible in children and adolescents, with acceptable rates of response and GVHD. Table 1. Patient, donor and harvest characteristics Variable N=25 Age, median(range in years) 10 (1-21) Gender, n(%) Male Female 17 (68%) 8 (32%) Diagnosis, n(%) ALL-B ALL-T AML CML 16 (64%) 2 (8%) 5 (20%) 2 (8%) Time from diagnosis to transplant (months) 17.2 (1.9-153.5) Conditioning regimen, n(%) Cy 1500mg/m2 + Flu 75mg/m2 + Bu 9.6mg/kg (IV) Cy 1050mg/m2 + Flu 75mg/m2 + Bu 12 mg/kg (oral) Cy/VP-16/RT Cy/Flu/Mel 16 (64%) 6 (24%) 2 (8%) 1 (4%) Donor, n(%) Mother Father Sister 20 (80%) 3 (12%) 2 (8%) Donor age, median(range in years) 38 (17-49) Infused CD34+ x 106/kg, median(range) 11 (3.2-20) Disclosures No relevant conflicts of interest to declare.

Treatment with Hypomethylating Agents before Allogeneic Stem Cell Transplant Improves Survival for Patients with Chronic Myelomonocytic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4347-4347 ◽  
Author(s):  
Piyanuch Kongtim ◽  
Uday R. Popat ◽  
Antonio M. Jimenez ◽  
Sameh Gabella ◽  
Riad O. El Fakih ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Progression Free Survival ◽  
Cell Transplant ◽  
Hypomethylating Agents ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Unrelated Donors ◽  
Conditioning Regimens

Abstract Introduction Allogeneic hematopoietic stem cell transplant (allo-SCT) is the only curative treatment modality for patients with CMML. Here we retrospectively reviewed the data for patients with CMML who received an all-SCT at our institution to identify factors associated with improved survival and determine whether treatment with hypomethylating agents (HMA) before transplant improves survival for these patients. Methods All 83 patients 18 years of age or older with a diagnosis of CMML confirmed at The University of Texas MD Anderson Cancer Center who underwent allo-SCT between April 1991 and December 2013 were identified through review of the institutionÕs medical records and included in this analysis. Forty, 7, and 36 patients had CMML-1, CMML-2 and CMML that had progressed to AML (CMML/AML) respectively. The median age was 57 years. CMML specific cytogenetic risk at diagnosis (Such E, hematologica, 2011) was good, intermediate, and high risk in 46, 19, and 18 patients respectively. Seventy-eight patients received induction treatment before transplant, 37 receiving HMA (either 5-azacytidine or decitabine) for at least 3 courses and 41 receiving 1-2 courses of cytotoxic chemotherapy. Among the patients who received induction therapy, 15 patients in HMA group and 9 patients in convention chemotherapy group achieved a complete remission before transplant. Thirty, 47 and 6 patients received transplants from matched related donors (MRD), matched unrelated donors (MUD), and mismatched related or unrelated donors (MMD), respectively. The sources of hematopoietic stem cells were peripheral blood for 48 patients (57.8%) and bone marrow for 35 patients (42.2%). Conditioning regimens varied; most patients received either fludarabine in combination with busulfan or fludarabine combined with melphalan. Sixty-four patients received myeloablative and 19 patients received reduced intensity conditioning regimens. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate. Patient and transplant characteristics did not significantly differ between the patients treated with HMA and the patients treated with conventional chemotherapy or given supportive care alone. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), Treatment related mortality (TRM), relapse incidence through last follow-up and incidences of acute GVHD and chronic GVHD. All of these outcomes were measured from the time of allo-SCT. Results Median follow up duration for 29 survivors was 48 months. Seventy-five patients engrafted (90.4%) with median time to neutrophil and platelet engraftment of 13 and 15 days respectively. Patients treated with a HMA had a significantly lower cumulative incidence (CI) of relapse at 3 years post-transplant (22%) than those treated with other agents (35%; p=0.03), whereas TRM at 1 year post-transplantdid not significantly differ between the groups (27% and 30%, respectively; p=0.84). Acute GVHD all grades and grade 2-4 were seen in 28.2% versus 35.8% (p=0.05) and 12.8% versus 11.3% (p=0.72) in patients who received a HMA compared to those who treated with other agents respectively. CI of chronic GVHD was 35% in patients treated with a HMA versus 19.2% in those treated with other agents (p=0.36) while CI of chronic extensive GVHD was seen in only 26.7% versus 19.2% respectively (p=0.64). The lower relapse rate resulted in a significantly higher 3-year PFS rate in patients treated with a HMA (43%) than in those who received other treatments (27%; p=0.04) (Figure 1). However, therapy with HMA before transplant did not significantly influence the 3-year OS rate (45% in those treated with HMA and 39% in those treated with other agents; p=0.22). The independent prognostic factors for PFS were a blast count of < 5% before transplant (HR 0.36, 95%CI 0.14-0.78), treatment with a HMA (HR 0.44, 95% CI 0.23-0.86), a transplant from an MRD (HR 0.41, 95% CI 0.22-0.94), development of grade 2-4 acute GVHD (HR 2.7, 95% CI 1.27-5.77), and development of chronic GVHD (HR 0.15, 95% CI 0.05-0.45). Conclusion We conclude that treatment with hypomethylating agents before allo-SCT may improve survival in patients with CMML. Figure 1. Progression free survival Figure 1. Progression free survival Disclosures Alousi: Therakos, Inc: Research Funding. Andersson:Otsuka Research and Development, Inc.: Consultancy.

Shortened-Duration Tacrolimus after Nonmyeloablative HLA-Haploidentical (NMA haplo) BMT with High-Dose Posttransplantation Cyclophosphamide (PTCy) Facilitates Strategies for Relapse Reduction

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 831-831 ◽  
Author(s):  
Yvette L. Kasamon ◽  
Ephraim J. Fuchs ◽  
Marianna Zahurak ◽  
Gary L. Rosner ◽  
Heather J. Symons ◽  
...  
Keyword(s):  
Graft Failure ◽  
Acute Gvhd ◽  
Risk Index ◽  
Chronic Gvhd ◽  
Stopping Rules ◽  
High Dose ◽  
Stopping Criteria ◽  
Gvhd Prophylaxis ◽  
Grade 3

Abstract Background: With PTCy as GVHD prophylaxis, outcomes of NMA haplo and matched BMT are similar, and relapse rather than toxicity is the leading cause of treatment failure. Early discontinuation of IS may augment a graft-versus-tumor effect and permit early implementation of strategies to reduce relapse, but may increase GVHD. We present a completed, prospective single-center trial of stopping tacrolimus (tacro) 3 or 4 months earlier than our Day (D) 180 standard after NMA haplo BMT (ClinicalTrials.gov: NCT01342289). Methods: From 8/2011-11/2015,105 evaluable patients (pts) with hematologic malignancies received NMA haplo BMT on this trial. The primary objective was to evaluate the feasibility and safety of reduced-duration tacro, stopping tacro without taper before D 180.Transplant criteria included age ≤ 75, ECOG PS ≤ 2, LVEF ≥ 35%, FEV1 and FVC ≥ 40% predicted, transaminases < 5 x ULN and no prior allogeneic BMT. All received Cy (14.5 mg/kg IV D -6 and -5), fludarabine (D -6 to -2), TBI (200 cGy D -1) and T-cell replete bone marrow. GVHD prophylaxis consisted of high-dose PTCy (50 mg/kg IV D 3 and 4), mycophenolate mofetil (D 5-35) and tacro from D 5. Pretransplantation, pts were assigned to stop tacro early if eligible, contingent on having ≥ 5% donor T cells at ~D 56 onward, no relapse and no grade 2-4 acute or significant chronic GVHD. Tacro was first planned through D 90 (n=47), then through D 60 (n=55). A D 120 cohort (n=3) enrolled while D 90 safety data were maturing. For pts ineligible for planned early tacro cessation, IS was individualized and continued to at least D 180. Monitoring rules declared reduced IS feasible if ≥ 33% of pts stopped tacro early as planned. Safety stopping rules for early tacro cessation were based on ≥ 65% probability of a ≥ 20% incidence of grade 3-4 acute plus severe chronic GVHD, ≥ 10% nonrelapse mortality (NRM) or ≥ 5% graft failure, measured from the tacro stop date to ~D 180. Historical data from 212 haplo transplants at our center using the same regimen but tacro until D 180 informed safety risk calculations. Results: Of the 105 pts (median age 61, range 13-74), the most common diagnoses were acute leukemia (50%), MDS (17%), NHL (16%) and HL (8%). By refined Disease Risk Index, 11% were low risk, 70% intermediate and 19% high. Shortened IS was feasible in 63 pts (60%) overall. Ineligibility for shortened IS was due most commonly to GVHD, followed by low donor chimerism or graft failure and early relapse. Of the 47 pts in the D 90 cohort (median follow-up 44 months), 23 (49%) stopped tacro early as planned. Safety stopping criteria were not met. Of these 23 pts, 16 (70%) had no safety events before D 180, 5 (22%) developed grade 2 acute GVHD (1 complicated by severe chronic GVHD) and 2 (9%) developed grade 3-4 acute GVHD. Of the 55 pts in the D 60 cohort (median follow-up 14 months), 38 (69%) stopped tacro early as planned, and safety stopping criteria were likewise not met. Of these 38 pts, 25 (66%) had no safety events before D 180, 1 developed graft failure, 9 (24%) developed grade 2 acute GVHD and 3 (8%) developed grade 3-4 acute GVHD. GVHD outcomes by cohort relative to historical outcomes are shown in Figures A and B. In both cohorts, the D 180 CuI of grade 2-4 acute GVHD was < 40% and was < 10% for grade 3-4 acute GVHD and NRM. The 1-year CuI of any chronic GVHD was 11% for the D 90 arm and 13% for the D 60 arm (12% historically). The 1-year probabilities of PFS, OS and GVHD-free relapse-free survival (GRFS, Figure C) were 40%, 59% and 27% respectively for the D 90 arm and 63%, 77% and 53% respectively for the D 60 arm. Conclusion: These data suggest that reduced-duration tacro is feasible and carries an acceptable safety profile in pts receiving NMA haplo BMT with PTCy. Risks of acute GVHD, chronic GVHD, graft failure and NRM appear similar to historical outcomes with tacro until D 180. A larger prospective study is needed to define the optimal duration of IS that balances GVHD risk and relapse risk. However, these data show that many pts (60% in this trial) can discontinue tacro without taper well before D 180. There is even a suggestion of improved PFS and GRFS in the D 60 arm compared to the D 90 arm, although the trial was not powered for these endpoints. The favorable toxicity profile of the PTCy platform, coupled with the feasibility and safety of early tacro cessation, provides an ideal setting to incorporate novel posttransplantation approaches for relapse reduction. Disclosures No relevant conflicts of interest to declare.

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