scholarly journals Therapy for AML with Myelodysplasia-Related Changes (AML-MRC)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1340-1340
Author(s):  
Taiichi Kyo ◽  
Kouhei Kyo ◽  
Takeshi Okatani ◽  
Tetsuro Ochi ◽  
Kayo Toishigawa ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Survival Rate ◽  
Maintenance Therapy ◽  
Intensive Chemotherapy ◽  
Consolidation Therapy ◽  
Hematopoietic Stem ◽  
Elderly Aml ◽  
Significant Difference ◽  
Blast Count ◽  
Bone Marrow Blasts

Abstract Introduction Patients with AML-MRC are almost older and highly resistant to chemotherapy, so that they are thought to be not eligible for intensive chemotherapy (IC) compared with de novo AML. Reduced intensity chemotherapy, such as low-dose cytarabine and azacitidine (AZA), are used for AML-MRC therapy, but their overall survival (OS) is not satisfactory. Although chemotherapies for AML (except for M3) have not improved for 30 years, several supportive cares for IC have shown a great progress. In this background, we have used IC as induction, consolidation, and maintenance therapies, including AZA, for elderly AML-MRC to avoid relapses and obtain longer survivals. For patients, whose age are under 65 years, hematopoietic stem cell transplantations (HSCT) were mainly considered after IC treatments. Methods Between March 2012 and April 2015, 62 newly diagnosed AML-MRC were treated with idarubicin (IDR) 12 mg/m2 on days 1, 3, 5, 8, and enocitabine (BH-AC) 350mg/m2 on days 1-10 as an induction chemotherapy (IDR+BH-AC). Over 70 years patients, IDR and BH-AC were reduced to 10 mg/m2 and 300 mg/m2, respectively. On day 15, if bone marrow blasts were over 5%, etoposide 100 mg/m2 was additionally treated on days 16-19. Some fit patients, who reached complete remission (CR), were received cytarabine (Ara-C) 1 g/m2 on days 1-5 (bid) and mitoxantrone (MIT) 7 mg/m2 on days 2-4, as a consolidation therapy (Ara-C+MIT). As a maintenance therapy, AZA 75mg/m2 days 1-5 (i.v.) and IDR day1 + BH-AC days 1-4 (or aclarubicine 14 mg/m2 days 1-6 + BH-AC days 1-4) were sequentially treated for one year. If a relapse was observed, mainly AZA was treated to keep a good quality of life. Results Total number of patients was 62 (44 were male) and median age at diagnosis was 71 years (range 36-86). Median WBC was 3,800 x 109/L (600-129,200), median peripheral blast count was 16% (0-96), and median bone marrow blast count was 57% (22-95). Thirty-five patients had intermediate cytogenetics and 27 adverse. Twenty-nine patients, who had >5% bone marrow blasts on day 15, were additionally treated with etoposide. Median follow-up time was 25 months. After the induction therapy, 54 patients (87%) achieved CR, 5 (8%) partial remission, 2 (3%) were refractory, and 1 (2%) died. The CR rate of male was 82% (36/44) and female 100% (18/18). The CR rate of patients with intermediate cytogenetics was 86% (30/35), adverse 89% (24/27), <70 years 83% (20/24), and ≥70 years 89% (34/38). There were no significant differences between CR rates and gender, cytogenetics, or age, respectively. The CR rate of patients treated with etoposide after IDR+BH-AC was 83% (24/29) and without etoposide 91% (30/33). There was no significant difference between the two groups. Among patients with adverse cytogenetics, 67% (18/27) patients treated with etoposide, and intermediate 31% (11/35) (p=0.00983), so that patients with adverse cytogenetics tended to be resistant to IDR+BH-AC and needed the additional etoposide treatment. By Kaplan-Meier method, two year survival of 62 patients was 50.1% (95% CI, 33.9-64.3) and 53.2% (95%CI, 35.0-68.4) in patients achieving CR (n=53, excluding one withdrawn patient). The rate of CR duration for 2 years was 48.2% (95% CI, 30.7-63.7). The median survival with adverse cytogenetics in CR was 18 months (95% CI, 11-25) and that of intermediate was not reached (95% CI, 18-NA). There was a significant difference between OS with adverse cytogenetics in CR and intermediate (p=0.00463). Thirty-two patients in CR received the consolidation therapy, median age was 70 years (range 36-82), 2 patients died due to fungal infection. On the other hand, 21 patients in CR, median age was 77 years (range 59-86), did not have the consolidation, but the maintenance therapy. The survival rate of two groups were almost the same. Ten patients underwent HSCT, 8 in CR and 2 in refractory or relapse, and 2 patients died due to HSCT-related events. HSCT did not influence on OS and CR duration. Conclusions Our intensive chemotherapy for AML-MRC showed a great efficacy and a good tolerability. The additional treatment with etoposide after IDR+BH-AC was especially effective for patients with adverse cytogenetics. Although the 2-years survival rate of elderly AML-MRC was 50% in our study, further efforts are needed to obtain a longer survival, especially for patients with adverse cytogenetics. Disclosures No relevant conflicts of interest to declare.

A Randomized Study with or without Intensified Maintenance Chemotherapy in Patients with Acute Promyelocytic Leukemia Who Had Become Negative for PML-RARα Transcript after Consolidation Therapy: The Japan Adult Leukemia Study Group (JALSG) APL97 Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2009-2009 ◽  
Author(s):  
Norio Asou ◽  
Yuji Kishimoto ◽  
Hitoshi Kiyoi ◽  
Masaya Okada ◽  
Yasukazu Kawai ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Maintenance Therapy ◽  
Acute Promyelocytic Leukemia ◽  
Fusion Transcript ◽  
Promyelocytic Leukemia ◽  
Term Therapy ◽  
Consolidation Therapy ◽  
Maintenance Chemotherapy ◽  
Hematopoietic Stem ◽  
Significant Difference

Abstract The use of all-trans retinoic acid (ATRA) has markedly improved therapeutic outcome in patients with acute promyelocytic leukemia (APL). Non-cross resistance between ATRA and chemotherapeutic drugs has contributed to not only a high complete remission (CR) rate but also a decrease in the relapse rate, leading to the significant improvement in disease-free survival (DFS) and overall survival (OS) rates. However, it is not clear whether maintenance chemotherapy actually prevents relapse in APL patients treated with ATRA and chemotherapy. If short-term therapy without maintenance shows identical DFS rates as compared to long-term therapy with maintenance, it would be beneficial for quality of life of patients as well as to medical costs. In these aspects, to determine an efficacy of maintenance/intensification chemotherapy, this study was designed to compare the DFS and OS rates in previously untreated adult patients with APL who showed absence of PML-RARα fusion transcript at the end of consolidation therapy and were randomly allocated to either maintenance therapy or observation. Of 302 registered, 283 patients were assessable and 267 (94%) achieved a CR. Predicted 6-year OS and DFS rates were 83.7% and 69.2%, respectively. The PML-RARα fusion gene was amplified using bone marrow samples at the diagnosis and after consolidation therapy by the reverse transcriptase-polymerase chain reaction analysis. The detection limit of PML-RARα fusion transcript in this assay was 10-4. Among 235 patients who completed 3 courses of consolidation chemotherapy, five (2.1%) were positive for the PML-RARα fusion transcript. Three of them subsequently relapsed and another one patient received allogeneic hematopoietic stem cell transplantation. On the other hand, 230 patients (97.9%) showed no PML-RARα transcript in the bone marrow cells at the end of consolidation. Of these, 175 patients were randomly assigned to receive moderately intensive and intermittent maintenance chemotherapy (n=89) or to observation (n=86). Predicted 6-year DFS was 63.2% for the chemotherapy group and 81.8% for the observation group, showing no statistically significant difference (p=0.102). Predicted 6-year OS in patients assigned to observation was 98.7% and was significantly higher than 85.9% in those allocated to maintenance therapy (p=0.013). These results indicate no benefit from adding maintenance chemotherapy in APL patients who are negative for PML-RARα fusion transcript after 3 courses of intensive consolidation.

Improved Outcome After Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation (RI-HCT) for Myelodysplastic Syndrome (MDS) Using Tacrolimus/Sirolimus-Based Gvhd Prophylaxis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2771-2771 ◽  
Author(s):  
Ryotaro Nakamura ◽  
Joycelynne Palmer ◽  
Pablo Parker ◽  
Anthony Stein ◽  
Tracey Stiller ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis ◽  
Significant Difference ◽  
One Year ◽  
The Impact ◽  
Bone Marrow Blasts ◽  
Improved Outcome

Abstract Abstract 2771 Poster Board II-747 We previously reported an encouraging result with RI-HCT for MDS (Bone Marrow Transplant 2007; 40:843-50) using flugarabine/melphalan conditioning and cyclosporine (CSA)/mycophenolate (MMF) as GVHD prophylaxis. In order to further improve upon the outcome in the RI-HCT setting, we initiated a series of clinical trials at City of Hope National Medical Center designed to evaluate the impact of tacrolimus (FK)/sirolimus (SIRO)-based GVHD prophylaxis. Here we report the combined, updated results from a consecutive case-series of 89 patients with MDS (including AML progressed from MDS) who underwent RI-HCT from 2000 to 2008 and received either CSA/MMF (n =44) or FK/SIRO (n=45)-based GVHD prophylaxis. All patients received fludarabine 125 mg/m2 plus melphalan 140 mg/m2 followed by an allogeneic HCT (peripheral blood: n=83, bone marrow: n=6) from an HLA-identical sibling (SIB: n=35) or unrelated donor (MUD: n=54). Additional ATG was given to 12 patients. For MUD transplants a short course of methotrexate was added to CSA/MMF or FK/SIRO. The median age was 59 years (range: 20-71) and 31 (35%) patients were female, 58 (65%) were male. Diagnoses at transplant were RA (n=21), RARS (n=1), RAEB/RAEBT (n=36), and AML from prior MDS (n=31). Cytogenetic risk was low in 15 (17%), intermediate in 37 (41.5%), high in 37 (41.5%) patients. By IPSS criteria (for MDS only), 2 patients had low, 24 had int-1, 20 had int-2, and 12 had high-risk MDS. Twenty-seven patients had therapy-related MDS including 14 with prior autologous HCT. The median follow-up time for surviving patients was 39 months (range: 24-68) for the CSA/MMF group and 17 months (range: 4-39) for the FK/SIRO group. All but two patients (1 in CSA/MMF, 1 in FK/SIRO) engrafted with the median neutrophil recovery at 15 days (range: 11-55). The baseline patient, disease and transplant characteristics were similar between CSA/MMF and FK/SIRO, except for an increased percentage of therap-related MDS in the CSA/MMF group (43% vs. 18%, p<0.01). The median donor chimerism by STR at day 30 post-transplant was 100% in both groups (p=0.6). FK/SIRO was associated with a significantly reduced one-year non-relapse mortality (NRM) (11.4%) compared with CSA/MMF (36.2%, p=0.01). This improvement in NRM translated into a trend for improved overall survival (81.4% vs. 52.3%, p=0.1) and disease-free survival (72.2% vs. 52.3%, p=0.08) at one year. While we observed no significant difference in acute GVHD grade II-IV between CSA/MMF and FK/SIRO, FK/SIRO was associated with a significant reduction in grade IV GVHD (0% versus 26%, p<0.01) and a trend for III-IV GVHD (31% vs. 55%, p=0.1). There was no significant difference in chronic GVHD between FK/SIRO (60%) and CSA/MMF (56%, p=0.8). In multivariate analysis, the use of FK/SIRO was independently associated with improved NRM after adjusted for donor type, therapy-related MDS, %bone marrow blasts, and HLA match status (Table). In conclusion, FK/SIRO-based GVHD prophylaxis was associated with an improved outcome after RI-HCT for MDS attributable to the reduced risk for severe acute GVHD.Variables for NRMHazard Ratio (95% CI)p-valueDe novo (n=62) Therapy-related (n=27)baseline 0.75 (0.31–1.89)0.55Sibling donor (n=35) Unrelated donor (n=54)baseline 2.17 (0.70–6.74)0.18Bone marrow blasts < or =10% (n=67) Bone marrow blasts >10% (n=22)baseline 2.13 (0.92–4.96)0.08HLA match (sibling donor or 10/10 MUD, n=72)HLA < mismatch MUD (<10/10 match, n=17)baseline 6.26 (2.11–18.55)0.001FK/SIRO (n=45) CSA/MMF (n=44)baseline 6.58 (2.15–20.14)0.001 Disclosures: Off Label Use: cyclosporine, cellcept, tacrolimus, sirolimus, and methotrexate for GVHD prophylaxis.

scholarly journals Does a Change in IPSS-R between Diagnosis and Transplant Have an Impact on Transplant Outcome in Patients with MDS? a Retrospective Analysis from the EBMT Chronic Malignancies Working Party

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 39-40
Author(s):  
Christof Scheid ◽  
Dirk-Jan Eikema ◽  
Riitta Niittyvuopio ◽  
Johan Maertens ◽  
Jakob Passweg ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Retrospective Analysis ◽  
Research Funding ◽  
Allogeneic Transplantation ◽  
Prognostic Impact ◽  
Transplant Outcome ◽  
Significant Difference ◽  
Blast Count ◽  
Positive Effect ◽  
Bone Marrow Blasts

IPSS-R is a well established prognostic factor for transplant outcome in patients with MDS, irrespective whether it is assessed at diagnosis or at transplant. However it is unclear how a change in IPSS-R, e.g. by reducing bone marrow blasts through therapy, would potentially affect transplant results. In particular the decision to treat patients before transplant or perform an upfront allogeneic transplantation can so far not be based on evidence. We did a registry search based in the MDS quality initiative conducted by EBMT to identify transplanted patients with MDS and sufficient data to calculate IPSS-R at diagnosis and before transplant. The search was limited to patients reveiving a first allogeneic stem cell transplantation in the period 2005 -2018. 1482 patients were identified. Median age at alloHCT was 59 (interquartile range 51-64) years, 60% were male. Donors were related in 36%, graft source was PBSC in 85% of cases. Conditioning was standard dose in 33% and reduced intensity in 67%. IPSS-R both at diagnosis and at transplant had a significant impact on OS and RFS after alloHCT. To investigate the effect of a change in IPSS-R between diagnosis and transplant we constructed 3 subgroups: stable IPSS-R, improved IPSS-R, worsened IPSS-R. A change in IPSS-R was noted in 77.5% of patients with prior chemotherapy, 72% with prior HMA and 59.8% of untreated patients. Univariate analysis showed no significant difference in OS or RFS in patients with stable IPSS-R compared to improved or worsened IPSS-R. In patients treated with chemotherapy before transplant OS and RFS was significantly worse with worsened IPSS-R, while this effect was not found in patient treated with hypomethylating agents (HMA) or untreated patients. The same analysis was performed regarding the difference in bone marrow blasts and the cytogenetics score: OS and RFS after transplant were significantly worse with increased blasts (p=0.04 and p=0.001) and a worsened cytogenetic score before transplant (both p&lt;0.001). While worsened IPSS-R, blast count or cytogenetic score had a negative impact on transplant outcome, the improvement of these parameters showed no positive effect on either OS or RFS in the total cohort or in the subgroups of untreated patients, after chemotherapy or after HMA treatment. In this retrospective analysis from a large cohort of patients with MDS we found that worsening of IPSS-R, blast count or cytogenetic score had a negative prognostic impact in chemotherapy-treated patients, while only worsened blast count and cytogenetics were significant negative factors in HMA-treated or untreated patients. Conversely we did not find a positive effect of improved IPSS-R, decreased blasts or improved cytogenetics in any of the subgroups of treated or untreated patients. Thus for MDS patients receiving an allogeneic transplantation our results provide no clear signal that prior therapy is able to improve transplant outcome. Disclosures Scheid: Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria; Takeda: Honoraria, Research Funding. Blaise:Jazz Pharmaceuticals: Honoraria. Chevallier:Incyte Corporation: Honoraria. Yakoub-Agha:Celgene: Honoraria; Novartis: Honoraria; Gilead/Kite: Honoraria, Other: travel support; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria.

5-Azacytidine Versus Intensive Chemotherapy or BSC in Elderly (>60 years) Acute Myeloid Leukemia Patients. A Retrospective Analysis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2612-2612 ◽  
Author(s):  
Josefina Serrano ◽  
Adolfo de la Fuente ◽  
Juan Bergua ◽  
José Falantes ◽  
Martín-Chacón Eusebio ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Elderly Patients ◽  
Retrospective Analysis ◽  
Intensive Chemotherapy ◽  
Bone Marrow Blast ◽  
Historical Cohort ◽  
Cox Regression Analysis ◽  
Elderly Aml ◽  
Blast Count

Abstract Abstract 2612 BACKGROUND: 5-Azacytidine (AZA) has proven to prolong overall survival (OS) in higher-risk MDS patients and elderly patients with WHO-defined AML and low bone marrow blast count (20–30%) compared to conventional care regimens. These exciting results have prompted us to seek the potential role of AZA on the treatment of elderly (> 60 years) patients with AML compared to best-supportive care (BSC) or intensive chemotherapy (ICT). PATIENTS & METHODS: We have performed a retrospective analysis in 182 elderly AML patients, median age: 70y (60–84). Out of them, 67 patients from 9 Spanish centers diagnosed between Jan/07 to Feb/11 and not eligible for ICT, received 5-AZA as first line therapy by compassionate use. AZA was administered subcutaneously (75–100 mg/m2/d) for 7 days of every 28d. Patients received a median of 6 AZA cycles (1–24). For comparisons, historical cohort (N= 115) diagnosed at same period from University Hospital Reina Sofia was used. Among them, 68 patients unfit for ICT had received only BSC consisting on oral chemotherapy agents, blood product transfusions and antibiotics with granulocyte colony-stimulating factor for neutropenic infection. In this historical cohort 47 patients had received ICT consisted of induction with cytarabine (100–200 mg/m2/d by continuous infusion) for 7 days plus idarubicin (9–12 mg/m2/d) for 3 days followed by Autologous (N=9) or Allogeneic (N=4) Transplant. Outcome measures were performed according to the International Working Group criteria (AML-IWG-2006). RESULTS: Clinical characteristics of patients are detailed in Table 1. Meaningfully, patients in ICT group were significantly younger than those in BSC or AZA arms and also had significantly better ECOG scores. By contrast, patients in AZA group had significantly lower WBC and bone marrow blast count than those receiving ICT. There were not statistical differences in the presence of MDS features or gender distribution (M/F) comparing three arms. Most importantly the percentage of patients with intermediate-adverse cytogenetics was comparable between three arms. Median follow-up for surviving patients from the start of therapy was 5, 13 and 7.4 months for BSC, ICT and AZA groups respectively. The 12 months Overall Survival (OS) was 9%, 52% and 43% for BSC, ICT and AZA groups respectively. The 2y-OS was 0%, 20% and 18% for BSC, ICT and AZA groups respectively. Median OS months for BSC were 2.03 whereas for ICT and AZA groups were significantly longer: 11.2 and 13.7 respectively (Figure 1). We found statistical differences when comparing OS in BSC group with either ICT or AZA, but there was not statistical differences comparing ICT with AZA groups (p=0,75, HR=0,13; 95% CI=0,2–1,2). In multivariable Cox regression analysis, considering variables such as cytogenetic risk group, % BM Blasts and type of treatment AZA vs ICT, only high ECOG scores (p=0,01, HR=2,76; 95% CI=1,2–6) were associated with inferior survival. CONCLUSIONS: These retrospective data suggest that AZA can be an effective alternative option for elderly AML patients unfit for ICT. In our experience, these patients can achieve comparable OS at 2 years than those suitable for ICT, although ECOG score remained the most independent significant variable impacting on outcome. There is a need for prospective clinical trials in order to determine the place of this approach within the growing therapeutic opportunities for elderly patients with AML. Disclosures: Off Label Use: Azacitidine in AML.

scholarly journals Acute myeloid leukemia–induced remodeling of the human bone marrow niche predicts clinical outcome

2020 ◽  
Vol 4 (20) ◽  
pp. 5257-5268
Author(s):  
Yiyang Chen ◽  
Lina Marie Hoffmeister ◽  
Yasmin Zaun ◽  
Lucas Arnold ◽  
Kurt Werner Schmid ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Survival Rate ◽  
Clinical Outcome ◽  
Myeloid Leukemia ◽  
Bone Marrow Niche ◽  
Dependent Manner ◽  
Hematopoietic Stem ◽  
Acute Myeloid ◽  
First Diagnosis

Abstract Murine models of myeloid neoplasia show how leukemia infiltration alters the hematopoietic stem cell (HSC) niche to reinforce malignancy at the expense of healthy hematopoiesis. However, little is known about the bone marrow architecture in humans and its impact on clinical outcome. Here, we dissect the bone marrow niche in patients with acute myeloid leukemia (AML) at first diagnosis. We combined immunohistochemical stainings with global gene expression analyses from these AML patients and correlated them with clinical features. Mesenchymal stem and progenitor cells (MSPCs) lost quiescence and significantly expanded in the bone marrow of AML patients. Strikingly, their HSC- and niche-regulating capacities were impaired with significant inhibition of osteogenesis and bone formation in a cell contact–dependent manner through inhibition of cytoplasmic β-catenin. Assessment of bone metabolism by quantifying peripheral blood osteocalcin levels revealed 30% lower expression in AML patients at first diagnosis than in non-leukemic donors. Furthermore, patients with osteocalcin levels ≤11 ng/mL showed inferior overall survival with a 1-year survival rate of 38.7% whereas patients with higher osteocalcin levels reached a survival rate of 66.8%. These novel insights into the human AML bone marrow microenvironment help translate findings from preclinical models and detect new targets which might pave the way for niche-targeted therapies in AML patients.

Shp-2 Heterozygous Hematopoietic Stem Cells Have Deficient Repopulating Activity Due to a Self-Renewal Defect.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1690-1690
Author(s):  
Rebecca J. Chan ◽  
Yanjun Li ◽  
Chris Shelley ◽  
Mervin C. Yoder
Keyword(s):  
Bone Marrow ◽  
Mononuclear Cells ◽  
Tyrosine Phosphatase ◽  
Embryonic Stem ◽  
Low Density ◽  
Loss Of Function ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Split Dose ◽  
Significant Difference

Abstract The protein tyrosine phosphatase, Shp-2, has been shown to be necessary for normal hematopoiesis based on embryonic stem (ES) cell-based assays; however, due to the early lethality of the homozygous Shp-2 mutant mice (Shp-2−/−) the role of Shp-2 in adult hematopoietic stem cell (HSC) function has never been examined. The Shp-2 heterozygous mice (Shp-2+/−) bear a mutant allele of the Shp-2 gene resulting in the production of a mutant protein lacking amino acids 46–110, which confers a loss of function. To test the hypothesis that Shp-2 is required for normal HSC activity, we compared the competitive repopulating ability of Shp-2+/− bone marrow-derived cells with WT cells. Total adult bone marrow low density mononuclear cells were isolated from Shp-2+/− and WT littermate controls (test cells, C57Bl/6 background, CD45.2+), mixed with a common pool of competitor (comp) cells (BoyJ background, CD45.1+), and administered to lethally irradiated (1100 cGy split dose) Gpi/BoyJ recipients. Based on peripheral blood chimerism, the repopulating ability of the Shp-2+/− cells was significantly lower than that of the WT cells (Figure 1, *p<0.0001 Shp-2+/− v. WT at ratio 1:2; **p=0.001 Shp-2+/− v. WT at ratio 1:1). We next converted the chimerism to repopulating units using the formula [competitor number x 105] X [% 45.2]/100 − [% 45.2] to quantitatively asses the repopulating defect in Shp-2+/− HSCs. We observed that the repopulating units of the Shp-2+/− cells was approximately 3-fold lower than that of the WT cells at both cell doses administered (Figure 2, *p=0.003 Shp-2+/− v. WT at ratio 1:2; **p=0.03 comparing Shp-2+/− v. WT at ratio 1:1). Multi-lineage analysis using two color fluorescence cytometry revealed a significantly lower contribution of Shp-2+/− cells to all lineages tested (B220, GR1, Mac, and CD4/8) compared to WT cells. As Shp-2 has been shown to participate in cell migration, we sought to rule out a homing deficiency of the Shp-2+/− HSCs. We performed short term homing assays and observed no difference in spleen-homed or bone marrow-homed Shp-2+/− and WT lin- cells twenty hours following transplantation. To evaluate self-renewal potential, we conducted serial transplantation experiments. Total bone marrow low density mononuclear cells were isolated from primary or seconary recipient mice with equal chimerism and transplanted into lethally irradiated (1100 cGy split dose) Gpi/BoyJ recipients. While no significant difference was observed between Shp-2+/− and WT engraftement in secondary transplants, eight weeks following tertiary transplantation, engraftment of the Shp-2+/− cells is significantly lower than that of the WT cells (WT 68.9% +/− 9.5 v. Shp-2+/− 26.1% +/− 11.7, n=6, p<0.0001) suggesting that a self-renewal defect contributes to the decreased HSC activity of the Shp-2+/− cells. These data demonstrate that Shp-2 function is not only necessary within the progenitor compartment to support proficient hematopoiesis, but is also needed within the HSC compartment to support normal HSC self-renewal. These findings provide insight into how oncogenic Shp-2 potentially may contribute to the dysregulation of hematopoiesis and the pathogenesis of childhood leukemias.

Leukocyte Alkaline Phosphatase Score as a Marker of Severity and Progression of Myelodysplastic Syndrome.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4625-4625 ◽  
Author(s):  
Jay Lipshitz ◽  
Sewanti Limaye ◽  
Dilip Patel
Keyword(s):  
Bone Marrow ◽  
Alkaline Phosphatase ◽  
Myelodysplastic Syndrome ◽  
Disease Activity ◽  
Disease Progression ◽  
Myelogenous Leukemia ◽  
Bone Marrow Blast ◽  
Leukocyte Alkaline Phosphatase ◽  
Significant Difference ◽  
Bone Marrow Blasts

Abstract Leukocyte Alkaline Phosphatase (LAP) Score is valuable in the work-up of certain hematological diseases. Most notably, the score is decreased in Chronic Myelogenous Leukemia and Paraoxysmal Nocturnal Hemaglobinurea but increased in leukemoid reaction to infection and Polycythemia Vera. Last year we reported the LAP scores of 14 patients with Myelodysplastic Syndrome (MDS). Our results showed that patients with less than 5% bone marrow blasts had significantly higher LAP scores than patients with 5–19% bone marrow blasts. We raised the possibility that LAP scores decrease as MDS progresses (Blood, Nov 2006; 108: 4865). In the present study we attempt to further evaluate the utility of LAP in MDS. In addition to our original cohort, bone marrow aspirate results and LAP scores were reviewed from 14 more patients with MDS, for a total of 28 patients. We again assessed the relationship of LAP to bone marrow blast percentage. Furthermore, we recorded a second LAP score, taken at a later date, from 16 of the 28 patients. For those patients with two LAP scores we compared the trend of LAP score to the interval activity of MDS, using transfusion requirement, complete blood cell count (CBC) and clinical assessment as markers of disease activity. In our analysis of LAP score relative to bone marrow blast percentage we again found a significant difference between patients with less than 5% blasts (n=8) and those with 5% to19% blasts (n=20). Patients with less than 5% blasts had significantly higher LAP scores (90.25 ± 18.27) than those with 5 to19% blasts (44.35 ± 52.09) (p<0.0048) (see charts 1 and 2). In our analysis of LAP score in relation to disease progression we found that among patients for whom LAP score decreased, 42.9% (3/7) had disease progression. In patients whose LAP score increased, 11.1% (1/9) had disease progression (p<0.2615) (chart 3). Overall, our results confirm that LAP scores do tend to be lower in patients with more severe disease, as assessed by bone marrow blast percentage. However, although a trend was observed toward change in LAP score correlating with disease activity this was not statistically significant, and larger prospective studies are necessary to assess whether LAP is an accurate marker of MDS progression. Chart 1: LAP scores of patients 1 through 8 with bone marrow blasts less than 5% (mean 90.25, median 96) Chart 2: LAP scores for patients 1 through 20 with bone marrow blasts of 5% to 19% (mean 44.35, median 30) Chart 1: LAP scores of patients 1 through 8 with bone marrow blasts less than 5% (mean 90.25, median 96) . / Chart 2: LAP scores for patients 1 through 20 with bone marrow blasts of 5% to 19% (mean 44.35, median 30) Chart 3: Percent of patients with disease progression among those with decrease in LAP score (white) and those with increase in LAP score (gray) (p<0.2615). Chart 3: Percent of patients with disease progression among those with decrease in LAP score (white) and those with increase in LAP score (gray) (p<0.2615).

Gabp Transcription Factor Is Required for Self-Renew and Proliferation of Hematopoietic Stem and Progenitor Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1284-1284
Author(s):  
Zhongfa Yang ◽  
Karen Drumea ◽  
James Cormier ◽  
Junling Wang ◽  
Xuejun Zhu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Bone Marrow ◽  
Transcription Factor ◽  
Progenitor Cells ◽  
Myeloid Cells ◽  
Mouse Bone Marrow ◽  
Hematopoietic Stem ◽  
Significant Difference ◽  
Stem And Progenitor Cells ◽  
Ets Domain

Abstract Abstract 1284 GABP is an ets transcription factor that regulates genes which are required for normal hematopoietic development. In myeloid cells, GABP is an essential component of a retinoic acid-inducible enhanceosome that mediates granulocytic gene expression and, in lymphoid cells, GABP regulates expression of IL7-R and the essential transcription factor, Pax5. GABP is a tetrameric complex that includes GABPa, which binds DNA via its ets domain, and GABPb, which contains the transcription activation domain. Genetic disruption of mouse Gabpa caused early embryonic lethality. We created mice in which loxP recombination sites flank exons that encode the Gabpa ets domain, and bred them to mice that bear the Mx1Cre recombinase; injection with pIC induced Cre expression and efficiently deleted Gabpa in hematopoietic cells. One half of the Gabpa knock-out (KO) mice died within two weeks of pIC injection in association with widespread visceral hemorrhage. Gabpa KO mice exhibited a rapid loss of mature granulocytes, and residual myeloid cells exhibited myelodysplasia due, in part, to regulation by Gabp of the transcriptional repressor, Gfi-1. We used bone marrow transplantation to demonstrate that the defect in Gabpa null myeloid cells is cell intrinsic. Although hematopoietic progenitor cells in Gabpa KO bone marrow were decreased more than 100-fold compared to pIC treated control mice, there was not a statistically significant difference in the numbers of Lin−c-kit+Sca-1− hematopoietic stem cells (HSCs) between KO and control mice. Genetic disruption of Gfi-1 disruption in HSCs caused increased cell cycle activity – an effect that is diametrically opposite of the effect of Gabpa KO; this suggests that the effect of Gabpa on HSCs is not due to its control of Gfi-1. In contrast, Gabpa KO HSCs exhibited a marked decrease in cell cycle activity, but did not demonstrate increased apoptosis. The defects in S phase entry of Gabpa null HSCs are reminiscent of the cell cycle defects in Gabpa null fibroblasts, in which expression of Skp2 E3 ubiquitin ligase, which controls degradation of the cyclin dependent kinase inhibitors (CDKIs) p21 and p27, was markedly reduced following Gabpa disruption. We showed that Gabpa KO cells express reduced levels of Skp2. We propose that GABP controls self-renewal and proliferation of mouse bone marrow stem and progenitor cells, in part, through its regulation of Skp2. Thus, Gabpa is a key regulator of myeloid differentiation through its control of Gfi-1, but it is required for cell cycle activity of HSCs, by a distinct effect that may be due to its control of Skp2 and CDKIs. Disclosures: No relevant conflicts of interest to declare.

5-Azacytidine (AZA) Compared to Intensive Chemotherapy in Elderly Acute Myeloid Leukemia (AML) Patients: Results of a Retrospective Single Centre Matched Analysis,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3620-3620 ◽  
Author(s):  
Elsa Lestang ◽  
Sameh Ayari ◽  
Patrice Chevallier ◽  
Thierry Guillaume ◽  
Fanny Rialland ◽  
...  
Keyword(s):  
Elderly Patients ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Intensive Therapy ◽  
Subcutaneous Administration ◽  
Intensive Chemotherapy ◽  
Single Centre ◽  
Secondary Aml ◽  
Elderly Aml ◽  
Significant Difference

Abstract Abstract 3620 AML in elderly patients is characterized by a poor prognosis, especially in those patients aged >70, and/or in frail patients with comorbidities or poor performance status (PS). Moreover, several studies already suggested that elderly AML patients with unfavorable karyotype may not benefit from intensive chemotherapy. With this background, and using a matched analysis, this report aimed to assess the outcome of a single centre series of elderly AML patients who received either non intensive therapy by hypomethylating agents, or standard induction with intensive therapy. All patients were aged over 60 and had de novo or secondary AML. For the purpose of this comparison, the cohort was divided in two distinct groups. Group A included 36 cases treated by intensive chemotherapy between 1995 and 2005 according to the GOELAMS AML-SA2002 or SA3&4 protocols (5+7 induction with idarabicine 5 mg/m2/d and cytarabine 100 mg/m2/d). In this group, patients who could achieve CR received either 3 or 6 consolidation courses delivered over 1 or 2 years (according the protocol AML-SA2002 versus SA3&4). Group B included another 36 patients who were treated between 2006 and 2010 with AZA according to the recommendations of the “compassionate use program” authorized by the French Health Agency (one cycle of AZA = 7 days of subcutaneous administration 75mg/m2 every 28 days until progression).In this group, response was assessed after 3 cycles and qualified using IWG criteria. These two groups were matched based on cytogenetic features and age. The median age for the total cohort was 72 years (range, 60–86). Groups were comparable for WBC, % marrow blasts infiltration, WHO subtypes, and cytogenetic features at diagnosis. A higher rate of secondary AML was observed in the AZA arm. CR and CR with incomplete hematological recovery (CRi) rates were significantly higher in the intensive vs. AZA arm (63% vs. 28%, p<0.0001). However, there was a trend for a higher rate of partial remission (PR) in the AZA Arm (25% vs. 5%, p=0.02). With a median follow-up of 13.3 months (range, 5–80) from diagnosis, median overall survival (OS) was comparable between the two arms: 10.4 vs. 10.3 months, p=0.3) In multivariate analysis for OS including treatment strategy, the strongest prognostic factors were an unfavorable karyotype (HR=2.05, 95%CI, 1.09–3.85; p=0.03), PS status (0 vs. 1–2; HR=2.04 95%CI, 1.16–3.58; p=0.01) and platelets number at diagnosis (analyzed as a continuous variable) (HR=1, 95%CI, 0.99–1.00; p=0.04). Of note, the treatment arm was not found to be a significant determinant for OS: (AZA vs intensive chemotherapy.; HR=1.86, 95%CI, 0.86–3.16; p=0.13). This analysis suggests that the use of AZA as an alternative to intensive chemotherapy in elderly patients with de novo or secondary AML may lead to similar OS, despite a significant difference in terms of CR and CRi rate. The different mechanism of action of AZA in comparison to conventional chemotherapy, and the higher rate of PR that can be achieved after AZA therapy might contribute to improved OS through relatively long lasting disease control. These results set the frame for a prospective controlled trial to test AZA as an ambulatory alternative to standard intensive chemotherapy in elderly AML patients, especially those patients with unfavorable karyotype or poor PS and comorbidities. Disclosures: No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document