scholarly journals CPX-351 Induces Remission in Newly Diagnosed Pediatric Secondary Myeloid Malignancies

2021 ◽  
Author(s):  
Yixin Hu ◽  
Kenneth J Caldwell ◽  
Mihaela Onciu ◽  
Sara M Federico ◽  
Marta Salek ◽  
...  
Keyword(s):  
Hematopoietic Cell Transplantation ◽  
De Novo ◽  
Young Patients ◽  
Molar Ratio ◽  
Newly Diagnosed ◽  
Dismal Prognosis ◽  
De Novo Aml ◽  
Cornelia De Lange ◽  
No Innovation ◽  
Favorable Safety

Secondary myelodysplastic syndromes and acute myeloid leukemia (sMDS/AML) are rare in children/adolescents and have a dismal prognosis. The mainstay therapy is hematopoietic cell transplantation (HCT) but there has been no innovation in cytoreductive regimens. CPX-351, a fixed 5:1 molar ratio of liposomal cytarabine/daunorubicin, has shown favorable safety and efficacy in elderly individuals with sAML and children with relapsed de novo AML. We report the outcomes of seven young patients (six with newly diagnosed sMDS/AML and one with primary MDS/AML) uniformly treated with CPX-351. Five patients had previously received chemotherapy for osteosarcoma, Ewing sarcoma, neuroblastoma, or T-ALL; one had predisposing genomic instability disorder (Cornelia de Lange); and one MDS-related AML and multi-organ failure. The median age at diagnosis of myeloid malignancy was 17 (13-23) years. Patients received 1-3 cycles of CPX-351 (cytarabine 100mg/m2 plus daunorubicin 44mg/m2) on days 1, 3, and 5, resulting in complete morphologic remission without overt toxicity or treatment-related mortality. This approach allowed for adding FLT3 inhibitor as individualized therapy in one patient. Six patients were alive and leukemia-free at 0.5-3.3 years after HCT. One patient died from disease progression before HCT. Concluding, CPX-351 is an effective and well-tolerated regimen for cytoreduction in pediatric sMDS/AML warranting prospective studies.

scholarly journals Liposome-Encapsulated Cytarabine and Daunorubicin (CPX-351) Induces Remission in Newly Diagnosed Pediatric Secondary Myeloid Malignancies

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4415-4415
Author(s):  
Kenneth J Caldwell ◽  
Yixin Hu ◽  
Mihaela Onciu ◽  
Sara M Federico ◽  
Marta Salek ◽  
...  
Keyword(s):  
Hematopoietic Cell Transplantation ◽  
De Novo ◽  
Young Patients ◽  
Molar Ratio ◽  
Newly Diagnosed ◽  
Driver Genes ◽  
Myeloid Malignancies ◽  
Dismal Prognosis ◽  
Cornelia De Lange ◽  
Copy Number Changes

Abstract Secondary myelodysplastic syndromes and acute myeloid leukemia (sMDS/AML) are rare myeloid neoplasms in children/adolescents and have a dismal prognosis. The mainstay therapy is hematopoietic cell transplantation (HCT) but there has been little therapeutic innovation for decades and outcomes remain poor. CPX-351, a fixed 5:1 molar ratio of liposomal cytarabine/daunorubicin, has shown favorable safety and efficacy in elderly individuals with sAML and children with relapsed de novo AML, which led the FDA to recently expand the label of CPX-351 to include pediatric patients with secondary AML, however, no data has been reported in this patient group. We report the outcomes of seven young patients with newly diagnosed sMDS/AML uniformly treated with CPX-351. Five patients had previously received chemotherapy for osteosarcoma, Ewing sarcoma, neuroblastoma, or T-ALL; one had predisposing genomic instability disorder (Cornelia de Lange syndrome); and one presented with MDS-related AML and multi-organ failure. The median age at diagnosis of myeloid malignancy was 17 (13-23) years. We identified somatic mutations and copy-number changes across 16 leukemia driver genes in six cases (including TP53 in two), abnormal karyotypes in six cases and rearrangements involving MECOM or NIM1K-TERT in two patients. Additional genomic studies identified pathogenic germline mutations in CHEK2 and SMC3 each in a single patient . Patients received 1-3 cycles of CPX-351 (100 units/m 2 on days 1, 3, and 5) resulting in complete morphologic remission without overt toxicity or treatment-related mortality. This approach allowed for adding FLT3 inhibitor as individualized therapy in one patient. Six patients were alive and leukemia-free at 0.51-3.25 years after HCT. One patient died from disease progression before HCT. Concluding, CPX-351 is an effective and well-tolerated regimen for cytoreduction in pediatric secondary myeloid malignancies warranting further investigation Figure 1 Figure 1. Disclosures Triplett: Miltenyi: Other: Travel, meeting registration.

Allogeneic Hematopoietic Cell Transplantation with FLAMSA-RIC Can Overcome the Poor Prognosis of Primary Refractory or Relapsed AML

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1938-1938
Author(s):  
Dominik Schneidawind ◽  
Birgit Federmann ◽  
Christoph Faul ◽  
Wichard Vogel ◽  
Lothar Kanz ◽  
...  
Keyword(s):  
Overall Survival ◽  
Salvage Therapy ◽  
Hematopoietic Cell Transplantation ◽  
De Novo ◽  
Free Survival ◽  
Secondary Aml ◽  
Off Label ◽  
Dismal Prognosis ◽  
De Novo Aml ◽  
Refractory Aml

Abstract Abstract 1938 Introduction: Patients with relapsed or primary refractory AML have a dismal prognosis. Even salvage therapy with allogeneic hematopoietic cell transplantation (HCT) could not improve outcome due to high incidence of relapse and high non-relapse mortality (NRM). Recently, promising results in patients with unfavorable karyotype or treatment refractory AML have been reported using a sequential treatment with aplasia inducing chemotherapy consisting of Fludarabine, Ara-C and Amsacrine (FLAMSA) followed within 3 days by reduced intensity conditioning (RIC) for allogeneic HCT (Schmid et al., Blood 2006 Aug 1;108(3):1092–9). Methods: We report a retrospective analysis of our single center experience with FLAMSA-RIC in primary refractory or relapsed AML patients. We searched our database for patients receiving FLAMSA-RIC in the past 10 years. Details on characteristics and clinical course of the patients were confirmed by retrospective chart review. Results: We retrospectively identified and analyzed 51 consecutive patients (f=22, m=29) transplanted after FLAMSA-RIC at our institution from 2006–2011. At time of HCT patients were refractory after chemotherapy (n=22) or had an untreated relapse (n=29). Data on molecular and cytogenetic markers were available in 36 and 44 patients, respectively. 34 were initially high-risk because of unfavorable karyotype (n=25) or molecular genetic alterations (n=9). Median age of patients was 56 years (range, 20–72) and diagnosis of all patients was acute myeloid leukemia (de-novo AML, n=27, secondary AML, n=24). FLAMSA (Fludarabine 30 mg/m2 day −12 to −9, AraC 2000 mg/m2 day −12 to −11 and Amsacrine 100 mg/m2 day −12 to −9) was used as salvage therapy followed by RIC (Fludarabine 30 mg/m2 day −5 to −4/Busulfan 0.8 mg/kg day −6 to −4, n=10; TBI 4Gy on day −5/Cyclophosphamide 60 mg/kg on day −4 to −3, n=28; Busulfan 0.8 mg/kg day −6 to −4/Cyclophosphamide 60 mg/kg for matched and mismatched unrelated donors (MUD/MMUD) or 40 mg/kg for matched related donors (MRD) on day −3 to −2, n=13). As GVHD prophylaxis calcineurin inhibitor combined with mycophenolate mofetil and anti-thymocyte globuline (ATG-Fresenius®, 10 mg/kg for MRD and 20 mg/kg for MUD/MMUD) was used. 10 patients were transplanted from MRD, 16 from MUD, 21 from a MMUD and 4 from a MMRD. 14 patients received DLI (2 × 106 - 1 × 108 /kg after a median of 186 days, range 72–922) in absence of GVHD in case of mixed chimerism or relapse after HCT. Current overall survival (OS) was 18/51 patients with a median follow-up of 410 days (range, 179–1557) of patients alive resulting in a Kaplan-Meier estimated 2-year OS and event-free-survival (EFS) of 34% and 29%, respectively. There was no significant difference between the different RIC regimens with 50% Fludarabine / Busulfan vs. 26% TBI 4Gy / Cyclophosphamide and 40% Fludarabine / Busulfan (p=0.37). Causes of death were relapse (n=19), infections (n=5), GVHD (n=2), multi-organ-failure (n=5), cerebral hemorrhage (n=1) and progressive multifocal leukencephalopathy (n=1). Cumulative incidence of relapse at 2 years with death due to NRM as competing risk was 40% and cumulative incidence at 2 years of NRM with death due to relapse as competing risk was 27%. 2-year OS was inferior in patients with secondary AML compared to patients with de-novo AML (28% vs. 38% p=0.79). The outcome in the elderly subgroup defined by age ≥60 years (median age 67, n=22) was similar to the group of younger patients (median age 46, n=29) with 2-year OS of 31% vs. 37% (p=0.87). Patients with a blast count < 10% in the bone marrow at time of HCT had a better outcome with 64% vs. 25% OS (p=0.09). 2-year-OS was inferior in patients being refractory after chemotherapy (25% vs 38%, p=0.78). Incidence of acute GVHD (aGVHD) ≥II and chronic GVHD (cGVHD, limited, n=11, extensive, n=3) was 22% and 27%, respectively. Presence of aGVHD did not influence survival while presence of cGVHD was associated with an improved overall survival after HCT (58% vs 24%, p=0.009). Conclusion: FLAMSA-RIC followed by allogeneic HCT enables long-term disease free survival, even in primary refractory or relapsed AML patients. The sequential approach of this regimen seems to overcome the dismal prognosis of these patients. Its moderate toxicity allows the application of this curative salvage therapy option even in an elderly patient population. Disclosures: Off Label Use: The use of some agents in the conditioning is off-label.

Overall survival (OS) and stem cell transplant (SCT) in patients with FLT3 mutations treated with CPX-351 versus 7+3: Subgroup analysis of a phase III study of older adults with newly diagnosed, high-risk acute myeloid leukemia (AML).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e18507-e18507 ◽  
Author(s):  
Bruno C. Medeiros ◽  
Donna Hogge ◽  
Laura F. Newell ◽  
Dale L. Bixby ◽  
Scott R. Solomon ◽  
...  
Keyword(s):  
High Risk ◽  
De Novo ◽  
Phase Iii ◽  
Molar Ratio ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Open Label ◽  
Serious Adverse Events ◽  
Flt3 Mutations ◽  
De Novo Aml

e18507 Background: FLT3+ AML patients (pts; 20%-30% of AML pts) often have rapid post-induction relapse, highlighting the need for therapies that improve the bridge to SCT. CPX-351 is a liposomal formulation that delivers a synergistic 5:1 molar ratio of cytarabine (C) and daunorubicin (D). CPX-351 demonstrated efficacy versus 7+3 in a randomized, open-label, controlled phase III trial in pts aged 60-75 years with newly diagnosed, high-risk AML; our analysis investigated outcomes in the subset of FLT3+ pts. Methods: Pts were randomized 1:1 to induction with 1-2 cycles of CPX-351 (100 u/m2 [C 100 mg/m2 + D 44 mg/m2] on Days 1, 3, and 5 [2nd induction: Days 1 and 3]) or 7+3 (C 100 mg/m2/day x 7 days [2nd induction: x 5 days] + D 60 mg/m2on Days 1, 2, and 3 [2nd induction: Days 1 and 2]). Pts with complete remission (CR) or CR with incomplete platelet or neutrophil recovery (CRi) could receive up to 2 consolidation cycles. Results: Of the pts who had FLT3 mutations assessed and received study treatment, 22/138 (16%) pts in the CPX-351 arm and 20/136 (15%) pts in the 7+3 arm had baseline FLT3 mutations. AML subtypes in FLT3+ pts were: tAML (19%); AML after MDS with (38%) or without (10%) prior hypomethylating agents; AML after CMMoL (12%); and de novo AML with MDS karyotype (21%). In FLT3+ pts, median OS was longer with CPX-351 (10.25 mo) versus 7+3 (4.55 mo; HR = 0.57 [95% CI: 0.24, 1.33]; P= 0.093) and the rate of CR+CRi was higher (68% vs 25%). A greater number of FLT3+ pts treated with CPX-351 were able to undergo SCT (n = 10/22 [45%]; 4 pts were alive as of this analysis, after a median post-SCT follow up of 692 days [range: 96-769]) compared with 7+3 (n = 2/20 [10%]; neither pt still alive). The on-study safety profile of CPX-351 in FLT3+ pts was comparable to 7+3 and consistent with the overall study population. Serious adverse events were experienced by 7 (32%) FLT3+ pts in the CPX-351 arm and 10 (50%) in the 7+3 arm. Conclusions: CPX-351 demonstrated numerical improvement in median OS in older pts with newly diagnosed, FLT3+ high-risk AML and allowed more pts to undergo SCT. The analysis was limited by small number of pts. Clinical trial information: NCT01696084.

Efficacy and safety of aspacytarabine (BST-236) as a single-agent, first-line therapy for patients with acute myeloid leukemia unfit for standard chemotherapy.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7007-7007
Author(s):  
Jessica K. Altman ◽  
Jamie Koprivnikar ◽  
James K. McCloskey ◽  
Vamsi Kota ◽  
Olga Frankfurt ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
De Novo ◽  
Single Agent ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
First Line ◽  
Standard Chemotherapy ◽  
First Line Therapy ◽  
Line Therapy ◽  
De Novo Aml

7007 Background: Aspacytarabine (BST-236) is a prodrug of cytarabine, the backbone of acute myeloid leukemia (AML) standard of care chemotherapy, associated with toxicity which precludes its administration in older patients and patients with comorbidities. Aspacytarabine is inactive in its intact prodrug form until cytarabine is gradually released at pharmacokinetics which decrease the systemic exposure to peak toxic cytarabine levels, resulting in reduced systemic toxicity and relative sparing of normal tissues, enabling therapy with high cytarabine doses to patients otherwise unfit to receive it. Methods: A phase 2b open-label, single-arm study to evaluate the efficacy and safety of aspacytarabine as a first-line single-agent therapy in newly-diagnosed AML patients unfit for standard chemotherapy (NCT03435848). Aspacytarabine is administrated at 4.5 g/m2/d (containing 3 g/m2/d cytarabine) in 1-2 induction and 1-3 consolidation courses, each consisting of 6 daily 1-hour infusions. Patients with secondary AML, prior hypomethylating agent (HMA) therapy, and therapy-related AML, are eligible. Results: To date, in the ongoing study, 46 newly-diagnosed AML patients unfit for standard chemotherapy (median age 75 years) were treated with aspacytarabine and completed 1-4 courses of 4.5 g/m2/d aspacytarabine, including 26 patients (63%) with de novo AML and 17 (37%) with secondary AML. Six patients (13%) were previously treated with HMA (median 12 courses). The baseline median bone marrow blasts was 52%, and 54% and 29% of patients had adverse or intermediate European LeukemiaNet (ELN) score, respectively. Twenty (43%) patients had ECOG 2. Aspacytarabine is safe and well-tolerated in repeated-course administration. Grade > 2 drug-related adverse events include mainly hematological events and infections. The 30-day mortality rate is 11%. Of 43 patients evaluable for efficacy analysis to date, 15 patients (35%) reached a complete remission (CR) following 1 (13 patients) or 2 (2 patients) induction courses, all with complete hematological recovery (median 27.5 days, range 22-39 days). The CR rates in de novo AML patients and patients with adverse ELN score are 46% and 33%, respectively. Of the 11 patients evaluable to date for minimal residual disease (MRD) flow cytometry test, 8 are MRD negative (73%). While aspacytarabine treatment consists of a limited number of courses, median duration of response and median overall survival for responders are not reached at 12 and 24 months, respectively (end of follow up). Updated results will be presented at the meeting. Conclusions: The cumulative clinical data suggest that aspacytarabine, a time-limited single-agent treatment, is safe and efficacious as a first-line therapy for patients who are unfit for intensive chemotherapy, which may establish it as a new tolerable AML chemotherapy backbone. Clinical trial information: NCT03435848.

Etiology and Management of Therapy-Related Myeloid Leukemia

Hematology ◽  
2007 ◽  
Vol 2007 (1) ◽  
pp. 453-459 ◽  
Author(s):  
Richard A. Larson
Keyword(s):  
Myeloid Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
De Novo ◽  
Performance Status ◽  
Direct Consequence ◽  
Cytotoxic Therapy ◽  
Prognostic Features ◽  
Similar Disease ◽  
Primary Disorder ◽  
De Novo Aml

Abstract The diagnosis of therapy-related myeloid leukemia (t-MDS/t-AML) identifies a group of high-risk patients with multiple and varied poor prognostic features. These neoplasms are thought to be the direct consequence of mutational events induced by cytotoxic therapy. Their outcomes have historically been poor compared with those of people who develop acute myeloid leukemia (AML) de novo. The question arises whether a diagnosis of t-AML per se indicates a poor prognosis, or whether their bad outcomes result from other clinical and biologic characteristics. Because of lingering damage from prior cytotoxic therapy and, in some cases, the persistence of their primary disorder, patients with t-AML are often poor candidates for intensive AML therapy. The spectrum of cytogenetic abnormalities in t-AML is similar to de novo AML, but the frequency of unfavorable cytogenetics, such as a complex karyotype or deletion or loss of chromosomes 5 and/or 7, is higher in t-AML. Survival varies according to cytogenetic risk group, with better outcomes observed in patients with t-AML with favorable-risk karyotypes. Treatment recommendations should be based on performance status and karyotype. Patients with t-AML should be enrolled on front-line chemotherapy trials, appropriate for de novo AML patients with similar disease characteristics. Allogeneic hematopoietic cell transplantation can cure some patients with t-AML. Most important , the molecular and genetic differences that appear to determine the phenotype and the outcome of these patients need to be investigated further.

Study of Sequential Treatment of Newly Diagnosed De Novo AML Patients with DA and CAG Regimens as Remission Induction Therapy.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4630-4630
Author(s):  
Hui ping Sun ◽  
Wei Hong Liu ◽  
Jun min Li ◽  
Qiu sheng Chen ◽  
Yu Chen
Keyword(s):  
Bone Marrow ◽  
Induction Therapy ◽  
Peripheral Blood ◽  
De Novo ◽  
Classification Criteria ◽  
Sequential Treatment ◽  
Remission Induction ◽  
Newly Diagnosed ◽  
Fab Classification ◽  
De Novo Aml

Abstract Objectives To evaluate the efficacy and safety of sequential treatment of newly diagnosed de novo AML patients with DA and CAG regimens as induction therapy. Methods Those who were newly diagnosed as de novo AML (FAB classification criteria) were enrolled and DA regimen chemotherapy were administered. Bone marrow aspirates were performed and BM smears were examined at 48 hours since the end of chemotherapy. If severe hypocellularities were not achieved, the percentage of blasts in BM was between 20%–60% and peripheral WBC was in the range of (0.5–10) x109/L, the patients would receive CAG regimen therapy since 72 hours. Patients’ general status and the important parameters, such as peripheral blood count, liver function, renal function, thrombosis and hemostasis parameters were monitored throughout the course of the treatment and thereafter. When the clinical symptoms were relieved and peripheral blood counts returned to normal, or it was the end of the second or third week since the end of the CAG regimen, Bone marrow were examined again to evaluate the efficacy of the sequential therapy. Results 14 patients consisted of 9 male and 5 female patients were enrolled. Out of them, 2 were M1, 5 M2, 4 M4 and 3 M5 according to FAB classification criteria. Median of blasts in BM were 38.5%(20%–60%) before CAG regimen. Of the 14 patients, 10 reached CR, 2 PR and 2 NR. CR rate was 71.4% (10/14) and total response rate was 85.7%(12/14). Time to achieve CR was on 15th(14th–29th)day medianly since the end of the treatment. During the CAG therapy courses, the nadir of peripheral blood cell counts and the time when it occurred were as follows: WBC 1.0(0.2–3.5)(x109/L),10(1–23)(d); Hb 57.5(44–69) (g/L), 10(1–27)(d)and PLT 11.5(10–65)(x109/L), 12(3–23)(d), respectively. Neutropenia (WBC<1.0x109/L) and thrombocytopenia (PLT<20.0x109/L) were lasted for 0(0–24) and 11(0–21)days, respectively. Median units of transfusions of platelets and red blood cells required by each patient were 3(0–10)(u) and 4(0–12)(u), respectively. The most commonly observed side effect of the regimen was bone marrow proliferation inhibition. Infections, usually respiratoy tract infections, were the second. However, sepsis was rare, which appeared in 1 out of 14 patients. Conclusions DA and CAG regimens sequential treatment as remission induction chemotherapy in patients with newly diagnose de novo AML was highly effective and well tolerated. It would be beneficial for those who might not be sensitive enough to DA regimen chemotherapy only.

Homoharringtonine Based Triple-Drug Regimen as Induction Chemotherapy for De Novo Acute Myelogenous Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2002-2002
Author(s):  
Jie Jin ◽  
Wenbin Qian ◽  
Hui Liu ◽  
Daozi Jian ◽  
Wenyuan Mai ◽  
...  
Keyword(s):  
Continuous Infusion ◽  
Neutrophil Count ◽  
Acute Myelogenous Leukemia ◽  
De Novo ◽  
Myelogenous Leukemia ◽  
Hematological Toxicity ◽  
Induction Treatment ◽  
Newly Diagnosed ◽  
Acute Myelogenous ◽  
De Novo Aml

Abstract HAA regimen, consisting of homoharringtonine (HHT), aclarubicin and cytarabine (Ara-C), is an efficacious chemotherapy regimen for induction treatment of acute myelogenous leukemia (AML). HHT, a plant alkaloid that is derived from a Chinese evergreen tree, has been shown to inhibit protein, DNA, and RNA synthesis by inhibition of chain initiation. HAA regimen consists of HHT administered at a dose of 4 mg/m2/day by continuous infusion over 4 hours or 2 mg/m2 intramuscular injection twice daily on days 1–3, aclarubicin administered at a dose of 12 mg/m2/day by continuous infusion over 2 hours on days 1–7, and cytarabine (Ara-C) given at a dose of 75 mg/m2 twice daily on days 1–7. Granulocyte colony-stimulating factor (Lenograstim) 5 μg/kg/day subcutaneously was started from the day neutrophil count <0.5×109/l, and continued until the day neutrophil count >1.0×109/l on 3 successive days. For patients with partial remission (PR) after the evaluation of the first course of the therapy, another same induction HAA regimen was administered. Between May 1999 and June 2006, 80 patients consisted of 31 male and 49 female patients were enrolled. All patients had newly diagnosed with de novo AML and had not received any induction treatments before. Out of them, 3 were M1, 44 M2, 2 M4, and 31 M5 according to FAB classification criteria. The median age was 36 (14–59) years. Of all the 76 patients with cytogenetic analysis available, 13 had favorable karyotype, 58 intermediate karyotype, and 5 unfavorable karyotype. In all, 68 (85%) patients achieved complete remission (CR), and the first single course of this induction regimen resulted in a CR rate of 75%. The CR rate of 100%, 88% and 20% were achieved in patients with favorable, intermediate and unfavorable cytogenetics, respectively. We also found that patients with M5 achieved a CR rate of 74% (23/31), while patients with M1 or M2 94% (44/47). The toxicities associated with this regimen were no more than those expected with standard chemotherapy, and the most common non-hematological toxicity was infection. This study suggested that HAA regimen is a safe regimen and it is efficacious, well-tolerable induction therapy for newly diagnosed de novo AML, the use of G-CSF (Lenograstim) appears to be safe, with little risk of accelerating leukemic relapse. A high CR rate can be achieved with only one or two courses of this regimen. Besides, cytogenetics is an important prognostic factor.

The Size of the Dendritic Cell Population At Diagnosis Worsens Prognosis in Acute Myeloid Leukemia – Bigger Is Not Better

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4870-4870
Author(s):  
Marta I Pereira ◽  
Ana I Espadana ◽  
Emília Cortesão ◽  
Gilberto P Marques ◽  
Catarina Geraldes ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
World Health ◽  
Biological Behavior ◽  
Newly Diagnosed ◽  
Secondary Aml ◽  
De Novo Aml ◽  
Dc Component ◽  
Acute Myeloid

Abstract Abstract 4870 Background: Dendritic cells (DC) are a heterogeneous population of lineage-negative antigen-presenting cells derived from CD34+ hematopoietic progenitors, present in tissue, blood and bone marrow (BM), where plasmacytoid DC (pDC) are a normal finding, representing 0.2 ± 0.1% of cell populations (Matarraz et al, 2010). DC neoplasms include solid tumors (such as DC sarcomas) and an entity classified by the World Health Organization (2008) as an acute myeloid leukemia (AML)-related precursor neoplasm: blastic pDC neoplasm/leukemia, an aggressive disease with poor prognosis, with no clinical trials to orient consensus regarding the most effective treatment; it is usually chemo-resistant, although some cases respond to AML-like regimens and allogeneic hematopoietic stem cell transplant. It is not clear if the presence of an increased DC population in non-DC AML confers pDC neoplasm-like biological characteristics to the former. Aims: This study aims to evaluate whether an increase in the size of DC populations in newly-diagnosed non-DC AML affects the latter's biological behavior, as represented by the overall survival (OS) of patients with the disease. Methods: We reviewed all AML diagnosed in our Hospital between January 1st 2008 and December 31st 2010, identifying 146 patients. We excluded 9 patients who had no flow cytometry immunophenotyping (IP) performed, and 7 whose first IP was performed after treatment was instituted. In that time frame, we also diagnosed 4 pDC neoplasms. Of the 130 patients included, 91 had their presenting IP performed on BM aspirate, while the remaining 39 were phenotyped on blood samples. The size of the DC populations and blastic DC maturation were determined on these samples. Patients were classified into 2 groups according to the size of the DC component; one (the Non-DC Group) had a DC component of up to 0.3% (in practice, the highest value in this group was 0.2%); the other (DC Group) had a percentage over this limit (the lowest value being 1.0%). OS data was determined for both groups; special consideration was given to age strata, separating patients under 65 years of age (Under-65) from those 65 or older (Over-65) and etiology (distinguishing de novo AML from AML secondary to therapy, myelodysplasia or myeloproliferative diseases). The percentage of DC identified by IP did not influence nor alter the type of treatment instituted. Results: We found that the presence of a DC component above the normal BM interval (as determined by Matarraz et al) was associated with a significantly decreased OS, with patients with DC components over 0.3% presenting with a median OS of 2.4 months (mean: 6.4 ± 1.6) and those with a component under 0.3% with a median OS of 8.6 months (mean: 17.0 ± 1.9) (p = 0.033). In our series, patients Over-65 had a median OS of 2.9 months (mean = 6.9 ± 1.0) and those Under-65 a median of 21.3 months (mean = 22.5 ± 2.5), p < 0.001. The differences in OS according to DC component were attenuated in patients Over-65 (median = 1.8 vs. 3.9 months, p = NS), whereas in patients Under-65 the median survival was 2.7 months (mean: 8.7 ± 2.9) for the DC Group and 24.4 months (mean: 24.3 ± 2.7) for the non-DC Group (p = 0.035). The differences in OS were also significant for de novo AML (median = 2.4 vs. 16.0 months, mean = 4.7 ± 1.9 vs. 20.5 ± 2.6, p = 0.017), but not statistically relevant for secondary AML (median = 4.4 vs. 5.5 months, mean = 8.4 vs. 10.8, p = NS). Discussion: In this study, we found that an increase in the size of the DC component as determined by IP at diagnosis on newly-diagnosed AML had a negative impact on prognosis, with a significant decrease in median and mean OS in patients with a percentage of DC over the upper limit of the normal interval. We also determined that the decreased survival was primarily attributed to the better-prognosis groups (patients under 65 and with de novo AML), whereas the effect of the worsened prognosis was attenuated in those patients with a bad prognosis at the outset (patients over 65 and with secondary AML). If data from DC neoplasms could be extrapolated, we could suggest that AML with increased DC components are less chemo-sensitive, which would explain the OS differences found in the Under-65 group, as well as the no-difference found in the Over-65 Group, which is frequently undertreated due to comorbidities. Conclusion: Our study suggests that the size of the DC component at diagnosis as determined by IP is a new prognostic marker predictive of decreased survival. Disclosures: No relevant conflicts of interest to declare.

Assessment Of Human Equilibrative Nucleoside Transporter 1 (hENT1) – Expression By Flow Cytometry In Acute Myeloid Leukemia and Myelodysplastic Syndromes and Correlation To Clinical Outcome In Acute Myeloid Leukemia Patients Treated With Intensive Chemotherapy

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2582-2582 ◽  
Author(s):  
Frauke Bellos ◽  
Bruce H. Davis ◽  
Naomi B. Culp ◽  
Birgitte Booij ◽  
Susanne Schnittger ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Molecular Genetic ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Equity Ownership ◽  
De Novo Aml ◽  
Very High ◽  
Acute Myeloid

Abstract Background Nucleoside analogs depend on cellular hENT1 expression for entry into cells and cytotoxic activity. Studies suggest low cellular hENT1 levels correlate with poor response to such chemotherapies in solid tumors, data on AML and MDS is scarce. Aim To examine hENT1 expression by multiparameter flow cytometry (MFC) in newly diagnosed AML and MDS and correlate results to morphologic, cytogenetic (CG) and molecular genetic (MG) findings. To examine hENT1 expression with respect to clinical outcome in AML patients (pts) treated with intensive cytarabine-based chemotherapy (CHT). Methods We studied pts with newly diagnosed AML (n=145) and MDS (n=96), 133/108 male/female, median age 67.3 (AML) and 73.3 years (MDS). CG was done in 130 AML and 86 MDS. Pts included 107 de novo AML, 9 t-AML, 29 s-AML; FAB: 9 M0, 27 M1, 50 M2, 9 M3, 21 M4, 8 M4eo, 7 M5, 14 not classified; by CG (MRC): 21 favorable, 75 intermediate, 34 adverse. 91 were de novo MDS, 5 t-MDS; 1 RARS, 17 RCMD-RS, 37 RCMD, 3 5q- syndrome, 3 RAEB-1, 5 RAEB-2, 1 CMML, 24 not classified; 2 IPSS-R very low, 55 IPSS-R low, 8 IPSS-R intermediate, 8 IPSS-R high, 13 IPSS-R very high. hENT1 expression was quantified by a novel four color intracellular staining assay using monoclonal antibodies against hENT1, CD45, CD64 and myeloperoxidase. Median fluorescence intensities (MFI) of hENT1 were determined in myeloid progenitors (MP), granulocytes (G) and monocytic cells (Mo) and correlated to hENT1 MFI in lymphocytes to derive hENT1 index (index). Results No correlation of index to age, gender, hemoglobin level or counts for blasts, WBC or platelets was detected. In AML, we generally saw higher index by trend in the more favorable prognostic subgroups. M3/t(15;17)/PML-RARA+ displayed higher index in MP than non-M3 AML (4.24 vs 2.56, p<0.001). G index was lower in M0 (3.01) vs M1, M2, M4 and M4eo (5.66, 4.34, 5.35, 4.77; p=0.01, 0.028, 0.004, 0.043, respectively) and in M2 compared to M1 and M4 (4.34. vs 5.66 and 5.35, p=0.01 and 0.033, respectively). M2 showed lower MP index than M5 (2.42 vs 2.99, p=0.016). Considering CG, index in MP was higher in favorable vs intermediate and adverse pts (3.05 vs 2.58 and 2.53, p=0.034 and 0.023, respectively), Mo index was higher ín favorable vs adverse pts (3.17 vs 2.71, p=0.044). By MG, higher index in Mo and G was observed in RUNX1-RUNX1T1+ AML (4/83, 4.32 vs 3.04, p=0.01; 8.16 vs 4.60, p=0.002, respectively). Higher index for MP was found in FLT3-ITD mutated (mut) (18/111; 3.19 vs 2.62, p=0.012), CEPBA mut (4/26, 3.15 vs 2.35, p=0.004) and for Mo in NPM1 mut AML (23/104; 3.72 vs 2.84, p=0.02), whereas lower index for MP was found in RUNX1mut pts (13/65; 2.17 vs 2.59, p=0.031). De novo AML displayed higher MP index than s-AML (2.7 vs 2.28, p=0.008). Using lowest quartile of index for MP (2.1185) as cut-off, AML pts in the MRC intermediate group treated with CHT (n=38) had inferior OS if MP index was below vs above this cut-off (OS at 6 months 63% vs. 95%, p=0.017, median follow up 4.6 months). MDS showed lower Mo and MP index than AML (2.68 vs 2.96, p=0.021, 1.84 vs 2.65, p<0.001, respectively). By IPSS-R, significance was reached for higher index in Mo and MP in very low risk compared to low risk pts (3.39 vs 2.54, p=0.013 and 4.07 vs 1.78, p<0.001, respectively), MP in very low compared to intermediate and high risk pts (4.07 vs 1.95, p=0.004; 4.07 vs 1.76, p=0.002), and MP and G in very low vs very high risk pts (4.07 vs 1.71, p=0.005; 5.86 vs 3.85, p=0.001, respectively). IPSS-R intermediate vs poor and very poor showed lower G index (5.47 vs 3.59, p=0.018 and vs 3.85, p=0.034 respectively). Conclusion AML with genetic and molecular genetic good risk profile had higher hENT1 expression in MP, G and Mo, suggesting a causal mechanism for better response to CHT and better outcome. Consequently, AML with poor risk molecular genetics (RUNX1 mut) showed lower levels of hENT1 in MP. The detection of higher levels in FLT3-ITD mut pts is in line with reportedly good response to CHT, overall worse outcome being mostly due to early relapses. Strikingly, we saw differences in outcome in pts treated with CHT according to hENT1 expression with shorter OS in pts with low index for MP. Higher index in de novo AML than s-AML and MDS may be causal for better response to nucleoside-based CHT in de novo AML. Data for MDS may be interpreted accordingly, lower risk cases showing higher index in MP, G and Mo. Further analyses are needed to explore hENT1 expression in AML and MDS more comprehensively. Disclosures: Bellos: MLL Munich Leukemia Laboratory: Employment. Davis:Trillium Diagnostics, LLC: Equity Ownership. Culp:Trillium Diagnostics, LLC: Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

The Prevalence of Fanconi Anemia Among Patients with De Novo Acute Myelogenous Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2232-2232
Author(s):  
Andrzej Rochowski ◽  
Philip S Rosenberg ◽  
Todd A. Alonzo ◽  
Robert B. Gerbing ◽  
Beverly Lange ◽  
...  
Keyword(s):  
Cohort Studies ◽  
Fanconi Anemia ◽  
Null Hypothesis ◽  
Universal Screening ◽  
De Novo ◽  
Screening Strategy ◽  
Myelogenous Leukemia ◽  
Newly Diagnosed ◽  
Acute Myelogenous ◽  
De Novo Aml

Abstract Abstract 2232 The diagnosis of acute myeloid leukemia (AML) was the first presentation in approximately one-third of published cases of Fanconi anemia (FA) that led to the diagnosis of FA. Our objective therefore was to estimate the number of undiagnosed patients with Fanconi anemia (FA) who may present with acute myelogenous leukemia (AML), in order to justify a universal screening strategy. The probability of having FA among patients with AML, using Bayes rule, was calculated as: P(FAüAML) = [P(AMLüFA) × P(FA)]/P(AML). Data from the Surveillance, Epidemiology and End Results (SEER) Program, published FA cohort studies, and the Fanconi Anemia Research Fund were used to estimate these probabilities. P(FAüAML) was then applied to data on the time to recovery of an absolute neutrophil count (ANC) above 1000/μL from 892 de novo AML patients enrolled on Children's Oncology Group treatment protocol CCG-2961 between 1997 and 2002. A derived, exact binomial distribution of a one-sided Fisher hypothesis test was used to estimate the number of patients with FA among newly diagnosed AML patients required to reject the null hypothesis stating that the prevalence of FA among patients newly diagnosed with AML is less than an arbitrarily chosen threshold of 1%. From the published FA cohort studies, we estimated P(AMLüFA) in patients less than 19 years old at 0.5%/yr. Assuming an FA allele frequency of 1/300, autosomal recessive inheritance and an 80% FA survival rate until age of 18 years, P(FA) in the US population less than 19 years of age was estimated to be 5 × 10-5. SEER data were used to estimate the age-adjusted P(AML) in persons 0–19 yrs at 0.73/100,000. The estimated probability that a newly-diagnosed AML patient has FA is therefore ∼3%. In CCG-2961, ANC recovery >1000/ μL after the first round of AML induction chemotherapy occurred in a mean of 40 +/− 9.6 days. Eighteen percent (165/892) of the patients never achieved an ANC >1000 and 22% (193/892) had no ANC recovery at 60 days (2 SD from the mean). Based on our estimate of 3% FA patients among de novo AML cases 27 FA patients (3% of 892) could represent at least 14% (27/193) of patients who had no ANC recovery at 60 days. Using the exact binomial distribution we estimate that a sample size of 375 newly diagnosed AML patients would have 80% power and a type I error rate of <0.05 to reject the null hypothesis that the prevalence of FA is less than 1% among those 375 AML patients. For this test, the critical value is 8 FA cases in 375 AML patients. In conclusion, we suggest that at least 3% of newly-diagnosed AML patients may, in fact, have FA. Identification of 8 or more FA cases among 375 newly diagnosed patients with AML would justify a universal screening strategy. FA screening in the evaluation of patients with newly-diagnosed AML would require the development of rapid FA screening techniques. This would permit timely adjustment of the chemotherapy regimen in order to minimize FA-related chemotoxicities. Finally, the remaining of those patients who never achieved ANC recovery might be accounted for by the toxicity of the AML treatment due to polymorphisms in genes involved in the metabolism of chemotherapy or to other, undiagnosed, AML-prone genetic syndromes. Disclosures: No relevant conflicts of interest to declare.

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