Baseline karyotype at diagnosis remains the pivotal determinant of outcome in patients with acute myeloid leukemia (AML). The Medical Research Council (MRC) prognostic model is currently the ...benchmark for risk assessment in this patient population. However, the prognostic role of the complete spectrum of chromosomal abnormalities in AML patients undergoing allogeneic hematopoietic stem cell transplantation (allo-SCT) is currently unknown. Furthermore, their significance in conjunction with FLT3-ITD status has not been addressed thus far.
Using the Acute Leukemia Working Party/European Society for Blood and Marrow Transplantation multicenter database a retrospective analysis was performed to assess the clinical outcomes of AML patients undergoing allo-SCT with respect to specific recurring cytogenetic abnormalities complemented with FLT3-ITD status. We analyzed a cohort consisting of 8558 adult AML patients who underwent allo-SCT in first remission from either a matched sibling or a matched unrelated donor in 2006-2016.
Patients with inv(3)(q21q26)/t(3;3)(q21;q26), del(5q), monosomy 7, chromosome 17p abnormalities, t(10;11)(p11-14;q13-23), t(6;11)(q27;q23), as well as those patients with a monosomal or complex karyotype experienced significantly inferior leukemia-free survival (LFS) compared to patients with a normal karyotype. Del (9q), trisomy 14, and loss of chromosome X were associated with improved LFS rates. A novel prognostic model delineating 5 distinct groups incorporating cytogenetic complexity and FLT3-ITD status was constructed with significant prognostic implications.
Our analysis endorses the prognostic significance of the MRC predictive model in patients undergoing allo-SCT in CR1 with some specific modifications. Furthermore, consideration of FLT3-ITD and karyotypic complexity improved the projective capacity of the MRC model in transplanted patients.
Despite progress in their primary therapy, nearly half of patients (PTS) with DLCL will either relapse or fail to archieve a remission. Autologous transplantation may salvage those PTS with ...chemosensitive disease. However, PTS with high-risk disease or relapsing after autologous transplantation have a particularly poor prognosis. AlloSCT with RIC offers the advantage of a decreased transplant-related mortality combined with a Graft-versus-Lymphoma effect explaining its increasing use in PTS who fail standard therapy. We retrospectively analyzed all PTS with DLCL reported to the SFGM-TC registry, who underwent alloSCT after RIC. 51 PTS (median age 42 years, range 22 to 64 years) were transplanted from Oct. 2002 to Oct. 2004. 23% of PTS had received > 2 lines of prior therapy and 78% had relapsed after autologous transplantation. For 22% of PTS, alloSCT was the first graft. Median time from diagnosis to alloSCT was 33 months (6–126). Disease status at time of alloSCT was: complete remission (CR) n=22, partial remission (PR) n=18, stable disease (SD) n=2, progressive disease (PD) n=7. RIC consisted of fludarabine + busulfan in 27 PTS, fludarabine + total body irradiation in 10, fludarabine + cyclophosphamide in 7 and miscellaneous combinations in 7. GVHD prophylaxis consisted of cyclosporin A (CyA) alone in 18 PTS, CyA/methotrexate in 14 PTS, CyA/mycophenolate mofetil in 14 PTS and other immunosuppressive drugs in 5 PTS. 31 PTS received antithymocyte globulin. Stem cell source was peripheral blood stem cells in 43 PTS and bone marrow in 8. 47 donors were HLA-matched siblings, 4 were unrelated (3 donors HLA-matched and 1 donor with 1 HLA antigen mismatch). Median follow-up after alloSCT was 12 months (0–72). All PTS engrafted except one who died early after transplantation. Grade II to IV acute GVHD occurred in 16 PTS and extensive chronic GVHD in 8/43 valuable PTS. Non relapse mortality was 21% (multi-organ failure : 3, acute GVHD : 1, chronic GvHD : 1, interstitial pneumonia : 1, infection : 4, neurological complication : 1, unknown origin : 1). 20 PTS progressed after a median follow-up of 4.5 months (0–29) and 10 PTS died of progressive DLCL. 23 PTS remain alive and disease-free at a median follow-up of 17 months (1–72). Overall survival is 48% at 22 months. We observe a trend for better survival without statistical significance in PTS who received alloSCT as first graft compared to >1 graft. In PTS in CR or PR prior to transplantation, Kaplan-Meier analysis demonstrates a nearly significant trend for better survival compared to non-responders (55 vs. 28%, p=0,09), but it has to be noted that 3 of 7 PTS transplanted with PD are still alive. RIC followed by alloSCT seems to be feasible even in heavily pretreated PTS and offers the perspective of long lasting remission. Further prospective studies with RIC and alloSCT earlier in the disease course or in defined high-risk PTS in first relapse as an alternative to autologous transplantation should be undertaken.
Evidence of an impact of graft product on transplant outcome after PBSCT is actually rising. Here, we investigated retrospectively the potential impact of HSC recruitment procedure (i.e. G-CSF ...stimulation schedule and apheresis number) and graft composition (CD34+ and CD3+ cell number) on transplant outcome (GVHD, OS, EFS). Our analysis concerned 488 HLA matched sibling allogeneic reduced intensity conditioning (RIC) PBSCT for hematological malignancies (116 MM, 110 AML, 109 NHL, 41 CLL, 41 MDS, 24 CML, 19 HD, 17 ALL and 11 MPS) reported on the SFGM-TC registry between 1998 and 2004. Follow-up was updated in April 2005. RIC-PBSCT was performed during first line treatment in 225 (49%) patients and a previous HSCT was recorded in 55% of the cases. Before RICT, 161 patients were in Complete Response, 161 in Partial Response, 34 in Stable Disease and 132 in Progressive Disease. Regarding donors, median age was 49 years, sex mismatching and ABO incompatibility were seen in 222 and 162 patients respectively. CMV status was positive either in donor or recipient in 152 cases. G-CSF median duration was 5 days (3–7days) at a median dose of 10μg/kg/day (4.6–16). G-CSF was given bid in 40% of the stimulations. Filgrastim was used in 59% of the donors and Lenograstim in 41% of the donors. A single apheresis was performed in 107 donors, 2 in 298 donors, more than 2 in 93 donors. The median number of CD34+ cells infused was 5.6x106 CD34+/kg (1–26) and the median CD3+ cells was 302x106 CD3+/kg (63–996). Conditioning regimen was most frequently an association of Fludarabine Busulfan and Anti Thymocyte Globuline (246 cases, duration of ATG 1 day: 18%, 2 days: 20%, 3 days: 20%, 4 days: 8% 5 days: 33%) or Fludarabine + TBI 2 Gy (123 patients). GVHD prophylaxis was a cyclosporine based treatment in 478 patients 95% of the cases (+ Methotrexate: 29%, + Mycophenolate Mofetil: 26%). Median follow-up after transplantation was 35 months (range: 0–86). Acute GVHD (grade II-IV) and cGVHD incidences were 35% (n=163 on 488 patients) and 50% (n=217 on 430 patients) respectively. The 3-year OS was 40% and the 3-year EFS was 34%. Treatment related mortality was 12% at 1 year and 15% at 3 years. In multivariate analysis studying pre and post transplant factors, a significant impact was shown of G-CSF duration (HR: 0.79 (0.62–1) p=0,05), G-CSF daily dose (HR: 1.13 (1–1.28) p=0,04) on OS. Other variables also influenced OS (NHL vs AML, aGVHD grade II vs 0-I and III-IV vs 0-I and cGVHD: yes vs no) and EFS (Sex mismatch, ABO incompatibility, NHL vs AML, FBS ATG duration: 5 days vs 2 days, aGVHD grade II vs 0-I and III-IV vs 0-I and cGVHD: yes vs no). No influence of graft composition or stem cell recruitment was demonstrated on aGVHD and cGVHD incidences although we found a significant impact of conditioning (FBS ATG 1 day vs 2days and 5days vs 2days). In conclusion, this study demonstrates that, surprisingly, graft composition has no impact on transplant outcome. Prolonged administration of moderate dose of G-CSF seems to be the best schedule for PBSC recruitment.
We aimed to validate the MYelofibrosis SECondary to PV and ET prognostic model (MYSEC-PM) in 159 patients with myelofibrosis secondary to polycythemia vera (PV) and essential thrombocythemia (ET) ...from the European Society for Blood and Marrow Transplantation registry undergoing transplantation from matched siblings or unrelated donors. Furthermore, we aimed to test its prognostic performance in comparison with the Dynamic International Prognostic Scoring System (DIPSS). Score performance was analyzed using the concordance index (C): the probability that a patient who experienced an event had a higher risk score than a patient who did not (C > .5 suggesting predictive ability). Median follow-up of the total cohort was 41 months (range, 34 to 54), 45 months in post-PV and 38 months in post-ET myelofibrosis. Survival at 1, 2, and 4 years was 70% (95% CI, 63% to 77%), 61% (95% CI, 53% to 69%), and 52% (95% CI, 43% to 61%) for the total cohort; 70% (95% CI, 59% to 80%), 61% (95% CI, 49% to 73%), and 51% (95% CI, 38% to 64%) for post-PV; and 71% (95% CI, 61% to 81%), 61% (95% CI, 50% to 72%), and 54% (95% CI, 42% to 66%) for post-ET myelofibrosis (P = .78). Overall, the DIPSS was not significantly predictive of outcome (P = .28). With respect to the MYSEC-PM, overall survival at 4 years was 69% for the low-risk, 55% for the intermediate 1-risk, 47% for the intermediate 2-risk, and 22% (0% to 45%) for the high-risk groups. The prognostic model was predictive of survival overall (P = .05), whereas groups with intermediate 2 and high risk showed no significant difference (P = .44). Assessment of prognostic utility yielded a C-index of .575 (95% CI, .502 to .648) for the DIPSS, whereas assessment of the MYSEC-PM resulted in a C-statistics of .636 (95% CI, .563 to .708), indicating improvement in prediction of post-transplant survival using the new MYSEC-PM. In addition, transplantations from an unrelated donor in comparison with an HLA-identical sibling showed worse outcome (P = .04), and transplant recipients seropositive for cytomegalovirus in comparison with seronegative recipients (P = .01) showed worse survival. In conclusion, incorporating transplant-specific and clinical and mutational information together with the MYSEC-PM may enhance risk stratification.
Background: For many years the ALFA Group has used high dose DNR, i.e 80 mg/m2/day for 3d as part of the induction regimen for untreated adult AML pts. As the equivalence of DNR and Ida is not known ...we conducted a phase III study to compare high dose DNR to Ida. We also tested the effect of IL2 for maintenance.
Methods: Newly diagnosed AML, aged 50 to 70 years, were randomized to receive AraC 200 mg/m2/day IV x 7 d with either DNR: 80 mg/m2/d x 3 d (arm 1) or Ida: 12 mg/m2/d x 3 d (arm 2) or x 4 d (arm 3). Pts who failed could receive a salvage course with Mitoxantrone x 2 d and AraC1g/m2 12 hrs x 4d. Response was assessed after induction+/− salvage chemotherapy. CR pts received 2 consolidation courses according to the induction arm with DNR: 80 mg/m2 or Ida:12 mg/m2 for 1 day (first course) or 2 days (2nd course) and AraC:1g/m2/12 hrs x 4 days. Pts in CCR after the two consolidation courses were randomized to receive or not a maintenance immunotherapy with IL2: 5.106/m2 for 5 days monthly for12 months.
Results: From 2001 to 2006, 468 pts were included (median age: 60 years). The 3 treatment arms were well matched for pretreatment characteristics. CR was achieved in 360/468 pts (77%): 109 (70%) pts arm 1, 129 (83%) arm 2, 122 (78%) arm 3 (p=0.02).70 pts, (45%) pts in the DNR arm reached CR after 1 course vs 97 (62%) and 90 (57%) in Ida arms (p= 0.006). Pts in Ida arms experienced more grade 3 or 4 mucositis (p=0.004) but no differences were observed between the 3 arms for duration of hospitalization, time to PMN or plts recovery, incidence of grade 3 or 4 infectious episodes and treatment related mortality. 3 year cumulative incidence of relapse was 69%, 63%, 62% resp in arms 1,2,3 (p=NS). 3 year EFS was 19%, 30%, 26% resp (p=0.06 for arm 1 vs arms 2 and 3). 3 year OS was 31%, 40% 41% resp in arms 1,2,3 (p=NS). Age (< or >60 years), sex, initial WBC counts, initial LDH (nl or >nl), DNR or Ida arms, need for a salvage course were not predictive for relapse, while 2yCIR was 43%, 64%, 77% among respectively fav, intermediate and unfav cytogenetic risk groups resp (p=0.0046). Of the 219 pts alive in CR after consolidations, 161 (73%) were randomized for maintenance. Only 22 of the 77 pts randomized for IL2 completed the 1 year treatment. 32 and 23 pts stopped IL2 resp because of relapse or intolerance. There were no differences in relapse or OS in both maintenance arms.
Conclusion: Ida treatment even when compared to high doses of DNR yields higher CR rate and more CR after one course. This effect translated in slightly better EFS but not better CIR or OS. IL2 maintenance treatment at least as scheduled in this trial was difficult to apply and showed no impact on disease course.
Background: AML incidence increases with age. Allogeneic stem cell transplantation (Allo-SCT) offers the best leukemic control but is associated with high non-relapse mortality (NRM). Recent advances ...using non-myeloablative strategies have established the feasibility of allo-SCT in elderly patients. However in the context of AML, an important reduction of the intensity of the preparative regimen may be also associated with a loss of leukemic control, offsetting the impact of toxicity reduction in elderly.
Methods: We retrospectively analyzed AML patients in first complete remission (CR1) reported to the SFGM-TC, aged above 55 and transplanted from a HLA identical sibling donor prior to 01/01/05.
Results: 62 patients prepared with a non-myeloablative conditioning (NMAC) (fludarabine (75mg/m2) + TBI (2Gy)) (N=14) or a reduced intensity conditioning (RIC) (busulfan (4 to 8 mg/m2) + fludarabine (150 to 180 mg/m2) + thymoglobulin (2.5 to 12.5 mg/m2)) (N=48). GVHD prophylaxis used CSA+MMF for NMAC, CSA +/− MMF for RIC. With few exceptions, all patients in a given centre were treated identically. Major characteristics were: age 58 (55–67), M/F= 27/35. Time between diagnosis and allo-SCT: 171 days (101–467). BMT/PBSCT: 7/55. Pts have been considered for allo-SCT because of poor prognosis factors: no favorable cytogenetics (100%), secondary AML (15%), 2 chemotherapy course to achieve CR1 (24%) or M0, M6 or M7 FAB (20%). All pts engrafted. Acute GVHD occurred in 16 pts (grade 1: 6; grade 2: 6; grade 3–4: 4) and chronic GVHD in 18 pts (limited: 8; extensive: 10) with no difference in the 2 groups. The cumulative incidences of grade 2–4 aGVHD and cGVHD were 16% (95%CI: 7–25) and 29% (95%CI: 18–40) respectively. 15 pts relapsed and 8 died from NRM. Relapse and NRM cumulative incidences were 24% (95%CI: 13–35) and 13% (95%CI: 5–21) respectively. 49 pts were evaluable for cGVHD: of the 18 expressing cGVHD none have relapsed as compared to 12 of the 31 who did not present cGVHD (39%, 95%CI: 22–56) (p=.007). The 2 year KM survival and DFS probabilities are 63% (47–76) and 56% (42–69). In a landmark analysis investigating patients alive on day 100, 2 year DFS are 94% and 38% respectively with or without cGVHD (p=0.001) and 2 year KM OS are respectively 94% and 45% (p=0.01).
Conclusions: We conclude that such a strategy in elderly can afford a high relapse control with low NRM conducting to high survival probability at 2 years. Results are achieved through the allogeneic effect as expressed by cGVHD inviting to a careful immunomodulation in the early post transplant period to further improve results.
Background: More than 50% of newly-diagnosed patients with AML are older than 60 years of age. In this age group, the benefits of intensive chemotherapy are debated, due to excessive toxicity and ...short duration of response. Negative impacts of unfavorable cytogenetics and associated comorbidities are assumed to explain these results. Prolonged survival may, however, be observed in some patients even there is no well-established post-remission therapy at the present time.
Methods: In the randomized ALFA-9803 trial in AML patients aged 65 years or more, we randomly compared idarubicin or daunorubicin throughout the study (R1) and two different post-remission strategies (R2): one single intensive consolidation course similar to induction versus six ambulatory cycles with one dose of idarubicin/daunorubicin (day 1) and 2x60 mg/m2/d cytarabine SC (day 1 to 5) delivered in out-patients on a monthly basis. Primary endpoint was 2-year overall survival (OS). From Nov 1999 to Apr 2006, 416 patients with de novo (#353) or post-MDS AML (#63) were included (median actuarial follow-up, 34 months). Median age was 72 years. High-risk cytogenetics was defined as complex (5 abns or more), monosomy 7, chromosome 5 and 7 abns, or 3q abn. Associated comorbidities were scored prospectively.
Results: Complete remission (CR) rate was 57%, with 4% CRi and 10% induction deaths (ID), after a 4+7 induction with either 45 mg/m2/d daunorubicin or 9 mg/m2/d idarubicin (day 1 to 4) and cytarabine 200 mg/m2/d CIV (day 1 to 7), followed by lenograstim G-CSF until myeloid recovery. Salvage with intermediate-dose cytarabine and mitoxantrone was used in 54 patients. By multivariate analyses, only high comorbidity score (p=0.001) and advanced age (p=0.02) predicted ID. High-risk cytogenetics (p<0.001 and <0.001), high comorbidity score (p=0.001 and <0.001), high WBC (p=0.05 and <0.001), and advanced age (p=0.13 and =0.003) predicted lower CR rate and shorter OS, respectively. Median OS was only 4 months in a subset of about 20% of patients (high-risk cytogenetics and/or high comorbidity score and/or age 80+) who could thus be considered as “unfit” for intensive chemotherapy, even if meeting all usual selection criteria for an intensive approach. Median OS of the remaining 80% patients was 15 months. Long-term outcome, CR and ID rates did not differ according to R1. In the 164/236 CR patients randomized for R2 (69%), estimated 2-year OS from CR was 55% (95% CI, 43 to 66) in the ambulatory arm as compared to 36% (95% CI, 18 to 43) in the intensive arm (p=0.045). Remission duration was similar among both consolidation arms, while incidence of death in CR was lower in the ambulatory arm (1% versus 9% at 2 years).
Conclusion: These results indicate that an ambulatory post-remission strategy has an anti-leukemic efficacy similar to intensive consolidation in older patients with AML and could become a reference arm to which alternative strategies incorporating new agents should be compared. In addition, such an “out-patient” strategy is easier to apply in most patients who have reached CR after intensive induction.
To further delineate the cytokine involvement in human acute graft-versus-host disease (GVHD), we analyzed cytokine expression in peripheral blood mononuclear cells (PBMC) from patients who developed ...acute GVHD after allogeneic bone marrow transplantation and from those who did not.
We used a highly quantitative and sensitive polymerase chain reaction assay based on the coamplification of an internal standard, with the cDNA derived from the mRNA of interest. Results are expressed in copy numbers, after normalization to a fixed amount of actin, allowing comparison between different samples. After a myeloablative regimen, 22 patients with hematological diseases received an unmanipulated allograft from a matched sibling. They were subsequently submitted to prophylactic immunosuppression. We examined the transcription of genes encoding cytokines in PBMC and skin biopsies. We selected T helper 1 (interferon (IFNgamma, interleukin IL-2), T helper 2 (IL-4, IL-10), and inflammatory (IL-1, IL-6) cytokines.
Four weeks after bone marrow transplantation, the bulk of the PBMC population exhibited an increased expression of IL-1 and IL-6, with no major difference between GVHD+ and GVHD- patients. In addition, although IL-2 expression was not detected, increased levels of IFNgamma mRNA were observed in allografted patients, with higher levels in GVHD+ patients. In skin biopsies sampled at the beginning of GVHD, although low expression of IL-1 and IL-6 could be observed, neither type 1 (IL-2, IFNgamma) nor type 2 (IL-4, IL-10) cytokines could be detected.
These studies suggest that the occurrence of human GVHD does not seem to be clearly associated with a T helper 1-type cytokine pattern.
Previous studies have shown that BCR/ABL oncogene, the molecular counterpart of the Ph1 chromosome, could represent a privileged target to natural killer (NK) cells. In the present study, we showed ...that activated peripheral NK cells killed high-level BCR/ABL transfectant UT-7/9 derived from the pluripotent hematopoietic cell line UT-7 with a high efficiency. To further define the mechanisms controlling BCR/ABL target susceptibility to NK-mediated lysis, we studied the effect of IFNgamma, a key cytokine secreted by activated NK cells, on the lysis of these targets. Treatment of UT-7, UT-7/neo, and low BCR/ABL transfectant UT-7/E8 cells with IFNgamma resulted in a dramatic induction of human leukocyte antigen class I (HLA-I) molecules and subsequently in their reduced susceptibility to NK-mediated cytolysis likely as a consequence of inhibitory NK receptors engagement. In contrast, such treatment neither affected HLA-I expression on transfectants expressing high level of BCR/ABL (UT-7/9) nor modulated their lysis by NK cells. Our data further show that the high-level BCR/ABL in UT-7/9 cells display an altered IFNgamma signaling, as evidenced by a decrease in IFN regulatory factor-1 (IRF-1) and signal transducers and activators of transcription (STAT) 1 induction and activation in response to IFNgamma, whereas this pathway is normal in UT-7 and UT-7/E8 cells. A decreased HLA-I induction and nuclear phospho-STAT1 nuclear translocation were also observed in blasts from most chronic myelogenous leukemia patients in response to IFNgamma. These results outline the crucial role of IFNgamma in the control of target cell susceptibility to lysis by activated NK cells and indicate that the altered response to IFNgamma in BCR/ABL targets may preserve these cells from the cytokine-induced negative regulatory effect on their susceptibility to NK-mediated lysis.
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