Understanding how retinoic acid derivatives induce differentiation in non- M3 acute myelogeneous leukemia

Not available.

Successful Early Outcome with Low-Dose (400 cGY) Total Body Irradiation in Combination with Busulfan and Fludarabine Myeloablative Conditioning Followed By Matched Unrelated Donor Allogeneic Peripheral Blood Stem Cell Transplantation in a Patient with Non-Remission Acute Myelogeneous Leukemia with Diffuse Extramedullary Disease in Multiple Sites

Outcome after allogeneic stem cell transplantation (allo-SCT) is poor with 10-20% probability of long term survival in patients with acute myelogeneous leukemia (AML) not in remission at the time of transplant. The main cause of transplant failure in this high risk population is disease post-transplant relapse. We treated a 32 year-old male with undifferentiated AML (M0) who initially presented with leukocytosis, circulating blasts and a large anterior mediastinal mass abutting adjacent structures. A core biopsy of the mass revealed myeloid sarcoma. Patient developed respiratory distress requiring endotracheal intubation and mechanical ventilation. Cytogenetics revealed Hyperdiploid, 55, XY,+4,+6,+8,+9,+10,+11,+14,+19,+mar[12]/46,XY[14]. FLT3 ITD was positive. He did not respond to initial induction chemotherapy with 7+3 (daunorubicin 60 mg/m2/d and Cytarabine 100 mg/m2/d). He achieved morphologic and cytogenetic complete remission after re-induction with high dose cytarabine and mitoxantrone. He also received scheduled prophylactic triple intrathecal chemotherapies throughout his treatment course and started high dose cytarabine consolidation (HIDAC). His treatment courses were complicated by numerous medical problems, requiring a second prolonged hospitalization following third consolidation. He was intubated again due to diffuse alveolar hemorrhage. The patient was eventually discharged with tracheostomy collar and supplement oxygen, which was discontinued later on. A follow-up CT of chest showed increase in size of mediastinal mass but continuous CR in BM exam. While unrelated donor allogeneic SCT is in process, he received one course of decitabine. At the time of pre-transplant work-up, he relapsed of her AML first at his left conjunctivae and shortly after on his skin, presented with diffuse chloroma lesions on his trunk. He was treated with external radiation to his left eye with additional IT chemo (negative cytology). He underwent 10/10 HLA match unrelated donor allogeneic stem cell transplantation following PK-directed IV Busulfan with targeted AUC of 20,000 and Fludarabine 160 mg/m2 plus total body irradiation 200 cGY/d x 2 days. Skin lesions were active but bone marrow was in remission at the time of transplant. GVHD prophylaxis was tacrolimus and low dose methotrexate 5 mg/m2/d on days+1, +3, and +6 only. No ATG was given. His post-transplant course was relatively unremarkable. No major complications requiring re-admission to hospital occurred. His trach collar was kept thoughout his transplant and post-transplant courses due to tracheal stenosis. He achieved complete morphologic and cytogenetic remission with resolution all of his extramedullary leukemia including his mediastinal mass on day+100 evaluation. Currently he has been receving monthly 5-Azacitidine maintenance and clinically well on day+122. This case illustrates a successful early outcome after peripheral blood allogeneic stem cell transplantation using the combination of chemo-low dose radiation in a patient with non-remission AML with diffuse extra medullary disease. Optimum combination of radiation and chemotherapy in conditioning regimens may improve transplant outcomes in patients with non-remission AML and warrants prospective Phase I-II clinical trials. Disclosures No relevant conflicts of interest to declare.

MicroRNA 29b functions in acute myeloid leukemia

MicroRNAs (miRNAs) are associated with cytogenetics and molecular subtypes of acute myelogeneous leukemia (AML), but their impact on AML pathogenesis is poorly understood. We have previously shown that miR-29b expression is deregulated in primary AML blasts. In this work, we investigated the functional role of miR-29b in leukemogenesis. Restoration of miR-29b in AML cell lines and primary samples induces apoptosis and dramatically reduces tumorigenicity in a xenograft leukemia model. Transcriptome analysis after ectopic transfection of synthetic miR-29b into leukemia cells indicates that miR-29b target apoptosis, cell cycle, and proliferation pathways. A significant enrichment for apoptosis genes, including MCL-1, was found among the mRNAs inversely correlated with miR-29b expression in 45 primary AML samples. Together, the data support a tumor suppressor role for miR-29 and provide a rationale for the use of synthetic miR-29b oligonucleotides as a novel strategy to improve treatment response in AML.

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

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.

Corticosteroid Therapy Does Not Increase Relapse Rate after Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myelogeneous Leukemia and Myelodysplastic Syndrome Overt Leukemia.

Corticosteroid is often used after allogeneic hematopoietic stem cell transplantation (AHCT) to control graft-versus-host disease (GVHD). However, it is concerned that corticosteroid therapy may suppress graft-versus-leukemia (GVL) effect and may increase the risk of leukemia relapse after AHCT. The aim of the present study is to determine whether the corticosteroid administration increases the relapse after AHCT for acute myelogeneous leukemia (AML) and myelodysplastic syndrome overt leukemia (MDS overt leukemia). We analyzed 98 patients who received their 1st AHCT for AML (n=78; 47 1st or 2nd complete remission, 31 advanced stage) or MDS overt leukemia (n=20) from related (n=45; 37 HLA matched, 8 HLA mismatched) or unrelated (n=53; 37 HLA matched, 16 HLA mismatched) donors at our institution between 1997 - 2006. The median age was 42 years (range, 18–64). Conventional conditioning regimen was used in 71 patients and reduced-intensity conditioning regimen was used in 27 patients. GVHD prophylaxis was cyclosporine and methotrexate in 48 patients, tacrolimus and methotrexate in 49 patients, and cyclosporine alone in 1 patient. Univariate Cox regression analysis showed AML other than 1st or 2nd complete remission (CR) and HLA mismatch were the significant risk factors for relapse but corticosteroid administration (analyzed in time-dependent fashion) was not: AML other than 1st or 2nd CR (p=0.0230, hazard ratio(HR) 2.373, 95% confidence interval (CI) 1.126–4.999), HLA mismatch (p=0.0045, HR 2.776, 95% CI 1.373–5.613), and corticosteroid administration (p=0.8483, HR 1.067, 95% CI 0.551–2.065). In multivariate analysis, corticosteroid administration did not significantly increase the risk for relapse: HR was 0.760 (95% CI, 0.379–1.524, p=0.4394) after adjusting for disease status and HLA disparity. Corticosteroid is concerned to hamper GVL effect, resulting in increased relapse rate after AHCT. However, in this study, corticosteroid administration after AHCT was not a risk factor for relapse. This may be explained by the fact that among the 54 patients who had corticosteroid administration 45(88.9%) had acute and/or chronic GVHD, resulting in relatively strong GVL effect. On the other hand, there were 7 patients who had neither grade II to IV acute GVHD nor chronic GVHD but had corticosteroid administration. Among them 2 patients relapsed. In conclusion, the result of this study suggests that corticosteroid therapy does not increase relapse rate after AHCT at least in the presence of GVHD. However, larger number of patients is needed to evaluate the effect of corticosteroid therapy on relapse in the absence of GVHD.