HCT-CI Is Not a Useful Predictor for Non Relapse Mortality in Older Patients (>60 years old) Receiving RIC Transplant for AML or MDS

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4158-4158 ◽  
Author(s):  
Victor Noriega ◽  
Hugues de Lavallade ◽  
Victoria T Potter ◽  
Pramila Krishnamurthy ◽  
Judith C. W. Marsh ◽  
...  

Abstract Abstract 4158 Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative procedure for patients of high-risk acute myeloid leukaemia (AML) and Myelodysplastic syndromes (MDS). The development of reduced intensity protocols (RIC) has expanded this treatment modality to older patients and to those with comorbidities. The development of the HCT-CI has been an important advance in attempting to more effectively assess patient′s fitness and likely non-relapse mortality (NRM); however its prognosis significance in a population of elderly patients remains uncertain. We evaluated the impact of HCT-CI and other factors that may enhance risk stratification in patients of advanced age receiving a RIC HSCT with alemtuzumab T-cell depletion. 85 consecutive patients aged >60 years who received a RIC HSCT for MDS and AML between January 2002 and December 2010 were retrospectively analysed, All patients received an FBC conditioning regimen (fludarabine 150mg/m2 iv, busulphan 8mg/kg oral or 6.4 mg/kg iv, alemtuzumab 100mg iv) followed by HSCT from an HLA identical sibling (n=19) or volunteer unrelated donors (n=66). Median age was 64 years (range 60–72), with 57/28 male/female. Diagnoses included AML with trilineage dysplasia (AML-TLD n=47), RAEB I/II (n=17), CMML (n=8) and RCMD (n=13),cytogenetics (high risk n= 22), IPSS risk divided patients in Low/Intermediate 1 risk (n=13), Intermediate 2 (n=11), High risk (n=6), AML (n=47). A survival analysis for NRM, overall survival (OS), disease free survival (DFS) was performed including pre-transplant HCT-CI (HCT-CI 0 n=20, HCT-CI 1–2 n=21 and HCT-CI >=3 n=43), ferritin level (<1500 mg n=43, >1500 n=42), number of courses of high dose chemotherapy (=<2 courses n=49, > 2 courses n=33), disease status pre-transplant (CR n=75, no CR n=10), CRP level (<10 n=34, >10 n=25), age >= 65 (<65 n=53, >65 n= 32), albumin median (albumin median = 42g/L), median Inmunoglobulin G (IgG, median = 9,85g/L) and median Inmunoglobulin M (IgM, median = 0,79g/L). At last follow up 60/85 patient had died (NRM, n=25, relapse n=35; median follow-up, 3.5 years, range 0.3–9.5). HCT-CI score showed no statistically significant impact on 2-year NRM (27 %, 40% and 42% in patients having an HCI-CI score of 0, 1–2 and > =3 respectively, p=0.522, Figure) and 3-year NRM (27%, 52% and 49% respectively) or on 2-year OS (40 %, 39% and 29% in patients having an HCI-CI score of 0, 1–2 and > =3 respectively, p=0.577). Ferritin level, number of courses of high dose chemotherapy, CRP level, age >= 65, albumin level and IgM had not statistically significant impact on NRM or OS, while there was a trend of better outcome for patients with higher IgG level (2 and 3-year NRM 26% and 35% vs 53% and 61%, p=0,090, Figure 1). Of note -and as expected- patients in CR at the time of transplant had a better outcome (2 year OS of 38% vs 0%, p=0,008), and high risk cytogenetics was associated with poorer 2-year OS (41% vs 15% (p=0,006). In summary HCT-CI does not best identify patients at higher risk of NRM in patients older than 60 years receiving an alemtuzumab T-cell depleted RIC allo HSCT for AML or MDS while there is a trend toward worse NRM in patients with lower IgG level; this suggests that poorer humoral immunity before transplant might reflect higher risk of NRM although the underlying mechanism remains to be further investigated. Figure 1. Figure 1. Disclosures: No relevant conflicts of interest to declare.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 871-871 ◽  
Author(s):  
Carmelo Rizzari ◽  
Maria Grazia Valsecchi ◽  
Paola De Lorenzo ◽  
Maurizio Aricò ◽  
Giuseppe Basso ◽  
...  

Abstract Introduction: Cure rates of ALL in children aged less than one year (i.e. infants) at diagnosis are in the range of 35–40%. Encouraging results have been recently reported in infants by using intensified treatment, including high dose chemotherapy, with or without allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission (CR). Aim: To evaluate the impact of the two treatment strategies adopted in the AIEOP ALL 91 and 95 studies on the outcome of ALL in infants. Patients and Methods: Fifty-two infants with ALL were enrolled between 1991 and 1999 in two consecutive studies, named AIEOP ALL 91 and ALL 95. Infants with an identified t(4;11) translocation had to be included in the high risk (HR) groups whilst those without this genetic abnormality could be treated in the intermediate (IR) or HR groups according to presenting features and treatment response. Patients belonging to the IR groups received a traditional BFM back-bone based treatment (protocols I, M and II), while those classified in the HR groups underwent an tensified treatment including induction (BFM protocol IA only, in study AIEOP ALL 91, and IA+IB in study ALL 95), consolidation with either 9 blocks of non-cross-resistant drugs (ALL 91) or 3 blocks followed by the 8-drug reinduction regimen - BFM protocol II - repeated twice (ALL 95). All patients were given a continuation phase (reinforced in HR patients of study ALL 95 by vincristine/prednisone pulses). Overall treatment duration was 2 years in both studies. Results: Infants in studies ALL 91 (n=21) and ALL 95 (n=31) had similar biological and clinical characteristics. The overall event-free survival (EFS) at 5 years was 45.0% (SE 7.0%). The EFS, after censoring for HSCT in 1st CR, was 38.1% (SE 11.4%) in ALL 91 and 51.6% (SE 9.9%) in ALL 95 (p-value=0.29). Patients treated in the IR arm of the two studies had a similar outcome. Better results were obtained in patients treated in the HR arm of ALL 95 study, where 9/17 chemotherapy-only patients and 3/4 HSCT patients are alive in CCR as compared to 1/7 and 0/2, respectively, in patients treated in the ALL 91 study. Discussion: These data show that full traditional BFM therapy intensified by 3 post-induction chemotherapy blocks and double protocol II (adopted in study ALL 95), is associated with a better outcome in infants with HR ALL.


2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7098-7098
Author(s):  
D. Blaise ◽  
R. Tabrizi ◽  
C. Faucher ◽  
M. Mohty ◽  
J. Bay ◽  
...  

7098 Background: RIC-based ASCT can be used after intensive chemotherapy in pts with CR1AML(Blaise, Cancer, 2005). Initial disease control was high and was not related to selection bias (Mohty, Leukemia, 2005).Here, we investigated if this control was maintained after a long follow-up. Methods: 37 pts (age: 51 (26–60)) with high risk clinical characteristics (70%) (Age = 50 (N=22, 59%); severe comorbidity (30%)) and/or poor risk leukemic features (65%) (Cytogenetics (35%); 2 induction courses (27%); secondary leukemia (11%), High white blood cell counts(14%) or partial remission (3%)) were treated. After CR1, pts received at least either 1 course of high dose cytarabine (24 g/m2) and anthracycline (HIDAC: N=21) or HIDAC + 1 course of. melphalan (140 mg/m2) (HDMEL) with auto-SCT Pts (HIDAC +HDM N=16). All pts were then scheduled to receive ASCT prepared with RIC (fludarabine (180 mg/m2), busulfan (8 mg/kg), Thymoglobulin (2.5 to 10 mg/kg)) followed with BMT (28%) or PBSC (72%). Results: With a Median follow-up of 3 years (16–70 mths). 15 pts experienced aGVHD (grade 2–4 aGVHD cumulative incidence (CI):22% (9–35). 10 and 14 pts presented a limited and extensive cGVHD respectively (CI cGVHD:65 % (50–80). 3 deaths were attributed to non-relapse causes (NRD) (AGVHD: 1; CGVHD: 2° (NRD CI: 8% (0–17). In all, 9 pts relapsed at 5 mths (2–19) (24% (9–35). Relapse was associated with the absence of cGVHD (cGVHD: 8 (0–19), no cGVHD 44% (12–76), p=.05). 25 pts are still alive in CR1 for overall survival and leukemia-free survival (LFS) probability estimates at 4 years of 65 % (48–79%) and 66% (49–80%) respectively. When restricting the analysis to the 33 pts evaluable for cGVHD, cGVHD remained the only independent risk factor positively influencing LFS (cGVHD: 81% (59–92); no cGVHD (56% (27–81), p=.05) Conclusions: We conclude that RIC Allo-SCT preceded by adequate prior intensive chemotherapy might offers a relatively low NRD while exerting a sustained leukemia control even in high risk pts deserving prospective evaluation against standard strategy of conventional Allo SCT. No significant financial relationships to disclose.


Cancer ◽  
2006 ◽  
Vol 106 (11) ◽  
pp. 2327-2336 ◽  
Author(s):  
Emer O. Hanrahan ◽  
Kristine Broglio ◽  
Deborah Frye ◽  
Aman U. Buzdar ◽  
Richard L. Theriault ◽  
...  

1995 ◽  
Vol 13 (5) ◽  
pp. 1089-1095 ◽  
Author(s):  
W P Vaughan ◽  
E Kris ◽  
J Vose ◽  
P J Bierman ◽  
P Gwilt ◽  
...  

PURPOSE A phase I/II study was performed to evaluate the incorporation of hydroxyurea (HU) into high-dose chemotherapy of non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS Thirty-eight patients with primary refractory and refractory relapsed NHL were treated with carmustine (BCNU) (300 mg/m2 on day -8), cyclophosphamide (Cy) (2.5 g/m2/d on days -8 and -7), etoposide (E) (150 mg/m2 every 12 hours on days -6, -5, and -4), and HU (BCHE) with autologous hematopoietic stem-cell rescue. Twenty-one patients received HU in a dose escalation of 2 to 12 g/m2 intravenously (IV) by 72-hour continuous infusion. When the IV formulation was not available, 17 patients were given 18 g/m2 of HU orally in divided doses every 6 hours over the same 72-hour period. RESULTS The dose-limiting toxicity of 72-hour continuous infusion HU in this regimen was mucositis. Endotracheal intubation was necessary to protect the airway in two thirds of patients treated at 12 g/m2. Six patients (oral BCHE, five of 17; IV BCHE, one of 21) died with nonresponding or progressive disease and, at least in part, from the complications of the high-dose chemotherapy. Seventeen patients (45%) achieved complete remission (CR). More patients treated with IV BCHE achieved CR than patients treated with oral BCHE (12 of 21 v five of 17; P < .1, chi 2 test). Nine patients (two of 17 oral BCHE and seven of 21 IV BCHE) remain disease-free as of January 31, 1994, with a minimum follow-up time of 3 years. The lower mortality and higher response rate with IV BCHE translated into a significantly superior probability of progression-free survival (PFS) (33% at 4 year v 12% for oral BCHE; P = .048, log-rank test). CONCLUSION High-dose BCHE is effective treatment for primary refractory and refractory relapsed NHL. Continuous IV HU appears to be less toxic and more effective than intermittent oral HU in this regimen.


Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2854-2854 ◽  
Author(s):  
Stephan Stilgenbauer ◽  
Florence Cymbalista ◽  
Véronique Leblond ◽  
Alain Delmer ◽  
Dirk Winkler ◽  
...  

Abstract Abstract 2854 Alemtuzumab (A) proved to be efficacious in CLL patients (pts) with very poor prognosis, either due to fludarabine (F) refractoriness or due to unfavorable cytogenetics (17p-). However, rate and duration of remissions still remain unsatisfactory. Therefore, the French and German CLL study groups jointly embarked on this trial, trying to achieve higher overall response rates (ORR) by adding high-dose dexamethasone (D) to A and, simultaneously, investigating the consolidation effect of prolonged A maintenance or allogeneic stem-cell transplantation (allo-SCT), respectively. Induction treatment consisted of subcutaneous A 30 mg weekly × 3 for 28 days, combined with oral D 40 mg on days 1–4 and 15–18, and prophylactic pegfilgrastim 6 mg on days 1 and 15. Depending on the remission status, pts were treated for up to 12 weeks. If CR was documented at 4 or 8 weeks, or at least SD was achieved at 12 weeks, consolidation was scheduled with either allo-SCT or A maintenance with 30 mg every 14 days for up to 2 years (y), at the discretion of pt and physician. Between January 2008 and July 2011, 124 pts were recruited at 26 centers, 120 of whom were eligible. Pts were generally subdivided into three cohorts: 55 pts were refractory (i.e. no response or relapse within 6 months) to regimens containing F or a similar drug (i.e. pentostatin, cladribine, bendamustine). Non-refractory pts all exhibited 17p- and had either untreated (n=39) or relapsed CLL (n = 26) requiring therapy. The median age was high with 66/64/66 y in 17p- 1st line, 17p- relapse, and F-refractory pts, respectively. The three cohorts had 46/54/75% Binet C disease, 41/35/27% B symptoms, 38/42/53% reduced performance status (ECOG 1/2), median thymidine kinase levels of 35/49/24 U/L, median ß2MG levels of 3.8/5.5/4.6 mg/L, and IGHV was unmutated in 89/96/87%. In the F-refractory group, 53% exhibited 17p deletion and 22% had 11q deletion. Pretreated patients had received a median of 3 (F-refractory) or 2 prior lines (17p- relapse). 5 pts had previously undergone autologous and 1 pt allo-SCT. Treatment and efficacy data are currently available for 87 pts who completed induction therapy :17p- 1st-line (n=30), 17p- relapse (n=17), and F-refractory (n=40). Of these, 80/53/55% received the full induction of 12 weeks. ORR (best observed status) was generally high with 97/76/70%. CR was achieved in 20/0/5%. After a median follow-up of 11.8 months (mo), median progression-free survival (PFS) was 16.9/10.4/8.4 mo. Deaths are recorded in 13/27/36% of pts, with median overall survival (OS) not yet reached (>24 mo) in the 17p- 1st line group, and 15/12 mo in 17p- relapse/F-refractory pts. Consolidation treatment was performed as maintenance A (median duration 32 weeks, range 2 – 89) in 34%, and allo-SCT in 30%, with a median age of 66 and 61 y in these subgroups. The main reasons for going off-study without consolidation were death due to infection (14%, n=11, of these 6 without response, and 10 in the F-refractory cohort), CLL progression (12%), and other toxicity (5%). Among the 28 pts not receiving consolidation, there were 19 (68%) deaths, 15 of them in the F-refractory cohort. When comparing A maintenance and allo-SCT for consolidation, there were 9 (35%) and 7 (30%) PD events, respectively and there was so far no significant difference in PFS (median 17 mo in both groups) or OS. During induction, grade 3/4 hematotoxicity consisted of anemia in 28%, neutropenia in 47%, and thrombopenia in 44%. Grade 3/4 non-CMV infection occurred in 29% of 17p- 1st-line, 15% of 17p- relapsed, and 56% of F-refractory pts. CMV reactivation was observed in 54/25/40%, without severe sequelae recorded. During A maintenance, grade 3/4 toxicity consisted of neutropenia in 39% pts and thrombopenia in 4% pts with 6 SAEs (ITP, diarrhea, infection, erythema, tachycardia, and thrombosis). Conclusions: The combination of A and D shows high response rates in ultra high-risk CLL, with promising preliminary findings for PFS and OS, despite the high median age of the pts. The results compare favorably to ORR/CR of 68%/5%, and median PFS of 11.3 mo in the 17p- subgroup of the CLL8 study treated with FCR, consisting of younger pts (median 61 y). In F-refractory CLL however, when compared to the preceding CLL2H study with single agent A, the improved initial response by adding dexamethasone does not seem to translate into improved long-term results. More mature follow-up is needed, especially with respect to the impact of allo-SCT. Disclosures: Stilgenbauer: Amgen: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding. Off Label Use: Alemtuzumab in 1st line CLL treatment. Cymbalista:Roche (d) Mundipharma (e) Genzyme (e): Honoraria, Research Funding. Hinke:WiSP (CRO): Employment.


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 ◽  
...  

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.


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