scholarly journals Concomitant central venous sinus thrombosis and subdural hematoma in acute promyelocytic leukemia: middle meningeal artery embolization enables safe anticoagulation. Illustrative case

2021 ◽  
Vol 1 (23) ◽  
Author(s):  
Kushagra Maini ◽  
Feroze Afzal ◽  
Dan-Victor Giurgiutiu ◽  
Scott Y. Rahimi ◽  
Manan Shah ◽  
...  
Keyword(s):  
Acute Promyelocytic Leukemia ◽  
Clinical Course ◽  
Sinus Thrombosis ◽  
Middle Meningeal Artery ◽  
Promyelocytic Leukemia ◽  
Subdural Hemorrhage ◽  
Illustrative Case ◽  
Epidural Hemorrhage ◽  
Meningeal Artery

BACKGROUND Acute promyelocytic leukemia (APL) has long been associated with coagulation disorders. The proposed mechanism is a combination of fibrinolysis, proteolysis, platelet dysfunction, thrombocytopenia, and possibly disseminated intravascular coagulation. Hemorrhagic complications are prominent. OBSERVATIONS In this case, a 25-year-old female with newly diagnosed APL developed extensive cerebral venous thrombosis (CVT) and was initiated on a protocol with idarubicin and all-trans retinoic acid. The general recommendation for treating CVT is anticoagulation to stabilize the existing thrombus and prevent propagation. The patient was initiated on a heparin drip, but her clinical course was complicated by subdural hemorrhage (SDH) and epidural hemorrhage in the setting of thrombocytopenia. Anticoagulation was held, and her CVT propagated on follow-up imaging. To restart anticoagulation for CVT with a limited risk of SDH, the authors pursued middle meningeal artery (MMA) embolization. The patient was transitioned to apixaban and discharged to home. LESSONS MMA embolization enables safe anticoagulation in patients with concomitant CVT and SDH. The authors report the complex clinical course and effective management of this rare clinical scenario.

Morphological changes in chronic subdural hematomas following upfront middle meningeal artery embolization: sequence, timing, and association with outcomes

2021 ◽  
pp. 1-14
Author(s):  
MirHojjat Khorasanizadeh ◽  
Yu-Ming Chang ◽  
Alejandro Enriquez-Marulanda ◽  
Satomi Mizuhashi ◽  
Mohamed M. Salem ◽  
...  
Keyword(s):  
Late Stage ◽  
Morphological Changes ◽  
Prognostic Significance ◽  
Intermediate Stage ◽  
Middle Meningeal Artery ◽  
Structural Features ◽  
Artery Embolization ◽  
Subdural Hematomas ◽  
Meningeal Artery

OBJECTIVE Middle meningeal artery embolization (MMAE) is an increasingly utilized approach for the treatment of chronic subdural hematomas (CSDHs). The course of morphological progression of CSDHs following MMAE is poorly understood. Herein, the authors aimed to describe these morphological changes and assess their prognostic significance for the outcomes on follow-up. METHODS A single-institution retrospective cohort study of CSDH cases treated by upfront MMAE, without prior or adjunctive surgical evacuation, was performed. Clinical outcomes, complications, and the need for rescue surgery on follow-up were recorded. Hematomas were categorized into 6 morphological subtypes. All baseline and follow-up head CT scans were assessed for CSDH structural appearance, density, and loculation. Changes in CSDH size were quantified via 3D reconstruction for volumetric measurement. RESULTS Overall, 52 CSDHs in 45 patients treated with upfront MMAE were identified. Hematomas were followed for a mean of 92.9 days. Volume decreased by ≥ 50% in 79.6% of the CSDHs. The overall rescue surgery rate was 9.6%. A sequence of morphological changes after MMAE was identified. Hematomas that diverged from this sequence (5.4%) all progressed toward treatment failure and required rescue surgery. The CSDHs were categorized into early, intermediate, and late stages based on the baseline morphological appearance. Progression from early to intermediate and then to late stage took 12.7 and 30.0 days, respectively, on average. The volume of early/intermediate- and late-stage hematomas decreased by ≥ 50%, a mean of 78.2 and 47.6 days after MMAE, respectively. Early- and intermediate-stage hematomas showed a trend toward more favorable outcomes compared with late-stage hematomas. The density of homogeneous hypodense hematomas (HSDHs) transiently increased immediately after MMAE (p < 0.001). A marked decrease in density and volume 1 to 3 weeks after MMAE in HSDHs was detected, the lack of which indicated an eventual need for rescue surgery. In HSDHs, a baseline mean density of < 20 HU, and a lower density than baseline by 1 month post-MMAE were predictors of favorable outcomes. The baseline hematoma volume, axial thickness, midline shift, and loculation were not correlated with MMAE outcomes. Loculated, trabecular, and laminar hematomas, which are known to have unfavorable surgical outcomes, had MMAE outcomes similar to those of other "surgical" hematomas. CONCLUSIONS The current study was the first to describe the nature, sequence, and timing of morphological changes of CSDHs after MMAE treatment and has identified structural features that can predict treatment outcomes.

A propensity-adjusted comparison of middle meningeal artery embolization versus conventional therapy for chronic subdural hematomas

2021 ◽  
pp. 1-6
Author(s):  
Joshua S. Catapano ◽  
Andrew F. Ducruet ◽  
Candice L. Nguyen ◽  
Tyler S. Cole ◽  
Jacob F. Baranoski ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Conservative Management ◽  
Conventional Therapy ◽  
Surgical Intervention ◽  
Middle Meningeal Artery ◽  
Adjusted Analysis ◽  
Subdural Hematomas ◽  
Tertiary Center ◽  
Meningeal Artery

OBJECTIVEMiddle meningeal artery (MMA) embolization is a promising treatment strategy for chronic subdural hematomas (cSDHs). However, studies comparing MMA embolization and conventional therapy (surgical intervention and conservative management) are limited. The authors aimed to compare MMA embolization versus conventional therapy for cSDHs using a propensity-adjusted analysis.METHODSA retrospective study of all patients with cSDH who presented to a large tertiary center over a 2-year period was performed. MMA embolization was compared with surgical intervention and conservative management. Neurological outcome was assessed using the modified Rankin Scale (mRS). A propensity-adjusted analysis compared MMA embolization versus surgery and conservative management for all individual cSDHs. Primary outcomes included change in hematoma diameter, treatment failure, and complete resolution at last follow-up.RESULTSA total of 231 patients with cSDH met the inclusion criteria. Of these, 35 (15%) were treated using MMA embolization, and 196 (85%) were treated with conventional treatment. On the latest follow-up, there were no statistically significant differences between groups in the percentage of patients with worsening mRS scores. Of the 323 total cSDHs found in 231 patients, 41 (13%) were treated with MMA embolization, 159 (49%) were treated conservatively, and 123 (38%) were treated with surgical evacuation. After propensity adjustment, both surgery (OR 12, 95% CI 1.5–90; p = 0.02) and conservative therapy (OR 13, 95% CI 1.7–99; p = 0.01) were predictors of treatment failure and incomplete resolution on follow-up imaging (OR 6.1, 95% CI 2.8–13; p < 0.001 and OR 5.4, 95% CI 2.5–12; p < 0.001, respectively) when compared with MMA embolization. Additionally, MMA embolization was associated with a significant decrease in cSDH diameter on follow-up relative to conservative management (mean −8.3 mm, 95% CI −10.4 to −6.3 mm, p < 0.001).CONCLUSIONSThis propensity-adjusted analysis suggests that MMA embolization for cSDH is associated with a greater extent of hematoma volume reduction with fewer treatment failures than conventional therapy.

Studies on Treatment of Acute Promyelocytic Leukemia With Arsenic Trioxide: Remission Induction, Follow-Up, and Molecular Monitoring in 11 Newly Diagnosed and 47 Relapsed Acute Promyelocytic Leukemia Patients

Blood ◽  
1999 ◽  
Vol 94 (10) ◽  
pp. 3315-3324 ◽  
Author(s):  
Chao Niu ◽  
Hua Yan ◽  
Ting Yu ◽  
Hui-Ping Sun ◽  
Jian-Xiang Liu ◽  
...  
Keyword(s):  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Disease Free Survival ◽  
Promyelocytic Leukemia ◽  
Pcr Analysis ◽  
Remission Induction ◽  
Newly Diagnosed ◽  
First Choice ◽  
Wbc Count

Fifty-eight acute promyelocytic leukemia (APL) patients (11 newly diagnosed and 47 relapsed) were studied for arsenic trioxide (As2O3) treatment. Clinical complete remission (CR) was obtained in 8 of 11 (72.7%) newly diagnosed cases. However, As2O3 treatment resulted in hepatic toxicity in 7 cases including 2 deaths, in contrast to the mild liver dysfunction in one third of the relapsed patients. Forty of forty-seven (85.1%) relapsed patients achieved CR. Two of three nonresponders showed clonal evolution at relapse, with disappearance of t(15;17) and PML-RAR fusion gene in 1 and shift to a dominant AML-1-ETO population in another, suggesting a correlation between PML-RAR expression and therapeutic response. In a follow-up of 33 relapsed cases over 7 to 48 months, the estimated disease-free survival (DFS) rates for 1 and 2 years were 63.6% and 41.6%, respectively, and the actual median DFS was 17 months. Patients with white blood cell (WBC) count below 10 × 109/L at relapse had better survival than those with WBC count over 10 × 109/L (P = .038). The duration of As2O3-induced CR was related to postremission therapy, because there was only 2 of 11 relapses in patients treated with As2O3 combined with chemotherapy, compared with 12 of 18 relapses with As2O3 alone (P = .01). Reverse transcription polymerase chain reaction (RT-PCR) analysis in both newly diagnosed and relapsed groups showed long-term use of As2O3 could lead to a molecular remission in some patients. We thus recommend that ATRA be used as first choice for remission induction in newly diagnosed APL cases, whereas As2O3 can be either used as a rescue for relapsed cases or included into multidrug consolidation/maintenance clinical trials.

scholarly journals Early Detection of t(8;21) Chromosomal Translocations during Treatment of PML-RARA Positive Acute Promyelocytic Leukemia: A Case Study

2010 ◽  
Vol 4 ◽  
pp. CMO.S6446 ◽  
Author(s):  
Walter Kleine Neto ◽  
Mariana Serpa ◽  
Sabri Saeed Sanabani ◽  
Patricia Torres Bueno ◽  
Elvira Deolinda Rodrigues Pereira Velloso ◽  
...  
Keyword(s):  
Acute Promyelocytic Leukemia ◽  
Genetic Screening ◽  
Treatment Initiation ◽  
Single Case ◽  
Promyelocytic Leukemia ◽  
Chromosomal Translocations ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Here we describe a female patient who developed acute promyelocytic leukemia (APL) characterized by t(l5;17) translocation at diagnosis. The patient began treatment with all-trans retinoic acid (ATRA) + chemotherapy. During follow up, the patient was found to be negative for the t(15;17) transcript after 3 months of therapy which remained undetectable, thereafter. However, the emergence of a small clone with a t(8;21) abnormality was observed in the bone marrow and peripheral blood (PB) cells between 3 and 18 months following treatment initiation. The abnormal translocation observed in PB cells obtained at 3 months was detected after the second cycle of consolidation therapy and reappeared at 15 months during maintenance treatment, a period without ATRA. Although based on a single case, we conclude that genetic screening of multiple translocations in AML patients should be requested to allow early identification of other emerging clones during therapy that may manifest clinically following treatment.

Risk-Adapted Treatment of Acute Promyelocytic Leukemia: Updated Results of the Spanish PETHEMA LPA99 Trial Using ATRA and Anthracycline Monochemotherapy.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 590-590 ◽  
Author(s):  
Miguel A. Sanz ◽  
Pau Montesinos ◽  
Edo Vellenga ◽  
Chelo Rayon ◽  
Ricardo Parody ◽  
...  
Keyword(s):  
High Risk ◽  
Acute Promyelocytic Leukemia ◽  
Disease Free Survival ◽  
Promyelocytic Leukemia ◽  
Consolidation Therapy ◽  
Number Of Patients ◽  
Risk Patients ◽  
Low Toxicity ◽  
High Degree

Abstract Background: A first report of the PETHEMA LPA99 trial in acute promyelocytic leukemia (APL) showed that a risk-adapted treatment strategy combining ATRA and anthracycline alone for induction and consolidation results in high antileukemic efficacy and low toxicity. We report here an updated analysis of this trial including a significantly higher number of patients and longer follow-up. Methods: From November 1999 to July 2005, 564 patients (median age 40 years, range 2–83) with APL received induction with ATRA (45 mg/m2/d) until CR and idarubicin (12 mg/m2/d) on days 2, 4, 6 and 8. Patients in CR received 3 monthly courses of risk-adapted consolidation therapy as follows: “low-risk” patients (WBC <10×109/l and platelets >40×109/l), idarubicin 5 mg/m2/d × 4 (course #1), mitoxantrone 10 mg/m2/d × 5 (course #2), and idarubicin 12 mg/m2/d × 1 (course #3); “intermediate-risk “ (WBC <10×109/l and platelet <40×109/l) and “high-risk” (WBC >10×109/l) patients received ATRA (45 mg/m2/d × 15) in combination with reinforced chemotherapy (Idarubicin 7 mg/m2/d in the course #1 and two days instead of one in the course #3). Maintenance therapy consisted of 50 mg/m2/d mercaptopurine orally, 15 mg/m2/week methotrexate intramuscularly, and 45 mg/m2/d ATRA for 15 days every 3 months. Results: CR was achieved in 511 patients (91%). Except for three cases labelled as resistant, of the remaining 50 patients 56%, 24%, 16% and 4% died due to hemorrhage, infection, retinoic acid syndrome, and acute myocardial infarction, respectively. Multivariate analysis showed that WBC >10×109/l, age >60 years, male gender, and serum creatinine >1.4 mg/dl at presentation had independent predictive value of death during induction. The median follow-up of the cohort was 57 months (range 20–94 months). Thirteen patients (median age 72 years, range 4–81) died in remission and 99% of patients completed the entire assigned therapy. Thirty-six patients presented haematological relapse, 16 molecular relapse, and 8 secondary myelodysplastic syndrome or acute myeloid leukemia. Overall, the 5-year cumulative incidence of relapse (CIR), disease-free survival, and overall survival were 11%, 85%, and 84%, respectively. The 5-year CIR for low-, intermediate- and high-risk patients were 4%, 7% and 28%, respectively. Conclusions: A risk-adapted strategy combining ATRA and anthracycline monochemotherapy for induction and consolidation therapy results in high antileukemic efficacy, low toxicity and a high degree of compliance in newly diagnosed APL.

Treatment of Relapsed Acute Promyelocytic Leukemia with Oral Arsenic Trioxide: An Eleven-Year Experience

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2958-2958
Author(s):  
Wing-Yan Au ◽  
Sidney Tam ◽  
Anskar Y.H. Leung ◽  
Eric Tse ◽  
Cyrus Kumana ◽  
...  
Keyword(s):  
Ascorbic Acid ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Maintenance Treatment ◽  
Histone Deacetylase Inhibitors ◽  
Significant Proportion ◽  
Gemtuzumab Ozogamicin ◽  
Promyelocytic Leukemia ◽  
Hematopoietic Stem

Abstract Background. For patients with relapsed acute promyelocytic leukemia (APL), the optimal therapy after arsenic trioxide (As2O3)-induced complete remission (CR) is unclear. Autologous or allogeneic hematopoietic stem cell transplantation (HSCT) has been advocated. These strategies are associated with morbidity and considerable mortality, and not all patients are eligible. The role of maintenance therapy with As2O3 remains undefined. Materials and methods. From 1997–2008, 50 consecutive APL patients (25 men, 25 women, median age: 35 (12–72) years) in relapse (R1, n=47; R2, n=3) were treated with As2O3 until CR. This was followed by idarubicin consolidation (6 mg/m2/day × 9) in 43 patients. Seventeen patients did not receive maintenance treatment. Thirty-two patients received oral-As2O3 maintenance (10 mg/day × 14 every 2 months). All-trans retinoic acid (ATRA, 45 mg/m2/day) maintenance was used together with oral-As2O3 in 27 patients. As2O3 protocol was approved by the institutional review board at Queen Mary Hospital. All maintenance treatment was given in the outpatient clinic as oral medication. Results. Of 50 relapsed cases, As2O3-induced CR was achieved in 49 patients, 1 patient dying of pneumonia. At a median follow-up of 61 (6–122) months, 27 patients (19 with and 8 without As2O3 maintenance) had remained in remission. Further relapses (R2, n=20; R3, n=2.) occurred in 22 patients (13 with and 9 without As2O3 maintenance), at a median of 16 (6–28) months. Concomitant central nervous system (CNS) relapse occurred in 8 cases. Treatment of post-As2O3 relapses included oral-As2O3 (10 mg/day) + ATRA (45 mg/m2/day) with (n=10) or without (n=10) ascorbic acid (1 gm/day) until CR, and then maintenance with As2O3 + ATRA +/− ascorbic acid. Leucocytosis during treatment was controlled with mitoxantrone. In these 22 cases of post-As2O3 relapses, further remission was still achieved in 19 patients (CR3, n=18; CR4, n=1), with 3 patients dying from cerebral bleeding. At a median follow-up of 88 (8–98) months, 8 patients had remained in remission. Further relapses occurred in 11 patients. Salvage therapy consisted of As2O3+ATRA+ascorbic acid, together with chemotherapy (mitoxantrone, n=8; amascrine, n=3), gemtuzumab ozogamicin (n=4), and autologous HSCT (n=1). Eight patients finally died of refractory leukemia after a median of 6 (2–33) months. Three patients had remained in remission (CR4, n=2, CR5 n=1) at a median of 41 (26–102) months. On an intention-totreat basis, our oral-As2O3 treatment/maintenance regimen for patients with relapsed APL resulted in a 4-year overall survival of 71%, and event-free-survival of 53%. Conclusion. Our findings showed that an oral-As2O3-based treatment/maintenance strategy resulted in durable remission in a significant proportion of patients with relapsed APL. As most of the treatment is administered at home, this regimen involves much less financial, personnel and emotional costs as compared with HSCT strategies. Further improvement should be directed towards prevention of CNS relapses with appropriate prophylaxis in high-risk patients. For remissions at or beyond CR3, consideration of HSC harvest and storage at molecular remission should be considered. The use of demethylation agents and histone deacetylase inhibitors in combination with As2O3 remains to be investigated.

Single Agent Arsenic Trioxide Regimen for the Treatment of Newly Diagnosed Acute Promyelocytic Leukemia: Initial Results of a Multicenter Randomized Controlled Study From India to Study the Optimal Duration of Arsenic Trioxide Maintenance Therapy (IAPLSG04).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2082-2082 ◽  
Author(s):  
Vikram Mathews ◽  
Biju George ◽  
Farah Jijina ◽  
Cecil Ross ◽  
Reena Nair ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Single Agent ◽  
Promyelocytic Leukemia ◽  
Controlled Study ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Short Period

Abstract Abstract 2082 Poster Board II-59 Single agent arsenic trioxide (ATO) has proven efficacy in the management of newly diagnosed cases of acute promyelocytic leukemia (APL). To validate findings of an initial single center experience (Blood 2006:107; 2627) with this low cost, well tolerated, effective regimen, a multicenter study was undertaken in a resource constrained environment. Additionally, in an effort to improve on the earlier experience and study the role of duration of maintenance on reducing late relapses, patients were randomized to 6 vs. 12 months of ATO maintenance (ClinicalTrials.gov Identifier:NCT00517712). From July, 2004 to December, 2008, 182 patients were initially screened and enrolled based on morphological diagnosis of APL from 7 centers in India. Diagnosis was subsequently confirmed by molecular methods. Twenty seven cases were excluded from analysis (6 RT-PCR negative, 4 IC bleed at diagnosis, 5 septic/pneumonia at diagnosis, 9 withdrew consent prior to randomization and some were treated with other protocols, 1 withdrawn by investigator prior to randomization). Patients were treated with single agent ATO at standard doses (10mg/day for adults and 0.15mg/kg/day for pediatric patients) for up to 60 days in induction; this was followed by a 28 day consolidation after a 4 week break. Four weeks after completion of consolidation patients who were in molecular remission were randomized to 6 vs. 12 months of maintenance therapy with ATO administered for 10 days/month. Hydroxyurea was permitted for control of leucocytosis. Anthracyclines were permitted in induction for patients presenting with or WBC count rising >20×109/L in the first week, >50×109/L in the second week and for those who developed a differentiation syndrome. Of the 155 patients who could be evaluated 136 (87.7%) achieved hematological remission (CHR). One patient had primary induction failure and was removed from the study while the other 18 were induction deaths at a median of 17 days (range: 4 – 69). During induction, 52 (33.5%) patients received an anthracycline and 116 (75%) received hydroxyurea. A differentiation syndrome was documented in 25 (16%) cases and was fatal in one. Grade III/IV non hematological toxicity was seen in 26 (16.7%), which resolved in the majority after discontinuing ATO for a short period. One hundred and thirty six patients were randomized, 64 (47%) and 72 (53%) into a 6 and 12 month maintenance regimen respectively. A protocol change after randomization was done in 3 cases for persistent toxicity. Five (3.6%) patients did not complete the scheduled maintenance regimen due to poor compliance or was discontinued by the investigator. At a median follow up of 24 months, the 3-year Kaplan-Meir estimate of overall survival (OS), event free survival (EFS) and disease free survival (DFS) of the entire cohort was 76.87±4.33%, 71.57±4.64% and 80.69±4.77% respectively. Fourteen patients relapsed, the median time to relapse was 19.3 months (range: 9-51). The baseline characteristics of the two groups (6vs12 months) were not significantly different. Post randomization, the two groups were analyzed on an intention to treat basis. The OS, EFS and DFS of the two groups were not statistically significantly different. There was also no evidence that the group that received 12 months of maintenance had any increased incidence of toxicity. Single agent ATO based regimen as reported previously is well tolerated and results in durable remissions. Longer follow up is required to see if 12 months of maintenance therapy reduces risk of late relapses. Disclosures: No relevant conflicts of interest to declare.

Acute Promyelocytic Leukemia In Canada: Poor Outcomes In Older Patients Remain

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1714-1714
Author(s):  
Matthew D. Seftel ◽  
Anna Serebrin ◽  
Pascal Lambert ◽  
Julie Bergeron ◽  
Janeve Everett ◽  
...  
Keyword(s):  
Overall Survival ◽  
Clinical Trials ◽  
Acute Promyelocytic Leukemia ◽  
Older Patients ◽  
Early Death ◽  
Promyelocytic Leukemia ◽  
Survival Outcomes ◽  
Younger Patients ◽  
One Year

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.

Prognostic Impact Of MLL5 transcript Levels On Outcome Of Patients With Acute Promyelocytic Leukemia Treated With All-Trans Retinoic Acid and Anthracycline-Based Chemotherapy: An International Consortium On Acute Promyelocytic Leukemia Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2586-2586
Author(s):  
Antonio R Lucena-Araujo ◽  
Haesook T. Kim ◽  
Rafael Jacomo ◽  
Raul A Melo ◽  
Rosane Bittencourt ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Induction Therapy ◽  
Promyelocytic Leukemia ◽  
Early Mortality ◽  
Prognostic Impact ◽  
Transcript Levels ◽  
Healthy Donors ◽  
Laboratory Features

Abstract Background The MLL5 gene encodes a histone methyltransferase implicated in positive control of several genes related to hematopoiesis. Its close relationship with retinoic acid–induced granulopoiesis suggests that the deregulated expression of MLL5 might lead acute promyelocytic leukemia (APL) blasts to become less susceptible to differentiation-inducing ATRA effects. Here, we retrospectively determined the MLL5 transcript levels in samples from APL patients enrolled in the International Consortium on Acute Promyelocytic Leukemia (IC-APL) trial and analyzed its relationship with clinical and laboratory features, hematologic recovery, relapse, and survival. The results of the IC-APL have been previously reported (Blood 2013, 121(11) pp: 1935). In brief, complete hematological remission (CR) was achieved by 153/180 patients enrolled in Brazil, Mexico, Chile and Uruguay and after a median follow up of 28 months, the 2-year cumulative incidence of relapse (CIR), overall survival (OS) and disease-free survival (DFS) were 4.5%, 80% and 91%, respectively. Design and Methods One hundred and twenty-one APL patients (age, 15-73y) from seven different Brazilian institutions and treated according to the IC-APL protocol were included. The treatment schedule was identical to that adopted in the PETHEMA/HOVON LPA2005 trial, except for the replacement of idarubicin by daunorubicin. ATRA treatment was initiated immediately in all cases in which the diagnosis of APL was suspected based on morphology. As normal controls, total bone marrow (BM, n=8) and peripheral blood (PB, n=101) cells from healthy donors (age, 18-60y) were collected and mononuclear cells were isolated by Ficoll-Hypaque density gradient centrifugation. Additionally, 28 CBF-leukemia samples were included. Gene expression profile was analyzed by real-time quantitative PCR using the ABL FusionQuant Standard Kit as an endogenous control. Based on the continuous distribution of MLL5/ABL expression on APL samples (Figure 1), we adopted the median value of MLL5/ABL expression as cut-off to dichotomize APL patients in “low” and “high” MLL5 transcript levels. Results MLL5 expression was not different between APL, CBF-leukemia and healthy donors samples (Figure 1; P=0.19). There was no relevant difference between APL patients with low (n=62) and high (n=59) MLL5 transcript levels with respect to clinical and laboratory features, although high MLL5 transcript levels were more likely to be present in female gender (P=0.029). Overall, 102 (84%) achieved CR. Patients with low MLL5 transcript levels had significantly lower CR rate than patients with high MLL5 transcript levels (74% vs 95%; P=0.002). Twelve patients (10%) experienced early mortality (i.e., death during induction therapy) due to hemorrhage (n=6; 50%), disease progression (n=1; 8.3%), thrombosis (n=1; 8.3%), therapy-related infection (n=3; 25%) and differentiation syndrome (n=1; 8.3%); MLL5 transcript levels had no impact on early mortality (P=0.155). With a follow-up of 33 months among survivors (range, 1-72 months), patients with low MLL5 transcript levels had significantly lower 2-year OS (P=0.005) and 2-year DFS rate (P=0.037) than patients with high MLL5 transcript levels. Up to January 2013, a total of six relapses (5%) had been recorded. The 2-year CIR among patients with low and high MLL5 transcript levels was 14% (95%CI: 5% to 27%) and 2% (95%CI: 0.1% to 11%), respectively (P=0.04). We have further evaluated the prognostic impact of MLL5 transcript levels in those patients who remain alive after induction therapy (107 patients). Low MLL5 transcript levels were predictive of lower CR rate (P=0.042) and 2-year OS rate (P=0.009), but had no impact on DFS (P=0.106). Conclusion Our results show that MLL5 transcript levels may predict lower remission rate, short survival and higher risk of relapse in APL patients treated with ATRA and anthracycline-based chemotherapy. This is the first report describing the MLL5 expression as a prognostic factor in APL; nevertheless, our results should be confirmed in an independent cohort. Disclosures: No relevant conflicts of interest to declare.

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