Successful Engraftment Using Varied Stem Cell Sources, Low Toxicity, and Long-Term Survival Using a Bu/Flu/ATG Reduced Intensity Allogeneic Transplantation in High Risk Pediatric Patients Ineligible for Myelablative Therapy: Results of the Pediatric Blood and Marrow Transplant Consortium (PBMTC) Study ONC0313.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 623-623
Author(s):  
Michael A. Pulsipher ◽  
Haydar Frangoul ◽  
Michel Duval ◽  
Rakesh Goyal ◽  
Peter J. Shaw ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Chronic Gvhd ◽  
Allogeneic Transplantation ◽  
High Rate ◽  
Unrelated Donor ◽  
Group Setting ◽  
Term Survival ◽  
Cell Sources ◽  
Reduced Intensity

Abstract The role of reduced intensity conditioning (RIC) regimens in pediatric pts is unclear. To define the feasibility and toxicity of a bu/flu/ATG approach in pediatric pts ineligible for myeloablative transplant, we completed a trial at 25 North American and Australian institutions participating in the PBMTC. Forty six pediatric pts (age 2–20yrs, med 11) were enrolled with the following stem cell sources: 8 related donor (RD) BM (2 mismatched); 8 RD-PBSC; 10 unrelated donor (UD) BM; 8 UD-PBSC; 12 UD-CB. Qualifying indications included a previous allogeneic (n=22) or autologous (n=7) transplant, severe organ toxicity (n=8), invasive fungal infection (n=3), and other comorbidities (n= 6 pts, 4 with Down syndrome). Diagnoses included ALL (4 CR2; 11 CR3, 1 secondary), AML (7 CR2; 3 CR3; 3 secondary, 2 PR2+), MLL (1 CR3), CML (1 CR3), HD (3 CR3, 1 PR3), B-NHL (1 PR3), MDS (1 RA; 6 secondary), and JMML (1 PR2, 1 PR3). Patients received busulfan 0.8mg/kg/dose IV x 8 doses (target AUC 900–1100 uM/min), fludarabine 30mg/m2/d x 6 days, and thymoglobulin, 2.5 mg/m2/d x 1 day for RD and x 4 days for UD and UCB. GVHD prophylaxis consisted of cyclosporine (CSP) and mycophenylate mofetil (MMF, 15mg/kg bid). MMF was stopped at day +30 for RD and CB recipients and tapered between d +40–100 for UD recipients. CSP was tapered between d+42–100 for RD and d+100–180 for UD and UCB. Four pts rejected their grafts (9%), one after mismatched RD-BM, two after UD-BM and one after UCB. Two pts died prior to day 100 due to toxicity (4%) and the overall NRM was 11%. Acute GVHD occurred in 9/33 evaluable patients (grade I 9%, grade II 18%, no grade III-IV) and chronic GVHD occurred in 7/28 (25%) evaluable pts. Median follow up is 17 months (range 1–45 m). Two year EFS (events: rejection, relapse, death in remission) is 38% (SE 8) and 2yr OS is 51% (SE 9). No difference in outcome was noted based upon stem cell source, history of previous BMT vs. none, or ALL vs. myeloid disease vs. lymphoma. A trend toward improved survival was noted in “intermediate risk” patients (ALL CR2, AML CR2, and primary MDS without h/o previous BMT: 2yr OS 67 vs. 31%, intermediate vs. high risk, p=0.1). Patients who had undergone transplantation trended toward better survival when their previous myeloablative regimen did not contain TBI (2yr OS 82 vs. 31%, non-TBI vs. TBI, p=0.09). In conclusion, RIC using bu/flu/ATG in a cooperative group setting leads to engraftment in >90% of high risk pediatric pts using related or unrelated BM or PBSC, or unrelated CB. In spite of significant prior therapy, high risk disease, and a high rate of comorbidities in this cohort, the risk of NRM or GVHD is low. Prolonged survival has occurred not only in pts with myeloid disease (2yr OS 43% (SE 12)), but also in pts with ALL (2yr OS 49% (SE 15)), and lymphoma (2yr OS 50% (SE 35)). Flu/bu/ATG is a promising approach for pediatric pts ineligible for myeloablative transplant.

Durable Remission after Prophylactic Donor Lymphocyte Transfusion Following Allogeneic Stem Cell Transplantation with Reduced Conditioning for High-Risk AML and MDS.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 299-299
Author(s):  
Michael Schleuning ◽  
Christoph Schmid ◽  
Georg Ledderose ◽  
Johanna Tischer ◽  
Meike Humann ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Allogeneic Transplantation ◽  
Chronic Infections ◽  
Term Survival

Abstract Prophylactic transfusion of donor lymphocytes (pDLT) is an attractive form of maintenance therapy after allogeneic stem cell transplantation in patients with high risk of relapse. However, clinical experience is limited, and disease response is often achieved at the expense of severe graft-versus-host disease (GvHD). We here report our data on pDLT in high-risk AML and MDS. Cells were given within a prospective protocol that contained a sequence of chemotherapy, reduced intensity conditioning for allogeneic transplantation, and pDLT (FLAMSA-regimen). For pDLT, patients had to be in CR at least 120 days from transplantation, off immunosuppression for 30 days, and free of GvHD. 22/86 patients alive at day +120 fulfilled the criteria for pDLT. They had been transplanted for refractory or relapsed leukemia (n=9 each) or in CR1 because of unfavorable cytogenetics (n=4). 14 patients had an unfavorable karyotype, 8 with complex aberrations. Reasons for withholding pDLT in 64 patients included cGvHD or prolonged immunosuppression (n=38), refractory or relapsed leukemia (n=15), refusal of patient or donor (n=4 each), a history of grade IV acute GvHD (n=2), and chronic infections (n=3). The median time from transplant to first pDLT was 167 days (range 120–297). Median follow up of transfused patients is 696 days (range 209–1341). Ten patients received 1, 6 patients received 2, and 6 patients received 3 transfusions in escalating doses, containing a median of 1x106, 5x106 and 1x107 CD3+ cells/kg at pDLT 1, 2 and 3, respectively. Reasons for giving less than 3 transfusions were GvHD, relapse or refusal of the patient. Induction of GvHD was the main complication; grade III acute GvHD developed in 1, and chronic GvHD in 7 patients. So far, 5 patients have relapsed despite pDLT. One died of refractory leukemia, whereas 2 achieved secondary CR following adoptive immunotherapy. Two patients are currently under treatment. At present, 18/22 patients are alive and in CR at a median of 423 days post DLT. The current leukemia free survival at two years from first pDLT is 79%. Nineteen patients were complete chimeras at time of pDLT. pDLT converted mixed into complete bone marrow chimerism in 1, but failed in 2 cases. In our experience, pDLT is safe after allogeneic transplantation for high risk AML, when given at low doses and to a selected group of patients. Results are encouraging, and long term survival can be achieved. However, further studies need to define more precisely the contribution of pDLT to the therapeutic effect of the entire procedure.

Favorable Long-Term Survival After Reduced-Intensity Allogeneic Transplantation for Multiple-Relapse Aggressive Non-Hodgkin's Lymphoma

2009 ◽  
Vol 27 (3) ◽  
pp. 426-432 ◽  
Author(s):  
Kirsty J. Thomson ◽  
Emma C. Morris ◽  
Adrian Bloor ◽  
Gordon Cook ◽  
Don Milligan ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Chronic Gvhd ◽  
Autologous Transplantation ◽  
B Cell Lymphoma ◽  
Allogeneic Transplantation ◽  
Published Data ◽  
Term Survival ◽  
Experienced Treatment ◽  
Reduced Intensity

Purpose The role of allogeneic transplantation with reduced-intensity conditioning in diffuse large B-cell lymphoma (DLBCL) is currently unclear, with relatively little published data. We report the outcome of reduced-intensity transplantation (RIT) in a cohort of 48 consecutive patients with relapsed/refractory DLBCL (30 patients with de novo disease and 18 patients with transformed follicular lymphoma) who underwent transplantation with an alemtuzumab-containing regimen, with a median follow-up of 52 months. Patients and Methods Patients had experienced treatment failure with a median of five lines of prior therapy, including autologous transplantation in 69%, and 17% of patients were chemotherapy refractory at transplantation. Median age was 46 years, and 38% of patients had matched/mismatched unrelated donors. Conditioning was with alemtuzumab, fludarabine, and melphalan, and additional graft-versus-host disease (GVHD) prophylaxis was with cyclosporine. Results All patients were successfully engrafted. Only 17% of patients developed grade 2 to 4 acute GVHD, with 13% experiencing extensive chronic GVHD. Four-year estimated nonrelapse mortality was 32%, and relapse risk was 33%. Twelve patients received donor lymphocyte infusions ± chemoimmunotherapy for relapse, and five patients obtained durable remissions, giving current progression-free survival (PFS) and overall survival (OS) rates at 4 years of 48% and 47%, respectively. Patients who had chemotherapy-sensitive disease before RIT had current PFS and OS rates at 4 years of 55% and 54%, respectively. Chemotherapy-refractory patients had a poor outcome. Conclusion The encouraging survival rates with extended follow-up suggest a role for RIT in chemotherapy-sensitive relapsed DLBCL, even in patients who have previously experienced treatment failure with autologous transplantation. Future studies will be required to determine whether any subset of patients with relapsed DLBCL should be considered for RIT versus autologous transplantation.

Efficacy of Reduced Intensity Conditioning (RIC) with FLU-BU-ATG and Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Pediatric ALL.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2314-2314 ◽  
Author(s):  
Reggie Duerst ◽  
David Jacobsohn ◽  
William T. Tse ◽  
Morris Kletzel
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Chronic Gvhd ◽  
High Dose ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Pediatric All ◽  
Very High ◽  
Reduced Intensity

Abstract Reduced Intensity Conditioning (RIC) regimens prior to allogeneic HSCT have gained acceptance in the treatment of adults with myelodysplasia, leukemia and multiple myeloma. RIC reduces the risk for regimen related morbidity and mortality enabling patients with pre-existing medical conditions that would have been precluded from allogeneic HSCT to attempt a curative approach. The resilience of pediatric patients (pts) following high-dose conditioning regimens and the concern that ALL cells are inherently more resistant to a graft-vs-leukemia effect have limited accrual of pediatric ALL pts to RIC protocols despite the potential benefit for reduced long-term morbidity. We report the experience of 10 pediatric ALL pts (6 M, 4 F, median age 9.5 years) treated for recurrent ALL with RIC and allogeneic HSCT. A uniform RIC regimen comprised of fludarabine, 30 mg/m2 for 6 consecutive days (days −10 through −5), followed by intravenous busulfan, 0.8 – 1 mg/kg for 8 doses or targeted AUC 4000 μMol*min for 2 doses (days −5 and −4) and equine ATG, 40 mg/kg or rabbit ATG, 2 mg/kg for 4 days (days −4 through −1) was administered. Pts with prior CNS involvement received whole brain (2400 cGy) and spinal (1800 cGy) irradiation immediately prior to the RIC. Stem cell sources included 7 unrelated donors and 3 matched sibs. 9 of 10 stem cell donations were peripheral blood stem cells (PBSC). The median cell doses infused were 6.5 x 108 MNC/kg and 4.2 x 106 CD34+ cells/kg. Graft-versus-host disease (GVHD) prophylaxis was cyclosporin A (CsA) alone in 5 patients, CsA and mycophenolate mofetil in 5 pts. Growth factor support was not used. Each of the pts had at least two very high-risk features--prior HSCT (n = 6), CR > 3/refractory disease (8), prior CNS disease (6), Ph+ (2), pre-exisiting neurologic (1) or cardiac (1) dysfunction or aspergillous infection (1). Full donor chimerism was achieved in 9 of 10 with a median time to reach an ANC >500/μl of 16 days (range 11–62) and an unsupported platelet count > 20,000/μl was achieved in 8 of 10 at a median of 25 days (15–67). 2 pts developed Gr IV acute GVHD, 2 of 5 pts surviving more than 100 days developed chronic GVHD. Only 3 patients have relapsed: 1 refractory T-ALL pt recurred day +27 and 2 Ph+ pts had a molecular relapse day +61 and +196. The latter pt is in subsequent continuous molecular remission for over 1 year on imatinib therapy. 6 pts have died, 5 in the first 100 days of HSCT from complications of GVHD (2), relapse (1), pulmonary failure (in 1 pt S/p 3 prior allogeneic HSCT) and PTLD (1). 1 pt succumbed from complications of chronic GVHD day +756. The RIC regimen and supportive care are primarily an outpatient experience. During the first 30 days post HSCT, pts spent an average of only 9 days in hospital (23 of the first 100 days). Despite very high-risk features, 4 of 10 pts survive (3 CCR) at a median of 500 days post HSCT. Thus, RIC and allogeneic HSCT also offers promise for efficacy in pediatric ALL.

Fludarabine Is Superior to Cladribine When Added to Busulfan and Low Dose TBI as Reduced Intensity Conditioning for Allogeneic Hematopoietic Cell Transplantation (HCT): A Prospective Randomized Trial.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1825-1825
Author(s):  
M. Markova ◽  
Juliet N. Barker ◽  
John E. Wagner ◽  
Jeffrey S. Miller ◽  
Mukta Arora ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Cell Transplantation ◽  
Cumulative Incidence ◽  
Unrelated Donor ◽  
Reduced Intensity Conditioning ◽  
Purine Analogues ◽  
Hematopoietic Stem ◽  
Platelet Recovery ◽  
Reduced Intensity

Abstract Purine analogues have been combined with alkylator/irradiation as immunosuppressive and anti-tumor conditioning prior to allogeneic hematopoietic stem cell transplantation (HCT) though differing purine analogues have not been compared. We prospectively tested Fludarabine (F) 40 mg/m2/d x 5d vs. Cladribine (C) 10 mg/m2/d x 5d plus Busulfan (Bu) (2mg/kg q12h x 2d) and total body irradiation (T) 200cGy followed by cyclosporine and mycophenylate mofetil in 19 recipients of matched sibling peripheral blood stem cell and 13 unrelated donor (URD) marrow HCT. Patients in each randomly assigned cohort [FBuT vs. CbuT] were similar in age (median 52 years in both groups), diagnosis (leukemia/MDS 38 vs. 31%; lymphoid malignancy 57 vs 69%), extensive pre-HCT therapy (56 vs. 63%), high risk disease status (81 vs. 93%) and Karnofsky (median 90 in each)[all p= NS] though fewer FBuT were URD recipients 25% vs. CBuT 56%, p=0.07. Engraftment was prompt in both groups (median 11 vs. 12 days), but the cumulative incidence of neutrophil engraftment was 75% (95% C.I. 54–96%) using CBuT vs. 100% with FBuT (p<0.01) and randomization was halted. Platelet recovery was prompt (median FBuT 18 vs CBuT 24 days) and after FBuT 75% (95% C.I. 49–100) vs. CBuT 69% (43–95) recovered platelets > 50,000/μL by day +180, p=0.19. The cumulative incidence of GVHD after FBuT vs. CbuT was similar (acute grade II/IV 56 vs. 69%, p=0.26) and (chronic 50 vs. 31%, p=0.27). Transplant related mortality at day +180 was also similar [FBuT 25% (4–46) vs. CbuT 38% (14–61), p=0.47]. Survival was equivalent: at 1 year 50% in each group; at 3 years FBuT 25% vs. CBuT 38%, p=0.55. Multivariate analyses adjusted for age, donor type, diagnosis and stage as well as conditioning regimen showed lower relative risk (RR) of engraftment with CBuT (RR 0.6 (95% C.I. 0.2–1.3) p=0.16) and with URD RR 0.4 (0.2–1.0) p=0.04). RR of Platelet recovery was equivalent with FBuT (RR 0.7 (0.3–1.7) p=0.45) but inferior with URD (RR .16 (.05–.5) p<0.01). RR of GHVD II/IV similar with FBuT RR 1.1, p=0.95, but more frequent with URD RR 2.0, p=.2 and high risk status patients (RR 4.5, 1.5–13.5, =<0.01). Prevalence of remission (CR or PR) at 18 months was high and was similar in both groups (FBuT 100% vs CBuT 86%, p=NS). These data suggest that older patients with advanced hematologic malignancies can achieve satisfactory post-transplant outcomes using either of these combination/reduced intensity conditioning regimens. Fludarabine may be superior to cladribine as a component of pre-HCT conditioning with Bu/TBI due to reduced risks of graft failure. Further modifications of the regimen may confirm universal engraftment with even lower peri-transplant morbidity.

Cytomegalovirus Reactivation and Relapse Following Allogeneic Stem Cell Transplantation Using a Reduced Intensity Conditioning Regimen.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5104-5104
Author(s):  
Revati Rao ◽  
Kevin Chin ◽  
Geoff Chan ◽  
Kellie Sprague ◽  
Andreas Klein ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Antiviral Therapy ◽  
Allogeneic Stem Cell Transplantation ◽  
Chronic Gvhd ◽  
Attributable Mortality ◽  
Reduced Intensity Conditioning ◽  
Cmv Reactivation ◽  
Reduced Intensity

Abstract Background: Recent studies have reported CMV reactivation rates of 42% to 65% in patients treated with allogeneic stem cell transplantation using reduced intensity conditioning regimens (RIT). However, published data on RIT patients who experience CMV reactivation, are treated successfully with antiviral therapy to eliminate detection, and who subsequently develop CMV relapse, is sparse. Methods: We performed a retrospective cohort analysis of 106 patients who underwent RIT at Tufts-New England Medical Center using a preparative regimen of pentostatin, extracorporeal photophoresis, and reduced total body irradiation, from 1997–2003. All patients received identical graft-versus-host disease (GVHD) prophylaxis, which consisted of IV cyclosporine and PO methotrexate. CMV serostatus was determined on all patients prior to transplant. All patients were screened weekly by CMV antigen capture assay after day +14. Patients did not receive CMV prophylaxis. CMV reactivation was defined as 2 consecutive positive (>2.1 pg/mL) CMV DNA measurements. CMV reactivation was treated with either Ganciclovir 5mg/kg IV daily or Valganciclovir 450mg PO BID until whole blood CMV DNA levels were no longer detectable. Patients were treated with antiviral therapy until a documented negative CMV DNA assay. Those found to have detectable CMV DNA after adequate therapy were then defined as having CMV relapse. Patients were also assessed for incidence of GVHD and mortality. Attributable mortality was defined as mortality in patients who had CMV relapse compared to those who had CMV reactivation without relapse. Fisher’s exact test was used to compare proportions, Kruskal-Wallis was used to compare means, and survival and time to reactivation and relapse were analyzed by Kaplan-Meier Results: Of 106 patients, 49 (46.2%) were CMV seropositive prior to transplant. Twenty -five (51%) of forty-nine CMV positive patients developed CMV reactivation at a median of 43 days (range 26 – 312 days) after receiving stem cells. Among patients with CMV reactivation, 36 were MRD and 13 were MUD. Nine (36%) of 25 patients with CMV reactivation developed CMV relapse. CMV relapse occurred at a median of 16 days (range 4 – 77 days) after CMV reactivation. CMV reactivation occurred earlier among those who relapsed (median 34 days, range 26 – 70 days) compared to those who did not relapse (median 55.5 days, 27 – 312 days, p=.03). Peak viral load was significantly higher in CMV relapsers (median 55.3 pg/mL, range 14.5 to 486.8) compared to non–relapse patients (median 4.4 pg/mL, range 2.1 – 58.2, p=. 0007). There was no difference in acute GVHD in the groups (100% vs. 75%, p=.26). However, those who did relapse had a higher incidence of chronic GVHD than those who did not (89% vs. 38%, p=.03). There was no difference in median survival between non-relapse and relapse patients (13 months vs. 16 months, p=. 99). The attributable mortality rate due to CMV relapse was 23%. Conclusions: Our results suggest there is a subgroup of patients who are at high risk for CMV relapse in the post RIT setting. Risks for CMV relapse include early reactivation and higher peak CMV viral loads. In addition, there was a higher risk of chronic GVHD in CMV relapse patients. We have identified a high- risk subset of patients who reactivate CMV for whom additional therapeutic strategies may be warranted.

Allogeneic Stem Cell Transplantation Using a Reduced Intensity Conditioning (RIC) Regimen Has the Capacity To Produce Durable Remissions and Long Term Disease-Free Survival in Patients with High Risk Acute Myeloid Leukemia (AML).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1141-1141
Author(s):  
S. Tauro ◽  
S. Mackinnon ◽  
K. Peggs ◽  
G. Begum ◽  
P. Mahendra ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Disease Free Survival ◽  
Allogeneic Transplantation ◽  
Disease Relapse ◽  
Reduced Intensity Conditioning ◽  
Free Survival ◽  
Disease Free ◽  
Reduced Intensity

Abstract The toxicity of allogeneic stem cell transplantation (SCT) can be substantially reduced by the use of a reduced intensity conditioning (RIC) regimen and this has increased the proportion of patients with myeloid malignancies eligible for allogeneic transplantation. However, the capacity of RIC allografts to produce durable remissions in patients with AML and MDS has not yet been defined and consequently their role in the management of these diseases remains conjectural. Seventy-six patients with high risk AML or MDS were allografted using a fludarabine/melphalan RIC regimen incorporating alemtuzumab. The median age of the cohort was 52 years (range 18–71 years). There were 46 males and 30 females; 41 patients received an allograft from an unrelated donor and 35 from a matched sibling donor. The 100 day transplant related mortality was 9% and no patient developed greater than Grade 2 graft-versus-host disease (GVHD). With a median follow-up of 36 months (range 13–70 months) 27 patients were alive and in remission with a 3y actuarial overall survival (OS) and disease-free survival (DFS) rate of 41% and 37% respectively. The 3y OS and DFS of patients with AML in complete remission (CR) at the time of transplantation was 48% and 42% respectively. In a multivariate setting, Cox regression analysis demonstrated prognostic significance of disease stage at the time of transplant with improved DFS in patients with AML in CR at the time of transplantation (HR=2.03, 95% CI=1.02–4.07). Disease relapse was the commonest cause of treatment failure occurring at a median time of 6 months post-transplant. Fourteen out of 27 (52%) patients relapsed within 6 months and 23/27 (85%) within twelve months defining a relatively narrow window for therapeutic intervention to prevent disease recurrence. The extended follow-up in this series identifies a high risk of early disease relapse but provides evidence that RIC allografts are capable of producing sustained disease free survival in a significant number of patients with AML who would be ineligible for allogeneic transplantation using a myeloablative conditioning regimen.

Fludarabine, Amsacrine, High-Dose Cytarabine and Total Body Irridation Followed by Allogeneic Stem Cell Transplantation for the Treatment of High Risk or Relapsed Acute Lymphoblastic Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5086-5086
Author(s):  
Fabian Zohren ◽  
Thorsten Graef ◽  
Ingmar Bruns ◽  
Akos Czibere ◽  
Fenk Roland ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Chronic Gvhd ◽  
Good Condition ◽  
White Blood Count ◽  
High Dose ◽  
Unrelated Donor ◽  
Grade Iii

Abstract In this prospective study we examined the use of an intensified conditioning regimen followed by allogeneic blood-stem-cell transplantation (BSCT) for the treatment of young adults in physically good condition with relapsed or high risk acute lymphoblastic leukaemia (ALL). Eleven patients with ALL received FLAMSA chemotherapy (fludarabine 30mg/m2 - cytarabine 2000mg/m2 -amsacrine 100 mg/m2 on day −10, − 9, − 8and −7), Anti-Thymocyte-Globulin (ATG 20 mg/kg BW on day −6, −5 and −4) and fractionated TBI (2 x 2 Gy on day −3, − 2 and −1) followed by matched unrelated donor (n=10) or matched sibling donor (n=1) SCT. The principle reasons for high risk stratification were refractory disease during first-line induction therapy (6, 55%), relapse (2, 18%), extramedullary disease manifestation (1, 9%), ALL subtype (6, 55%), unfavorable cytogenetics (5, 45%) and white blood count >30000 μL at time of diagnosis (3, 27%). After a median follow-up time of 604 days (range 202 – 1042 days) 8 patients (73%) are alive and 3 patients (27%) died. The median overall survival was not reached. Two patients died after relapse on days +121 and +449, another patient died from treatment related complications (HUS-TTP) on day +87. One patient relapsed on day +200 and is currently alive, the remaining 7 patients are alive and free of desease. Treatment related toxicities were acceptable. With 6 out of 11 patients developing grade III/IV infections during neutropenia, infectious complications remained of major importance. Other non-haematological side effects seen within this group of patients were less frequent and almost exclusively limited to gastrointestinal toxicities. Five patients (45%) had grade III/IV mucositis and 5 patients (45%) had grade III/IV nausea, while 4 patients (36%) showed grade III/IV diarrhoea. There was no case of acute toxicity related to the cardiavascular or central nervous system. The incidence of acute GvHD (aGvHD) was 36% (n = 4) and limited to grades II-III. Eight patients were evaluable for chronic GvHD (cGvHD). Out of those 4 patients (36%) developed cGvHD (3 limited disease, 1 extensive disease). We conclude that allogeneic transplatation after the FLAMSA-ATG-TBI regimen is feasible and provides effective therapy for this group of high-risk patients.

High Rates of Early Donor Chimerism and Low Risk of Chronic GVHD Can Be Achieved in Poor Risk Patients Undergoing Unrelated Donor Stem Cell Transplantation Using a Reduced Intensity Conditioning Regimen Incorporating Fludarabine, Busulfan, and Rabbit ATG.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5080-5080
Author(s):  
Mehdi Hamadani ◽  
Patrick Elder ◽  
Farrukh Awan ◽  
David Krugh ◽  
William Blum ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Reduced Intensity Conditioning ◽  
Post Transplant ◽  
Ebv Reactivation ◽  
Risk Patients ◽  
Reduced Intensity

Abstract Reduced intensity conditioning (RIC) regimens are increasingly used for allogeneic stem cell transplantation (allo-SCT) in patient groups with relative contraindications for transplantation since they promote effective engraftment of donor cells with minimal regimen related toxicity. However, following unrelated donor (URD) transplantation, high rates of acute and extensive chronic GVHD have mitigated the overall benefits of this approach. We pursued a strategy designed to enhance early full donor hematopoietic chimerism while potentially reducing the risk of severe acute and extensive chronic GVHD using an RIC regimen containing fludarabine (F), busulfan (B), rabbit antithymocyte globulin (A) (FBA) followed by URD SCT in 30 consecutive high risk patients (pts). Criteria for selection included advanced age (>55yrs), prior autograft, and/or high co-morbidity index (median 2, range 0–4). There were 24 male and 6 female pts with a median age of 53 years (range 22–66yrs). Diagnoses included AML (N=10), NHL (N=7), Hodgkin’s lymphoma (N=6), advanced CML (N=4), and advanced CLL (N=4). Nine pts had previously undergone autologous SCT. 43% had a Karnofsky performance status of 70 or 80% at the time of transplant. 80% were matched with their donor at HLA-A, B, C, and DRB1 by high-resolution DNA typing, while 3 were mismatched at 1 antigen and 3 mismatched at 1 or 2 alleles. All pts were conditioned with F (30 mg/m2/day, days −7 to −3), B (0.8 mg/kg/dose IV x 8 doses) and A (2.5 mg/kg/day, days −4 to −2) followed by micro-dose methotrexate and tacrolimus. Stem cell source included peripheral blood (n=26) or bone marrow (n=4). All pts engrafted neutrophils and platelets promptly (median 15 and 16 days, respectively). There were no primary graft failures. Rates of grade II-IV and III-IV acute GVHD were 43% (n=13) and 23% (n=7) respectively. Nine pts (30%) developed chronic GVHD but extensive chronic GVHD was seen in only 10% (n=3). Day 100 TRM was 10% (n=3). Causes of death included disease progression=2, post-transplant lymphoproliferative disorder (PTLD) =1 and sepsis=1. CMV and EBV reactivation occurred in 30% (n=9) and 20% (n=6) respectively. 2 pts developed PTLD requiring rituximab. Three pts had BK-virus associated hemorrhagic cystitis. Lineage-specific chimerism analysis showed 100% donor CD33+ at all time points (days 30, 60, 100) and median donor CD3+ chimerism of 94% at day +30 and 100% at day +100. One patient had secondary graft failure. 23 pts (76%) were in CR after SCT. The median follow-up of surviving patients is 6 months (range 1–32 months). Kaplan-Meier estimates of overall survival (OS) and progression free survival (PFS) at 1year are 62% and 43% respectively. Using the Log-Rank test, OS (P=0.95) and PFS (P=0.65) was not statistically significant between recipients of matched and mismatched grafts. In conclusion, this approach using FBA and a tacrolimus based GVHD prophylaxis achieved rapid donor chimerism and a favorably low incidence of TRM, acute, and chronic GVHD despite being tested in a poor risk group of pts. Although rates of infectious complications were within expected ranges, the rate of both EBV reactivation and disease relapse warrant further exploration of this approach using lower doses of ATG (e.g. 5–6mg/kg total dose) combined with post transplant immunomodulation.

Mismatch at 1-2 HLA Loci Does Not Reduce Survival Following Alemtuzumab-Based Reduced Intensity Unrelated Donor Allogeneic Transplantation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3008-3008
Author(s):  
Adam J Mead ◽  
Kirsty J Thomson ◽  
Emma C Morris ◽  
Ronjon Chakraverty ◽  
David C. Linch ◽  
...  
Keyword(s):  
Stem Cell ◽  
Molecular Typing ◽  
Graft Failure ◽  
Chronic Gvhd ◽  
Significant Trend ◽  
Hla Typing ◽  
Mixed Chimerism ◽  
Unrelated Donor ◽  
Significant Difference ◽  
Reduced Intensity

Abstract Most candidates for reduced-intensity allogeneic stem cell transplantation (RIC) do not have a human leukocyte antigen (HLA)-matched sibling donor available. Improved HLA-typing techniques allow more stringent matching of unrelated donors (UD), but have reduced the likelihood of identifying a fully matched UD (MUD), defined as a 10/10 locus match by molecular typing. Whilst donors matching at 8–9/10 HLA loci (MMUD) are considered appropriate by some groups, it is unclear the degree to which HLA-mismatch increases procedural toxicity and how this is influenced by different regimens. Availability of alternative stem cell sources such as umbilical cord blood makes it important to clearly define such risks. We therefore analyzed outcomes of 99 consecutive patients who underwent RIC using an UD in our institution from October 1998 to July 2008. Donor selection was performed according to standard criteria, including molecular typing for HLA-A, -B, -C, DRB1 and DQB1. Donors were 10/10 HLA-matched (n=62) or mismatched at up to 2 HLA loci (n=37). Conditioning was 20mg/d alemtuzumab for 5 days, fludarabine 30mg/m2 for 5 days and melphalan 140mg/m2 for 1 day, with cyclosporine from day -1. Peripheral blood stem cells were used in 51 (30 MUD, 21 MMUD) and bone marrow in 48 (32 MUD, 16 MMUD). Median age was 47 years (13– 67), and underlying disease was AML (n=9), myeloma (n=13), Hodgkin (n=18) or non- Hodgkin lymphoma (n=40), and others (n=19). Patients had a median of 4 previous lines of treatment (0–9) and 49 had failed a prior autograft. There were no significant differences between the groups in terms of age, sex, prior autograft, number of treatment lines, or chemosensitivity at transplantation. There were significantly more CMV seropositive recipients in the MMUD group (P.002). Neutrophil recovery (&gt;0.5 × 109/l) occurred at a median of 12 days (9–57) and did not differ between MUD and MMUD (median 11 vs 12 days). Two patients, both MUDs, had primary graft failure and engrafted following CD34 top-up. Three patients rejected the graft, all MMUDs (P.07 for MUD vs MMUD). Secondary graft failure occurred in 3 cases, all MMUDs (P.07 for MUD vs MMUD). All 3 received CD34 top-up with subsequent improvement in counts in one, another died shortly after infusion of cells and 1 remains cytopenic 4 years following the transplant. Of 40 at risk cases, CMV reactivation requiring treatment occurred in 35 (88%; 85% MUD and 90% MMUD). Donor lymphocyte infusions (DLI) were administered in 35 cases, 23 for disease relapse and 12 for mixed chimerism alone, with no significant difference between MUD (n=25, 40%) and MMUD (n=10, 27%, P.4). There was no difference in the incidence of grade 2–4 acute graft-versus-host disease (aGvHD) between MUD (27%) and MMUD (30%, P.7). Prior to DLI, only 3 cases of grade 3 aGvHD occurred (2 MUD and 1 MMUD) and no grade 4 aGvHD. Chronic GvHD (cGvHD) at 1 year occurred in 30%, with a non-significant trend for a lower incidence in MUD versus MMUD patients (24% vs 40%, P.1). Extensive cGvHD at 1 year was 15% (MUD 13% and MMUD 18%, P.6) excluding post-DLI GvHD, and was 26% at 1 year (MUD 26% and MMUD 27%, P.4) and 40% at 3 years (MUD 34% and MMUD 46%) including post-DLI GvHD. With a median follow-up of 3.0 years, transplant related mortality (TRM) for the whole cohort was 14% at 100 days and 28% at 1 year, with no significant difference between MUD (13% and 30%) and MMUD (16% and 27%). Overall survival (OS) at 3 years was 46% for the whole cohort (45% for MUD, 48% for MMUD). The outcome of 1 (n=20) versus 2 (n=17) locus mismatched transplants was also compared. There was a non-significant trend to increased grade 2–4 aGvHD (16% versus 39%, P.2) in the 2 locus MMUD group but extensive cGvHD (including post-DLI GvHD) at 1 year was not different (30% vs 24%, P.6). Survival was not inferior in the 2 locus MMUD group relative to the single mismatches, with 100 day TRM (20% 1 locus vs 13% 2 locus, P.5), 1-year TRM (43% 1 locus vs 19% 2 locus, P.5), and 3 year OS (32% 1 locus vs 63% 2 locus, P.3). We conclude that 8–9/10 MMUD-RIC is a viable option using T-cell depletion with 100mg alemtuzumab in vivo, without a significant adverse impact on TRM or OS compared with 10/10 MUD. The long-term OS of 48% following MMUD-RIC is encouraging given the inclusion mainly of patients with multiply relapsed/refractory hematological malignancy.

Busulfan Dosing May Affect Survival Following Reduced Intensity Stem Cell Transplantation in Patients with Acute Myelogeneous Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4328-4328
Author(s):  
Karen K Ballen ◽  
Steven L McAfee ◽  
Bimalangshu R Dey ◽  
Christine Dube ◽  
Eyal C Attar ◽  
...  
Keyword(s):  
Stem Cell ◽  
Complete Remission ◽  
Total Dose ◽  
Conditioning Regimen ◽  
Allogeneic Transplantation ◽  
Unrelated Donor ◽  
Gvhd Prophylaxis ◽  
Acute Myelogeneous Leukemia ◽  
Reduced Intensity

Abstract Abstract 4328 The prognosis for patients with acute myelogeneous leukemia over age 60 is poor, with a 5 year survival of less than 10%. Reduced intensity allogeneic transplantation has been employed in an attempt to improve survival. We report 23 patients who received reduced intensity allogeneic transplantation after a conditioning regimen of busulfan and fludarabine. Fifteen patients received a transplant from a matched sibling donor,1 patient from a 5/6 matched child and 7 patients from a fully matched (10/10) unrelated donor. We treated 10 patients with the reduced intensity conditioning regimen of busulfan IV 0.8 mg/kg daily Days -6, -5, -4, -3 (total dose 3.2 mg/kg) and fludarabine IV 30 mg/m2 Days -6,-5, -4, -3 (total dose 120mg/kg). After November, 2007, 10 patients were treated with twice daily busulfan IV 0.8mg/kg (total dose 6.4 mg/kg) with the same dose of fludarabine. Three patients were treated on a national protocol in which the same dose of busulfan (6. 4 mg/kg) was administered but given at 0.8 mg/kg four times daily for 2 days on Days -4 and -3 with fludarabine. GVHD prophylaxis was cyclosporine or tacrolimus with either cellcept or (after July, 2008) methotrexate. Seven recipients of unrelated donor or mismatched transplants also received rabbit antithymocyte globulin 1.5 mg/kg Days -3, -2, -1 (total dose 4.5 mg/kg) as part of their GVHD prophylaxis. Median age was 65 years (range 46-70 years). Fourteen patients were in 1st complete remission, 8 were in 2nd complete remission, and one patient had active disease at the time of transplant. Two patients had received a prior autologous stem cell transplant and 2 patients had received a prior allogeneic transplant. The median days to neutrophil (ANC >500) and platelet engraftment (plt >20K) were 15 and 14 respectively. The median length of stay was 25 days (range 13-40 days). Median follow-up was 12 months among the 10 patients still alive. The incidence of acute GVHD Grades II-IV and chronic GVHD were 44% and 35% respectively. Transplant related (non relapse) mortality at 100 days and at 6 months was 0. The overall non-relapse mortality was 4%. Relapse rate was 67% in the daily busulfan group and 46% in the higher dose busulfan group. The one-year overall and disease-free survivals for all patients were 44% and 25% respectively. Causes of death were relapse in 12 patients and in one patient sepsis six years after transplant. In multivariate analysis, disease status, age, and GVHD did not predict for survival, perhaps due to the small sample size. There was a trend to improved survival in the higher dose busulfan group but the follow up was shorter for these patients. In summary, 1) Reduced intensity transplantation is tolerated well in an older population with acute myelogeneous leukemia, with no transplant related mortality at Day 100 or at 6 months post transplant; 2) Relapse rermains the most common cause of death; 3) There was a trend to improved survival with a twice daily busulfan dosing. Future studies will address the outcomes of twice daily busulfan dosing in a larger cohort of older patients with AML in complete remission. Disclosures: Spitzer: Genzyme: Consultancy.

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