scholarly journals Obesity in Children with Acute Promyelocytic Leukemia: What is its Incidence and Prognostic Significance?

Author(s):  
Kathryn Laurie ◽  
Paul Lee ◽  
Alfred Rademaker ◽  
Todd Alonzo ◽  
Yi-Cheng Wang ◽  
...  

Objective: To compare outcomes data of obese and non-obese pediatric patients with acute promyelocytic leukemia from the Cancer and Leukemia Group B trial C9710 and the Children’s Oncology Group trial AAML0631. Methods: Data including demographics, adverse events, overall survival and event free survival was analyzed, with a focus on mortality in obese patients. Results: The incidence of obesity was 34% on C9710 and 35% on AAML0631. There was significantly lower overall survival in the obese population on AAML0631. Thirteen patients died during therapy or in follow up; seven of these occurred during induction. Conclusion: The incidence of obesity is higher in patients with APL compared to the general population. The presence and degree of obesity can influence OS on the most current treatment regimen. This implies the need for close management of obese patients at diagnosis as well as reinforces the need for further research on obesity driven APL

1997 ◽  
Vol 15 (5) ◽  
pp. 1786-1795 ◽  
Author(s):  
J L Slack ◽  
D C Arthur ◽  
D Lawrence ◽  
K Mrózek ◽  
R J Mayer ◽  
...  

PURPOSE To examine, in newly diagnosed patients with acute promyelocytic leukemia (APL), the prognostic significance of secondary cytogenetic changes and the relationship between such changes and the two major promyelocytic leukemia-retinoic acid receptor alpha (PML-RAR alpha) mRNA types. PATIENTS AND METHODS One hundred sixty-one patients with t(15;17)(q22;q11-12) enrolled onto Cancer and Leukemia Group B (CALGB) protocol 8461, a prospective study of cytogenetics in acute myeloid leukemia (AML), were studied. Eighty of these 161 patients were treated solely with chemotherapy and evaluated for response to treatment and survival. PML-RAR alpha mRNA type was determined using reverse transcriptase polymerase chain reaction (RT-PCR) in 56 patients. RESULTS The incidence of secondary cytogenetic abnormalities was 32%. Among 80 patients treated with chemotherapy, the presence of a secondary chromosome abnormality was associated with longer complete remission (CR) duration (median, 29.9 v 15.7 months; P = .03) and longer event-free survival (EFS) duration (median, 17.0 v 12.2 months; P = .03). There was no difference in overall survival (P = .28). In a separate group of 56 patients with both cytogenetic and molecular data, 32 had the type L PML-RAR alpha transcript (intron 6 PML breakpoint). Of these 32 patients, four (12.5%) had chromosome changes in addition to t(15;17), whereas 12 of 20 patients (60%) with the type 5 PML-RAR alpha transcript (intron 3 PML breakpoint) had secondary cytogenetic changes (P < .001). CONCLUSION (1) Secondary cytogenetic changes do not confer a poor prognosis in APL patients treated with anthracycline/cytarabine (Ara-C)-based chemotherapy; and (2) A highly significant relationship exists between the PML-RAR alpha 5 isoform (intron 3 PML genomic breakpoint) and secondary cytogenetic changes in APL.


Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1714-1714
Author(s):  
Matthew D. Seftel ◽  
Anna Serebrin ◽  
Pascal Lambert ◽  
Julie Bergeron ◽  
Janeve Everett ◽  
...  

Abstract Introduction Despite widespread use of all-trans retinoic acid (ATRA) in treatment of Acute Promyelocytic Leukemia (APL), recent studies in the US1 and Sweden2 have reported continuing high rates of early death. Patient age has appeared to be an important factor affecting outcomes. We studied the incidence and outcomes in the Canadian APL patients to determine which patients may be at higher risk, and to analyze the success of current management. Methods We used data from the Canadian Cancer Registry, which included all patients diagnosed between 1993-2007. We obtained incidence, Early Death (ED) (death within 30 days of diagnosis), and 1 and 5-year overall survival (OS). This was stratified by age, sex, and time period of diagnosis. Detailed information was obtained on a subset of patients managed at five Canadian leukemia referral centres from 1999 to 2010. Results There were 399 cases of APL diagnosed in Canada between 1993-2007.This accounted for 3.01% of Acute Myeloid Leukemia cases. Incidence (age-standardized to the 1991 Canadian census population) was 0.083/100000. The incidence was greater in the population aged 50 and over, with an incidence rate ratio (IRR) of 2.192 (95% C.I.1.80 - 2.67, p<0.001). ED was 21.8% overall, with a rate over three times higher in older patients as compared to younger patients. The ED rate was 10.6% in younger (<50 years) patients and 35.5% in older (≥50 years) patients. One-year overall survival was 84.1% in younger patients as compared to 52.3% in older adults. The rate of death at one year is nearly three times higher in the older patients. Five-year survival was 54.6%; this was 73.3% in the younger patients (<50), and 29.1% in the older group (≥50 years). There were 131 patients in the leukemia referral centre cohort, who predominantly received tretinoin (ATRA) based therapy. In this population, ED was 14.6%. Two-year OS was 76.5% (95% C.I. 68%-83%). Age over 60 predicted an inferior outcome at 2-years with a hazard ratio of 4.051 (95% CI 1.17-7.57). Conclusions To our knowledge, this is the largest nationwide epidemiologic study of APL. Despite widespread use of ATRA in Canada and low rates of ED reported in clinical trials (often 3-8%), we found that the real survival outcomes of APL were worse than anticipated. However they were similar to those reported recently from other developed counties1,2. The outcomes were much poorer for the older patients with APL. This included a higher rate of early death as well as poorer rates of survival at one, two and five year follow-up times. The ED rates of patients <50 more closely matched rates reported in clinical trials. We compared the survival outcomes of the entire population with APL to a sample of only patients treated at specialized referral centres. Despite receiving care in a specialized tertiary centre, the survival of older patients remained significantly poorer than the younger patients. The incidence of APL was also double in the older population as compared to the younger population. Overall the age-standardized incidence was lower in Canada than has been reported in other countries1,2. This emphasizes that, although APL is a type of AML that does affect younger patients, there is a large and important impact of this disease on older patients. Recent studies in the US and Sweden have also reported higher rates of APL in older populations and poorer rates of survival at various follow up times. Overall the patients with high-risk Sanz scores had the worst survival outcomes. The survival at most time points was slightly higher for patients scored as intermediate-risk compared to those who were in the low-risk category. When arsenic becomes widely available as a first line therapy it will be important to continue population-based analysis to see how this affects outcomes and whether the outcomes are difference in difference age groups or populations. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2001 ◽  
Vol 98 (9) ◽  
pp. 2651-2656 ◽  
Author(s):  
Joseph G. Jurcic ◽  
Stephen D. Nimer ◽  
David A. Scheinberg ◽  
Tony DeBlasio ◽  
Raymond P. Warrell ◽  
...  

Abstract The t(15;17) translocation in acute promyelocytic leukemia (APL) yields a PML/RAR-α fusion messenger RNA species that can be detected by reverse transcription–polymerase chain reaction (RT-PCR) amplification. Breakpoints within intron 3 of PML produce a short PML/RAR-α isoform, whereas breakpoints within intron 6 result in a longer form. Using RT-PCR, serial evaluations were performed on the bone marrow of 82 patients with APL (median follow-up, > 63 months) who received retinoic acid (RA) induction followed by postremission treatment with chemotherapy, RA, and biologic agents. Sixty-four patients attained a clinical complete remission and had at least 2 RT-PCR assays performed after completing therapy. Forty of 47 patients (85%) with newly diagnosed APL who were induced using RA had residual disease detectable by RT-PCR before additional therapy. After 3 cycles of consolidation therapy, residual disease was found in only 4 of 40 evaluable patients (10%). Among newly diagnosed patients who had 2 or more negative RT-PCR assays, only 3 of 41 (7%) had a relapse, whereas all 4 patients (100%) who had 2 or more positive results had a relapse. Among 63 newly diagnosed patients, those who expressed the short isoform appeared to have shorter disease-free and overall survival durations than patients who expressed the long isoform. These data indicate that 2 or more negative RT-PCR assays on bone marrow, performed at least 1 month apart after completing therapy, are strongly associated with long-term remissions. Conversely, a confirmed positive test is highly predictive of relapse.


1997 ◽  
Vol 15 (2) ◽  
pp. 483-490 ◽  
Author(s):  
E Estey ◽  
P F Thall ◽  
S Pierce ◽  
H Kantarjian ◽  
M Keating

PURPOSE To determine the effect of omission of cytarabine (ara-C) from treatment of newly diagnosed acute promyelocytic leukemia (APL), which allows administration of more anthracycline. PATIENTS AND METHODS Induction consisted of all-trans retinoic acid (ATRA) 45 mg/m2 daily until complete remission (CR) and idarubicin 12 mg/m2 daily for 4 days beginning on day 5 of ATRA. Patients in CR received two courses of idarubicin 12 mg/m2 daily for 3 days and then, until 2 years post-CR date, alternated three cycles of mercaptopurine, vincristine, methotrexate, and prednisone (POMP) with one cycle of idarubicin 12 mg/m2 daily for 2 days. Results in the 43 patients treated (41 with t(15;17) on standard or Southern analysis) were compared with those in 57 historic newly diagnosed APL patients given ara-C with either doxorubicin, amsacrine (AMSA), or daunorubicin without ATRA, using logistic and Cox regression to assess effects of non-treatment-related covariates on patient outcomes. RESULTS The CR rate in the current group was 77% (95% confidence interval [CI], 62% to 88%) and was not significantly different from the historic rate. In contrast, disease-free survival (DFS) in CR is superior in the current group (probability at 1 year 0.87; 95% CI, 0.73 to 1.0). This has translated into superior overall DFS for the current group (P = .03 adjusting for the predictive covariates initial WBC and platelet count; 1-year DFS probability 0.67; 95% CI, 0.52 to 0.82; median follow-up 102 weeks). The current treatment appears better both in patients with and without t(15; 17) on standard cytogenetic analysis. CONCLUSION Given the difficulties inherent in comparing sequential studies and recognizing the multiple differences in treatment between current and historic groups, our results suggest that a large randomized trial incorporating use of ATRA should assess the utility of omitting ara-C from treatment of newly diagnosed APL, thus allowing delivery of more anthracycline.


2001 ◽  
Vol 19 (7) ◽  
pp. 2033-2040 ◽  
Author(s):  
C.S. Chim ◽  
R. Liang ◽  
C.Y.Y. Tam ◽  
Y.L. Kwong

PURPOSE: To investigate the frequency of p15 and p16 gene promoter methylation in acute promyelocytic leukemia (APL), and to define its value in the detection of minimal residual disease (MRD) and treatment prognostication. PATIENTS AND METHODS: Bone marrow DNA obtained from 26 patients with APL at diagnosis and during follow-up was studied with the methylation-specific polymerase chain reaction (MS-PCR). Serial marrow DNA was studied by MS-PCR for MRD, and disease-free and overall survival were correlated with p15 methylation status at diagnosis. RESULTS: MS-PCR for p16 and p15 gene methylation has a maximum sensitivity of 10-4 and 10-5. At diagnosis, 19 patients (73.1%) exhibited p15 methylation, whereas only three patients (11.5%) exhibited p16 methylation, all of whom had concomitant p15 methylation. During follow-up, p16 methylation was acquired in two patients, one during the third hematologic relapse, and the other during transformation into therapy-related myelodysplastic syndrome. Six patients were evaluated serially with MS-PCR for p15 methylation at diagnosis and at follow-up examinations. Persistent p15 methylation preceded subsequent hematologic relapses in two patients, and conversion to negative MS-PCR for p15 methylation correlated with prolonged survival in another four patients. The 5-year disease-free survival of patients with p15 methylation was significantly inferior to that of patients without p15 methylation (15% v 62.5%; P = .02), and this remained significant in multivariate analysis. CONCLUSION: In APL, p15 but not p16 gene methylation is frequent. It is possible that p16 methylation is acquired during clonal evolution. p15 methylation is a potential marker of MRD and might be of prognostic significance.


Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4160-4160
Author(s):  
Paola Finsinger ◽  
Massimo Breccia ◽  
Clara Minotti ◽  
Ida Carmosino ◽  
Laura Cannella ◽  
...  

Abstract Abstract 4160 Acute Promyelocytic Leukemia (APL) is a rare subtype of Acute Myeloid Leukemia (AML) more common in younger adults, with a median age of 45 – 50 years at onset. The use of All-trans Retinoic Acid (ATRA) as tailored treatment has made APL a very curable disease also in patients aged > 60 years; however, there are only few case reports in very elderly APL patients. To address this issue, we revised clinical data and treatment results in 12 patients aged > 70 years with newly diagnosed APL followed at our Institution from 1/91 to 12/2008. Clinical characteristics at onset were as follows: M/F 7/5, median age 74.7 years (range 70.0 – 80.8), M3/M3v 11/1, median WBC 1.3 × 109/l (range 1.0 – 7.4), median PLTS 53 × 109/l (range 12 – 302), BCR1/BCR3 6/6. According to Sanz risk score, 7 patients were at low-risk and 5 at intermediate-risk; 6/12 patients had arterial hypertension, 4/12 a concomitant cardiologic disease, 3/12 a cerebro-vascular disease and 2/12 a previous neoplasia. Induction therapy consisted of ATRA + Idarubicin in 8 patients (2/8 with reduced Idarubicin dosage) and ATRA alone in 4 patients; in this latter group, however, 2/4 needed to add chemotherapy (CHT) based on Mitoxantrone + AraC due to hyperleukocytosis during ATRA treatment. All patients achieved both morphological and molecular Complete Remission (CR) after a median time of 50 (range 29 – 65) and 105 (range 51 – 239) days, respectively. Infective complications were observed in 10/12 patients (4 episodes of FUO, 6 sepsis, 2 cystitis and 1 oral abscess) while ATRA syndrome occurred in 2/12 patients; in addition, there were 3 episodes of cardiac ischemia and 3 episodes of paroxystic atrial fibrillation. All but one patient received consolidation therapy (based on CHT alone in 7 patients, CHT + ATRA in 3 patients and ATRA alone in 1 patient), followed by maintenance treatment in 8 patients. Four patients had a relapse (hematological in 3 cases and molecular in 1 case) after 8, 11, 35 and 56 months respectively. At present, 6 patients are still alive, 4 died due to disease progression (3) or senectus while in CR (1) and 2 were lost to follow-up while in CR: mean event-free survival and overall survival were 89.2 months (95%CI 52.6 – 125.8) and 99.9 months (95%CI 65.0 – 134.7), respectively. In conclusion, ATRA-based treatment of APL is safe and effective also in very elderly patients, with long-lasting disease-free and overall survival. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2011 ◽  
Vol 118 (25) ◽  
pp. 6535-6543 ◽  
Author(s):  
Wing-Yan Au ◽  
Cyrus R. Kumana ◽  
Harold K. K. Lee ◽  
Shek-Ying Lin ◽  
Herman Liu ◽  
...  

Abstract Seventy-six patients with acute promyelocytic leukemia (APL) in first complete remission after induction and consolidation by daunorubicin and cytosine arabinoside received oral arsenic trioxide (As2O3)-based maintenance. Three regimens were used: oral As2O3 (10 mg/day, regimen A, n = 20), oral As2O3 plus all-trans retinoic acid (ATRA, 45 mg/m2 per day, regimen AA, n = 19), and oral As2O3 plus ATRA plus ascorbic acid (1000 mg/day, regimen AAA, n = 37), each given for 2 weeks every 2 months for 2 years. Patients receiving A, AA, and AAA maintenance did not differ significantly in clinicopathologic features and risk factors. Headache, dyspepsia, reversible liver function derangement, and herpes zoster reactivation were adverse effects observed during maintenance. QTc prolongation and arrhythmias were not encountered. At a median follow-up of 24 months (range, 1-115 months), there were 8 relapses. The 3-year leukemia-free-survival, event-free-survival, and overall-survival were 87.7%, 83.7%, and 90.6%, respectively. Adverse prognostic factors included male gender for leukemia-free-survival, and unrelated cancers for overall survival. Age, presentation WBC count and platelet count, and the type of oral As2O3 maintenance regimens had no impact on survivals. Prolonged oral As2O3 maintenance was feasible and safe and resulted in favorable outcomes when used with a simple induction and consolidation regimen compared with other protocols composed of multiple chemotherapeutic agents.


1997 ◽  
Vol 15 (2) ◽  
pp. 466-475 ◽  
Author(s):  
J C Byrd ◽  
R B Weiss ◽  
D C Arthur ◽  
D Lawrence ◽  
M R Baer ◽  
...  

PURPOSE To examine the prognostic significance of extramedullary leukemia (EML) at presentation in patients with t(8;21)(q22;q22) karyotype. PATIENTS AND METHODS Consecutive patients with t(8;21) treated on Cancer and Leukemia Group B de novo acute myeloid leukemia (AML) treatment studies were examined for the presence of EML (granulocytic sarcoma, subcutaneous nodules, leukemia cutis, or meningeal leukemia) at initial presentation. Clinical features and outcome of t(8;21) patients with and without EML were compared. RESULTS Of 84 patients with t(8;21), eight (9.5%) had EML manifesting as granulocytic sarcoma (five paraspinal, one breast, and one subcutaneous) or symptomatic meningeal leukemia (n = 1). The pretreatment prognostic variables of t(8;21) patients with and without EML were similar. The hematologic complete remission (CR) rate for t(8;21) patients with EML was 50% versus 92% for those without EML (P=.006). The median CR duration for EML patients was 14.7 months. Patients with EML had a shorter survival (P = 0.002, median 5.4 months versus 59.5 months). This poor outcome may relate to inadequate local (radiation or intrathecal) therapy for patients with spinal or meningeal EML, resulting in residual/recurrent EML following induction chemotherapy (n = 2) or at relapse (n = 1) and permanent neurologic deficits (n = 4). Only one of the EML patients received high-dose cytarabine (HDAC) intensification; this is the only EML patient remaining alive in CR. CONCLUSION Patients with t(8;21) and EML have a low CR rate and overall survival. An aggressive local and systemic induction therapy should be considered for this patient subset. The effectiveness of HDAC intensification in t(8;21) patients with EML is uncertain and warrants further study.


Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4440-4440
Author(s):  
Young-Uk Cho ◽  
Hyun-Sook Chi ◽  
Seongsoo Jang ◽  
Chan-Jeoung Park ◽  
Je-Hwan Lee ◽  
...  

Abstract Fms-Like tyrosine kinase 3 (FLT3) mutations are related to poor prognosis in acute myeloid leukemia (AML), with the exception of acute promyelocytic leukemia (APL), in which the prognostic significance of this mutation is not firmly established even though it is more frequent than other FAB subtypes. We investigated FLT3 internal tandem duplications (FLT3/ITD) and/or D835 point mutations in both initial and relapse marrow samples from 120 AML patients, excluding APL. FLT3/ITDs were found in 18 initial and 16 relapse samples (15.0 and 13.3%, respectively). D835 mutations were found in one initial sample and 4 relapse samples. Two cases acquired FLT3/ITD at relapse, 4 cases lost mutations at relapse, and one had a different allele of FLT3/ITD at relapse. Patients who had FLT3/ITDs at initial diagnosis showed shorter median duration from diagnosis to relapse and shorter overall survival compared with those without mutations (median duration to relapse: 8.3 and 11.0 months, respectively, P = 0.074; overall survival: 12.2 and 20.8 months, respectively, P = 0.058). These findings were more pronounced when the FLT3/ITDs were acquired at relapse or discrepant patterns were noted between diagnosis and relapse (median duration to relapse: P = 0.047 and 0.044, respectively; overall survival: P = 0.002 and 0.038, respectively). In conclusion, the present study showed that patients with AML had heterogeneous patterns of FLT3/ITD or D835 mutations, either acquisition or loss of the mutations at relapse. The overall survival and relapse-free survival times were significantly shorter in the mutation acquisition group than in those with mutation loss at relapse.


Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 140-140 ◽  
Author(s):  
Ardeshir Ghavamzadeh ◽  
Kamran Alimoghaddam ◽  
Seyed Hamidolah Ghaffari ◽  
Shahrbano Rostami ◽  
Mohamad Jahani ◽  
...  

Abstract Acute promyelocytic leukemia (APL) is a unique type of hematologic malignancies with high cure rate. ATRA and chemotherapy is current standard treatment but Arsenic Trioxide (ATO) is most potent single agent against APL. Materials and methods: between may 2000 and October 2007 we treated 193 new cases by ATO alone. Patients received 0.15 mg/kg ATO as 2 hours daily i.v infusion till complete remission or 60 days, and then received the same dose as consolidation for 28 days, one months after CR. From 2006, increased ATO consolidation to 4 doses (two 28 days in first year and two 28 days in beginning of second and third years). They received Dexamethasone for treatment of APL differentiation syndrome. Patients followed by sensitive RT-PCR for MRD detection. Median follow up was 28 months (1–88) and 38% of cases followed for more than 3 years and 15% for more than 5 years. For treatment of patients after relapse we used ATO again by the same schedule. Results: Median age of patients was 29+/−13 years and median WBC count at was 2100+/−23319 at diagnosis and 35% of cases have WBC more than 10000 at first presentation. Remission rate was 82.7%. APL differentiation syndrome happened in 31% of patients during remission induction. we observed, by long term follow up that 67.7% of patients are alive. DFS for 2,3 and 5 years were 80%+/−3, 69%+/−4 and 64%+/−5 respectively. Overall survival of patients for 2,3 and 5 years were 86%+/−2, 79+/− 3 and 66%+/−5 respectively. WBC more than 10000 count at diagnosis was associated with increased mortality during remission induction phase (p value&lt; 0.001) but it has no association with DFS or overall survival. Also we observed that chance of relapse for patients with sustained remission at one, two, three and four years after remission induction were 24.6%,16.7%,5.8% and 3% respectively and chance of survival for these patients were 82.8%,88.9%,95% and 100% respectively. For patients who remained in CR after 3 years of remission induction DFS and OS for more than 4 years after remission induction were 94+/−3% for both. These results means that chance of cure for patients on CR is high. Patients who relapsed after first induction could achieve to CR by ATO alone again but their long term prognosis was not good and 68% of them finally died. One year, two, three and four years survival for this group were 88%+−4,72.6%,57.7% and 27+/−7% Conclusion: ATO treatment is an alternative treatment for APL with good long term result. Reduction of early mortality needs better referral system to earlier beginning of treatment and also better control o APL differentiation syndrome and bleeding (especially from lung and CNS).Also we suggest that for relapsed cases it is better to add other treatment modalities like ATRA, chemotherapy or BMT to improve long term results.


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