Favorable Outcome of Older Patients with AML and a Favorable Genotype NPM1mut FLT3-ITD Treated with Intensive Chemotherapy: A Subgroup Analysis of Cetlam Protocol 2003 & 2012

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2511-2511
Author(s):  
Marta Pratcorona ◽  
Jordi Lopez-Pardo ◽  
Ana Garrido ◽  
Salut Brunet ◽  
Josep-Maria Ribera ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Older Patients ◽  
Intensive Chemotherapy ◽  
Molecular Subgroup ◽  
Younger Patients ◽  
Favorable Prognosis ◽  
Molecular Features ◽  
Molecular Group ◽  
Wbc Count ◽  
Bone Marrow Blasts

Abstract Introduction Younger patients with acute myeloid leukemia and intermediate cytogenetic risk (AML-IR) harboring NPM1 mutation (NPM1mut) without FLT3 internal tandem duplication (FLT3-ITD) have a relatively favorable prognosis, and are not deemed as candidates to receive an allogeneic hematopoietic stem cell transplantation in first complete remission (CR1). However, it remains uncertain if this favorable prognosis is also maintained in older patients within the same molecular features with some conflicting results. Patients and methods We analyzed the cohort of patients ≥60 year-old considered fit for intensive chemotherapy and included in the CETLAM protocols LMA-2003 and LMA-2012 for patients up to 70, consisting of a standard induction chemotherapy, HiDAC post-remission therapy, followed by alloHSCT in selected patients with high-risk features. Overall we identified 192 patients between 60 and 71 year-old diagnosed with AML-IR with known NPM1 and FLT3 mutational status. Results We identified 192 AML-IR patients (93♀, 99♂) aged >=60 (median age was 65 years old (range: 60-71)), with a median WBC count 10.6 x 109/L (range: 0.23-400 x 109/L), median bone marrow blasts 65% (range: 20-100%). Overall, CR rate was 78%, five-year overall survival (OS) was 30±4%, and leukemia-free survival (LFS) was 31±4%. Patients were classified in three molecular groups depending on NPM1mut and FLT3-ITD: 40 patients harbored NPM1mut/FLT3 without ITD (FAV group), 98 patients had NPM1wt/FLT3wt, and 54 had a FLT3-ITD. Five-year OS of these 3 groups were: 64±9%, 25±6%, and 19±6%, respectively (p<0.001). Since the two latter groups, NPM1wt/FLT3wt and FLT3-ITD, did not show significant differences, we decided to group them in a sole subgroup (UNFAV group). There were no differences in the complete remission rate between patients of FAV and UNFAV groups (88% vs 78%, p=ns), but the cumulative incidence of relapse was significantly higher for patients of the UNFAV group (54 vs. 17.5%, p=0.000654). Multivariate analysis for OS, including WBC count, bone marrow blasts and molecular group (NPM1mut/FLT3wt vs. the other groups) identified WBC and molecular subgroup showed significance for the WBC count (HR=1.003, 95% CI: 1-1.006) and the molecular group (FAV vs. UNFAV, HR=0.345, 95% CI: 0.192-0.621). Interestingly, when we compared the outcome of the FAV group with a cohort of younger patients (up to 60, n=99) with the same molecular features included in these 2 protocols, the outcome did not differ depending on age (5-year OS 69±5% for younger patients, and 64±9% for older patients, p=0.463, and 5-yr LFS 67±5% for younger patients, and 55±12% for older patients, p=0.567). Moreover, the outcome of a small cohort of FAV patients older than 65 years (n=16) included in these protocols was relatively favourable, with a 5-yr OS and LFS not differing substantially from that of younger patients allocated in the same molecular subgroup. Conclusions The favorable impact of NPM1mut/FLT3-ITDneg genotype was maintained in a cohort of patients >60 who received intensive chemotherapy, with a high proportion of long-standing responses after HiDAC-based post-remission therapy. Disclosures No relevant conflicts of interest to declare.

White Blood Cell Count Nadir and Duration of Aplasia Do Not Associate with Treatment Outcome in Adult Patients with Acute Myeloid Leukemia Undergoing Intensive Chemotherapy

Chemotherapy ◽  
2020 ◽  
Vol 65 (3-4) ◽  
pp. 110-114
Author(s):  
Tatiana Marras ◽  
Michael Dettori ◽  
Giovanni Caocci ◽  
Giorgio La Nasa ◽  
Giovanni Sotgiu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myeloid Leukemia ◽  
Surrogate Marker ◽  
Adult Patients ◽  
Intensive Chemotherapy ◽  
Bone Marrow Aplasia ◽  
Count Nadir ◽  
Wbc Count ◽  
Bone Marrow Blasts

<b><i>Introduction:</i></b> Adult patients with acute myeloid leukemia (AML) are usually treated with intensive chemotherapy, leading to prolonged bone marrow aplasia. It is usually assumed that a short duration of aplasia could be a surrogate marker of poor therapeutic efficacy in clearing bone marrow blasts, especially in older patients. No studies have evaluated the usefulness of such a surrogate marker in younger AML patients treated with intensive chemotherapy. <b><i>Materials and Methods:</i></b> In the present study, we retrospectively assessed the role of white blood cell (WBC) count nadir and duration of aplasia in 68 patients with AML treated with intensive chemotherapy and potentially candidate to stem cell transplantation. <b><i>Results:</i></b> The median (interquartile range) bone marrow aplasia was 25 days, and the mean WBC count nadir from chemotherapy start was at day +12, whereas the median neutrophil recovery occurred at day +24. No significant differences were found between responders and nonresponders for mean aplasia duration (25 vs. 26 days, <i>p</i> value = 0.76), mean WBC count nadir (12 vs. 12 days, <i>p</i> value = 0.86), and median neutrophil recovery (24 vs. 24, <i>p</i> value = 0.67). <b><i>Discussion:</i></b> The present study evaluated the potential prognostic role of WBC count nadir and duration of aplasia, demonstrating that they are not associated with treatment outcomes in adult patients with AML treated with intensive chemotherapy. Therefore, a short duration of aplasia seems not linked to poor therapeutic efficacy in clearing bone marrow blasts. Our findings, although needing validation in larger and more homogeneous cohorts, may offer helpful clues in the management of aplasia of AML patients.

Influence of Age and Needle Gauge on Bone Marrow Biopsy Specimen Adequacy.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5581-5581
Author(s):  
Alec Goldenberg ◽  
Priscilla Kelley ◽  
Sherif Ibrahim ◽  
Filiz Sen ◽  
Cynthia Liu
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Biopsy ◽  
Older Patients ◽  
Response To Treatment ◽  
Specimen Length ◽  
Younger Patients ◽  
Biopsy Specimens ◽  
Clinical Diagnoses ◽  
The Mean ◽  
Biopsy Needles

Abstract Introduction. The quality and length of bone marrow biopsy core specimens should facilitate accurate diagnositic interpretation of marrow histopathology. A 11G specimen of length 1.6 cm or greater is considered adequate for pathologic evaluation by some authors. The length of specimens recovered with 11G needles appears to depend on needle design. We explored the possibility that the adequacy of bone marrow biopsy specimens may be influenced by patient age and the gauge of biopsy needles. Methods. 88 bone marrow core specimens were recovered from 72 patients using 11G SNARECOIL bone marrow biopsy needles. The mean age of these patients was 61.4 and the m/f ratio was 45/27. The clinical diagnoses were isolated anemia, cytopenias, leukemia, lymphoma, myeloma and other in 18.0%, 33.3%, 13.8%, 13.8%, 5.5% and 15.2% of the patients, respectively. 10 patients underwent multiple procedures (2–6) for evaluation of treatment efficacy. 106 patients underwent 127 bone marrow biopsy procedures using 8G SNARECOIL needles. The m/f ratio was 56/50 and the mean age of the patients was 63.1years. The clinical diagnoses were isolated anemia, cytopenia, leukemia, lymphoma, myeloma or other in 22.2%, 19.6%, 14.9%, 21.2%, 12.5% and 9.4% patients respectively. 13 patients underwent multiple procedures (range 2–4) for evaluation of response to treatment. Results. Although the mean length of the 11G and 8G specimens were statistically significantly the same (mean±SEM, 1.97±0.07 cm vs. 1.99±0.05 cm, respectively, p = 0.8), the distribution of specimen lengths was asymmetric or skewed for the 11G specimens (skewness(skw) =0.52) and nearly normal for the 8G specimens (skw =0.04). The deviation from a normal distribution suggested additional variable(s) might be effecting specimen length. The possible influence of age on specimen length relative to needle gauge was considered. The mean age of the patients biopsied with 11G needles was 61.4. The m/f ratios of the patients ≤64 and ≥65 were statistically the same (27/12 vs. 18/15, respectively, p = 0.2). The mean age of the patients biopsied with 8G needles was 63.1. The m/f ratios of the patients ≤64 and ≥65 were statistically the same (30/26 vs. 26/23, respectively, p =0.5). 11 G specimens from younger patients, ≤64, were more frequently adequate (1.6 cm or greater) (39/53 = 73.5%) than specimens from older patients ≥ 65 (18/35 = 51.4%), p = 0.03. Conversely adequate 8G specimens were recovered as frequently in older patients ≥65 years (40/55 = 72.7%) as they were in younger patients ≤64 years, (59/72 = 81.9%) p = 0.21. Moreover, in older patients, adequate biopsy specimens were recovered more frequently by 8G needles then by 11G needles (40/55=72.7% vs. 18/35 = 51.4%, respectively, p = 0.04). Conclusions. 1. Age influences the rate of recovery of adequate bone marrow core biopsy specimens. 2. 8G needles recover adequate specimens more frequently than 11G needles in older patients.

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.

Clinical features and tumor mutational profile of younger versus older patients with cholangiocarcinoma (CCA).

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 240-240
Author(s):  
Lipika Goyal ◽  
Stephanie Reyes ◽  
Apurva Jain ◽  
Rachna T. Shroff ◽  
Tri Minh Le ◽  
...  
Keyword(s):  
Risk Factors ◽  
Older Patients ◽  
Tertiary Care ◽  
Tumor Biology ◽  
Young Patients ◽  
Molecular Testing ◽  
Extrahepatic Cholangiocarcinoma ◽  
Younger Patients ◽  
Molecular Features ◽  
Significant Difference

240 Background: As seen in lung cancer, young patients with cancer can have different risk factors, presentation, and tumor genotype than older patients with the same disease. The clinical and molecular features of young patients with CCA have yet to be well characterized. Methods: Retrospective chart review was performed on patients with intrahepatic (ICC) or extrahepatic cholangiocarcinoma (ECC) across 5 institutions. Data on demographics, risk factors, treatments, pathology, and overall survival (OS) were collected. Tumor genotyping results from MGH SNaPShot and Foundation Medicine were analyzed. Log-rank tests and Kaplan-Meier survival curves were used for statistical analysis. Results: Of 567 patients analyzed, 134 (23.6%) were < 50 years old (yo) and 455 (80.2%) had ICC. When assessed for risk factors, younger patients ( < 50yo) were more likely to have primary sclerosing cholangitis (PSC) (p < 0.001) and less likely to have diabetes (p = 0.05), compared to older patients ( ≥ 50yo). Surgical resection rates were similar in younger vs older patients (41.9 vs 42.6%, p = 0.890), but younger patients had larger tumors (median size 7.1 vs 5.3cm p = 0.012). Younger patients were also more likely to receive palliative systemic chemotherapy (p < 0.001) and more lines of therapy (median, 2 vs 1 line, p < 0.001). Frequency of treatment with liver directed therapy did not differ between the two groups. Molecular testing was performed on 222/567 (39.1%) patients of which 84/134 (62.7%) were younger patients and 138/433 (31.9%) were older patients. FGFR aberrations were more common in younger patients versus older patients (17.6 vs. 5.7%, p = 0.002). Targeted therapy was given to 15/84 (17.9%) younger and 28/138 (20.3%) older patients based on results of mutational profiling. Finally, no significant difference was seen in OS between younger and older patients (22.9 vs 22.7 months, p = 0.89). Conclusions: Younger patients with CCA may have different risk factors, tumor biology, and tolerance of systemic therapy compared to older patients. Further study is needed as referral patterns to tertiary care centers and motivation of younger patients to seek tertiary care may impact these results.

A Phase II Study of Azacitidine (Vidaza™) for Patients with Myelofibrosis (MF).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2706-2706 ◽  
Author(s):  
Alfonso Quintas-Cardama ◽  
Hagop Kantarjian ◽  
Guillermo Garcia-Manero ◽  
Deborah Thomas ◽  
STeven Kornblau ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase Ii ◽  
Retinoic Acid Receptor ◽  
Jak2 V617f ◽  
Complete Response ◽  
Pegylated Interferon ◽  
Prior Therapy ◽  
Grade 3 ◽  
Wbc Count ◽  
Bone Marrow Blasts

Abstract Aberrant DNA methylation of promoter-associated CpG islands is a mechanism of epigenetic silencing frequently encountered in human neoplasia. Hypermethylation of several genes such as p15INK4B, p16INK4A, progesterone receptor, and the retinoic acid receptor β have been detected in patients (pts) with advanced-stage MF. Azacitidine (Vidaza™) is a hypomethylating agent that induces reactivation of methylated genes and has been approved for the treatment of pts with myelodysplastic syndromes. The objective of this phase II trial was to study the efficacy of azacitidine in pts with relapsed or refractory MF (primary, or secondary to essential thrombocythemia or polycythemia vera) or newly-diagnosed with a Lille risk score 1 or 2 (risk factor are white blood cell [WBC] count >30x109/L or <4x109/L, and hemoglobin [Hb] <10 g/dL). Azacitidine was given at 75 mg/m_ daily (dose level [DL] 0) for 7 days every 4 weeks for 6 cycles but this could be reduced to 50 (DL -1), 25 (DL -2), or 12.5 (DL -3) or increased to 100 (DL +1) mg/m_ according to toxicity or lack of response, respectively. Thirty-four pts have been treated, median age 66 years (range 39–82), time from MF diagnosis to azacitidine therapy 21 months (range 1–361), median Hb 10.3 g/dL (range 8.2–14.3), WBC 10.7x109/L (range 1.7–57.7), and platelets 205x109/L (range 11–1216). Pts had received a median of 1 prior therapy (range 0–6), including hydroxyurea (HU; n=16), anagrelide (AG; n=8), lenalidomide (n=6), thalidomide (n=6), etanercept (n=2), and pegylated interferon (n=2). Six pts had not received any prior therapy. The JAK2 V617F mutation was detected in 19 (70%) of 27 tested pts and 12 of 34 (35%) had abnormal cytogenetics. A total of 142 cycles have been administered. All 34 patients are evaluable for response and toxicity. Responses have been observed in 10 (29%) pts so far, including complete response (CR) in 1 (normal blood counts and <5% bone marrow blasts; off HU, AG, growth factors, and no transfusions), partial response (PR) in 7 (defined as at least 2 of the following: Hb increase by ≥2 g/dL, 50% increase in platelets, decrease of bone marrow blasts or organomegaly by ≥50%, normalization of WBC count without blasts, or reduction in bone marrow fibrosis), and hematologic improvement (HI) in 2 (defined as at least 2 of the following: decrease by ≥25% of pretreatment leukocytosis, splenomegaly, or marrow blasts, or increase of Hb by ≥1g/dl or platelets by ≥25%). The median time to best response was 7.5 weeks (range, 3 to 26). Fifteen (44%) pts discontinued azacitidine due to: lack of response in 7, transformation to acute myeloid leukemia in 2, death (unrelated to azacitidine therapy) in 1, pt’s decision in 1, grade 3–4 toxicity in 2, and other medical reasons in 2. Azacitidine has been generally well tolerated; 10 pts (29%) had grade 3 or 4 toxicity; neutropenia was the only grade 4 toxicity (in 4 pts). Eleven pts (32%) have required dose reduction to DL -1, of which 3 reduced to DL -2, and 9 pts (26%) escalated the dose to DL +1. In summary, azacitidine is well tolerated and has activity in a subset of pts with MF, with current overall response rate of 29%. Updated clinical results will be presented.

Elderly Acute Myeloid Leukemia: A Retrospective Analysis of 93 Cases.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4163-4163
Author(s):  
Xin Du ◽  
Yuchun Wang ◽  
Zesheng Lu ◽  
Jianyu Weng ◽  
Xiaoli Zou
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Allogeneic Bone Marrow Transplantation ◽  
Myelogenous Leukemia ◽  
Allogeneic Bone ◽  
Intensive Chemotherapy ◽  
Acute Myeloid

Abstract Abstract 4163 Background Acute myelogenous leukemia (AML) is generally looked upon as a heterogeneous group of different entities originating from the malignant transformation of a hematopoietic progenitor or stem cell. AML incidence increases with age. AML is associated with a poor prognosis, particularly in older patients. The poor prognosis in older adults is because of a combination of factors, including a larger proportion of cases with adverse-risk cytogenetics and other deleterious genetic and epigenetic changes, lower rates of achieving complete remission with intensive chemotherapy, higher risk of disease recurrence after achieving remission, greater comorbidity, inability to tolerate conventional allogeneic bone marrow transplantation regimens, and other adverse prognostic factors. The outlook for these patients remains dismal and little progress as been made in the last two decades. Current treatment of elderly AML consists of intensive chemotherapy with an anthracycline and a cytarabine. To evaluate our progress in the diagnosis, treatment and outcome of this condition, we reviewed the reports of 93 newly diagnosed acute myeloid leukaemia patients>/=55 years of age admitted to our department between 2003 and 2007. Methods A retrospective chart review was performed of 93 patients >/=55 years of age diagnosed with acute myeloid leukemia. The clinical efficacy was observed and the overall survival(OS) were analyzed. Results Median age of patients was 66 (range 55-88) years, 69 patients(74%) received a combination of an anthracycline and a cytarabine, either mitoxantrone per day on days 1, 2(MA),or 35 mg/m2 pirarubicin(TA) 7–8mg/m2 or idarubicin per day on days 1, 2 (IA). Each patient was given 100mg/m2 cytarabine intravenously per day for 7 days. And 24 patients (26%) were untreated. Total CR rate was 45% after 2 regimens. Only 3 patients happened to early death. The median period of the bone marrow depression is 19 days. The follow-up was ended at Aug 2008 year. Median survival of the treated patients was 256 days and it was significantly (P = 0.003) different from the untreated patients(66 days). Of the treated group, 7 patients were still alive, and the longest time was more than 6 years. Conclusions The prognosis of acute myeloid leukemia in older patients remains poor, but the anthracycline chemotherapy seems to improve the outcomes among older with AML. For this difficult patient cohort, it is a better treatment that can exert a more selective anti-leukaemic activity whilst not suppressing normal haemopoiesis or having significant systemic toxicities. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Dose-Adjusted Intensive Chemotherapy Is Safe and Tolerable in Older Patients with Ph-Negative Acute Lymphoblastic Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5158-5158
Author(s):  
Anne S. Renteria ◽  
Sangeetha Venugopal ◽  
Bridget Marcellino ◽  
Alla Keyzner ◽  
Marina Kremyanskaya ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Board Of Directors ◽  
Older Patients ◽  
Research Funding ◽  
Chemotherapy Regimen ◽  
Lymphoblastic Leukemia ◽  
Intensive Chemotherapy ◽  
Advisory Committees

Abstract Background The outcomes of older adults with acute lymphoblastic leukemia (ALL) remain poor when compared to younger ALL patients [PMID 19897583, 28419558, 22409379, 10653870]. Asparaginase (Asp) induces death of human lymphoblasts, and effective asparagine depletion is associated with improved outcomes in ALL. PEG-Asparaginase (PEG-Asp), which has a longer half-life than Asp, is a key component of the intensive chemotherapeutic regimens utilized for treatment of pediatric and younger adult ALL [PMID 29450465]. Frequently, older patients with Ph-negative ALL are not offered PEG-Asp containing pediatric chemotherapy regimen because of concerns related to tolerability and safety in this population [PMID 28355969]. Methods The Adult Leukemia Program at Mount Sinai Hospital developed an age-based, dose-adjusted, CALGB 10403 based intensive chemotherapy regimen for adults (≥40 years) with a diagnosis of Ph-negative ALL. For patients up to 60 years, prednisone (PRD) dose was reduced from 60 to 40 mg/m2/day from D1 to D28, and PEG-Asp reduced from 2500 to 1000 units/m2 (D4). For patients aged 61 years and above, PRD was further reduced to 25 mg/m2/day, and PEG-Asp to 1000 units/m2 on D4. In CD20+ ALL, rituximab x 8 doses were added to the regimen. CNS-prophylaxis consisted of intrathecal methotrexate at D1, D8 and D29 during induction, and during subsequent courses of chemotherapy based on the CALGB 10403 protocol. A PEG-Asp oriented supportive care plan was developed to prevent and treat Asp-related adverse effects. After the administration of PEG-Asp, Antithrombin III (ATIII) and fibrinogen levels were monitored on the same day, twice a week, for at least two weeks. If ATIII levels were < 70% and/or fibrinogen levels < 120 mg/dL, levels were corrected with the administration of ATIII concentrate and/or cryoprecipitate, respectively. Results Twelve patients with a median age of 58 years (45 - 76) were evaluable, and three patients were ≥ 70 years. Nine patients had B-cell ALL and three T-cell ALL. Three patients had a white blood cell count > 30 x103/µL at diagnosis. An ECOG status ≤ 2 at diagnosis was described in all patients, and all of them had multiple complex cytogenetic and molecular abnormalities. Ten patients had significant co-morbidities at diagnosis, including diabetes, hypertension, previous history of cancer, coronary artery disease, obesity, alcohol related chronic pancreatitis, and chronic diarrhea. Nine out of the twelve patients (75%) attained a bone marrow morphological complete remission (CR) at the end of induction (EOI), three of them with detectable minimal residual disease (MRD) that became undetectable after completing course II. Of the three patients who had ≥5% bone marrow blasts at EOI, one attained a CR with undetectable MRD at the end of course IA and another when switched to blinatumomab, and the third one died of progressive disease. No patient experienced early death. Five patients underwent allogeneic hematopoietic stem cell transplantation (HCT) while in CR (age range 46 to 60 years) and four remain in CR at last follow up (median 489 days, range 181 - 841), and one died of relapsed disease 67 days post-HCT. The other six patients who are receiving chemotherapy are alive and in remission at last follow up (median 272 days, range 52 - 639). The common adverse effects associated with PEG-Asp administration in this older group of patients were asymptomatic hypofibrinogenemia and depleted ATIII levels requiring supplementation (n=8), severe hyperbilirubinemia (n=1), and non-life-threatening venous thrombosis (n=1). Severe allergic reaction, clinical pancreatitis and cognitive impairment were not observed. Conclusion This age-based dose-adjusted PEG-Asp containing regimen was associated with an encouraging CR rate and a tolerable and manageable adverse event profile in this older patient population with significant co-morbidities. Treatment related mortality was 0%. Ten of 12 patients are currently in sustained remission, either with chemotherapy alone or following allogeneic HCT (median follow up 422 days, range 52 to 841 days). Treatment optimization for older patients with ALL utilizing an intensified, age-adjusted PEG-Asp containing induction and consolidation therapy regimen is associated with favorable outcomes and provides an effective bridge to potentially curative therapies such as HCT. Further prospective evaluation is under way. Table. Table. Disclosures Kremyanskaya: Incyte: Research Funding. Mascarenhas:Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Promedior: Research Funding; Janssen: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding.

Multivariate and Subgroup Analyses of a Multinational Phase III Trial of Decitabine in Older Patients with Newly Diagnosed Acute Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3618-3618 ◽  
Author(s):  
Jiri Mayer ◽  
Christopher Arthur ◽  
Jacques Delaunay ◽  
Grzegorz Mazur ◽  
Xavier Thomas ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Supportive Care ◽  
Older Patients ◽  
De Novo ◽  
Geographic Region ◽  
Phase Iii ◽  
Refractory Anemia ◽  
Newly Diagnosed ◽  
Wbc Count ◽  
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Abstract Abstract 3618 Introduction: A recent phase III trial compared efficacy and safety of decitabine with those of patient's treatment choice (TC) of supportive care or low-dose cytarabine in older patients with newly diagnosed acute myeloid leukemia (AML) and poor- or intermediate-risk cytogenetics (Kantarjian et al. J Clin Oncol 2012;30:2760; NCT00260832). At the planned clinical cutoff date in 2009 (396 deaths), a nonsignificant trend toward increased median overall survival (OS) was seen with decitabine (7.7 months; 95% confidence interval [CI] 6.2, 9.2 months) vs TC (5.0 months; 95% CI: 4.3, 6.3 months); estimated hazard ratio (HR) 0.85 (P=.108). A 2010 post hoc analysis of mature data (446 deaths) from this study showed that the median OS had not changed but HR had improved (0.82; 95% CI 0.68, 0.99; nominal P=.037) and favored decitabine versus TC. At the 2009 cutoff, remission rates (complete response [CR] or CR with incomplete platelet recovery [CRp] were significantly improved with decitabine (17.8%) vs TC (7.8%; P=.001). Decitabine was generally well tolerated. A multivariate analysis was conducted using the mature (2010) data to identify potential predictors of OS in this older population with AML. Methods: Eligible patients were aged ≥65 years with newly diagnosed de novo or secondary AML (≥20% blasts), poor- or intermediate-risk cytogenetics, and Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–2. Patients were randomized 1:1 to receive decitabine (20 mg/m2 intravenously once daily for 5 consecutive days every 4 weeks) or TC (supportive care or cytarabine 20 mg/m2 subcutaneously once daily for 10 days every 4 weeks), stratified by age, cytogenetic risk, and ECOG PS. A multivariate Cox proportional hazards model was used to investigate the effects of the following demographic and baseline characteristics on OS in addition to treatment effect: sex, age (<70, 70–<75, or ≥75 years), baseline cytogenetic risk (intermediate vs poor), AML type (de novo vs secondary), baseline ECOG PS (0/1 vs 2), geographic region (North America/Australia, Western Europe, Eastern Europe, Asia), baseline bone marrow blasts (>50% vs ≤50%), baseline platelet count (analyzed at each unit of 100 × 109/L) and baseline white blood cell (WBC) count (analyzed at each unit of 25 × 109/L). These potential prognostic factors were evaluated simultaneously, and values were not adjusted for multiple testing. Results: Of 485 randomized patients, 242 received decitabine and 243 received TC (cytarabine, n=215; supportive care, n=28). Baseline patient demographics and clinical characteristics were similar between groups and indicated a high-risk population: 71% of patients were aged ≥70 years, 35.3% had secondary AML, 36.0% had poor-risk cytogenetics, and 25.8% had ECOG PS 2 or higher; median baseline proportion of blasts in bone marrow was 46.0%. Patient characteristics that appeared to adversely affect OS at the 0.05 level included more advanced age, poorer baseline ECOG PS, poor cytogenetics, higher bone marrow blast count, low baseline platelet count, high WBC count, and geographic region (Western vs Eastern Europe) (Table). Conclusions: In older patients with AML, OS was associated with prognostic factors of age, ECOG PS, cytogenetic risk, baseline bone marrow blasts, baseline platelet counts, and baseline WBC in addition to responding differently to decitabine vs TC (supportive care or cytarabine). Treatment response is related both to patient and disease status in older patients with AML. Disclosures: Mayer: Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Decitabine is a nucleoside metabolic inhibitor indicated for treatment of patients with myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups. Delaunay:Novartis, Genzyme: Consultancy. Jones:Eisai Inc: Employment. Berrak:Eisai Inc: Employment. Kantarjian:Eisai: Research Funding.

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