Early Mortality in Acute Promyelocytic Leukemia May Be Higher Than Previously Reported.

Abstract Abstract 1015 Poster Board I-37 Background: Early mortality, mostly from hemorrhagic complications, occurs in less than 10% of patients currently treated in clinical trials for acute promyelocytic leukemia (APL). However, data about the proportion of patients developing such complications prior to clinical trial enrollment are scarce in the literature (Sanz M, et al Blood 2009). Approximately 5% of newly diagnosed patients with APL have been reported not to be eligible for participation in clinical trials due to very poor clinical condition, and their outcome has never been reported. However, enrollment on clinical trials may be difficult in specific clinical situations, such as after hours/weekend admissions and/or emergent requirement for therapy. This study reports the incidence, time of occurrence and clinical features of APL patients with a focus on early mortality. Methods: 150 consecutive APL patients treated at Stanford University between 8/1986 and 7/2009 were identified. Thirteen patients were excluded for lack of appropriate clinical information. Clinical features of patients with APL were analyzed for factors that might be relate to prognosis, including age, gender, white blood cell count, platelet count, fibrinogen, PTT, and INR. Continuous variables were compared with the t-test and categorical variables by Fisher's exact test or X-square statistic. The Kaplan–Meier method was applied to assess overall survival time. Results: Of the 137 patients included in this analysis, the median age at diagnosis was 45 (1-93) years and 78 (57%) were females. Using the PETHEMA criteria, there were 37, 46 and 20 patients with high-, intermediate- and low-risk disease (34 patients could not be classified based on partial/missing data). With a median follow-up time of 748 (0-6,235) days for the entire cohort, 52 (38%) have died. 19 (14%) and 11 (8%) of these patients died within 7 and 3 days of presentation, respectively. Patients with high-risk features had a 13% and 24% chance of dying with 3 and 7 days of presentation, respectively, with significantly inferior outcomes (p=0.045) when compared to those with intermediate-risk patients (6% and 13%) and low-risk disease (5% and 5%). Patients with unknown risk category faired similarly to low-risk patients. The most common cause of early mortality in these 19 patients was intracranial hemorrhage (n=11). Patients with early death (ED) (either <=3 or <=7 days) tended to be older than APL patients with non-early deaths (>7d), or APL patients alive as of their last follow-up (median age 54 years vs. 50 years vs. 39 years), and were more likely to have higher risk disease, though coagulopathy appeared not significantly different amongst the groups. Median fibrinogen, PTT and INR for each individual group are presented on Table 1. The 3-year overall survival (% +/- SE) of the low, intermediate, and high risk patients was 90+/-7, 74+/-7, and 64+/-8, respectively, though early mortality (death within 7 days) was a major determinant of this stratification (p=0.045). Conclusions: Risk of early death in APL patients appears to be higher than previously reported in clinical trials, where trial registration may exclude patients requiring urgent therapeutic interventions. In this cohort, 25% and 13% patients with high- and intermediate-risk APL died within 7 days of presentation, respectively. Risk group stratification was very predictive of risk of early death. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

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

Blood ◽

10.1182/blood.v122.21.1714.1714 ◽

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.

Download Full-text

Renal Cell Carcinoma Recurrence After Nephrectomy for Localized Disease: Predicting Survival From Time of Recurrence

Journal of Clinical Oncology ◽

10.1200/jco.2005.04.8280 ◽

2006 ◽

Vol 24 (19) ◽

pp. 3101-3106 ◽

Cited By ~ 165

Author(s):

Scott E. Eggener ◽

Ofer Yossepowitch ◽

Joseph A. Pettus ◽

Mark E. Snyder ◽

Robert J. Motzer ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Overall Survival ◽

High Risk ◽

Renal Cell ◽

Scoring System ◽

Median Survival Time ◽

Low Risk ◽

Intermediate Risk ◽

Risk Patients ◽

Localized Disease

Purpose Prognostic factors for patients with metastatic renal cell carcinoma (RCC) are well established. However, the risk profile is unknown for patients with recurrent RCC after a nephrectomy for localized disease. Patients and Methods From January 1989 to July 2005, we identified patients with localized RCC treated by nephrectomy who subsequently developed recurrent disease. We applied a validated prognostic scoring system previously developed for patients with metastatic RCC. Each patient was given a total risk score of 0 to 5, with one point for each of five prognostic variables (recurrence < 12 months after nephrectomy, serum calcium > 10 mg/dL, hemoglobin < lower limit of normal, lactate dehydrogenase > 1.5× upper limit of normal, and Karnofsky performance status < 80%). Patients were categorized into low- (score = 0), intermediate- (score = 1 to 2), and high-risk subgroups (score = 3 to 5). Results Our final cohort included 118 patients, with a median survival time of 21 months from the time of recurrence. Median follow-up time for survivors was 27 months. Overall survival was strongly associated with risk group category (P < .0001). Low-risk, intermediate-risk, and high-risk criteria were fulfilled in 34%, 50%, and 16% of patients, respectively. Median survival time for low-risk, intermediate-risk, and high-risk patients was 76, 25, and 6 months, respectively. Two-year overall survival rates for low-risk, intermediate-risk, and high-risk patients were 88% (95% CI, 77% to 99%), 51% (95% CI, 37% to 65%), and 11% (95% CI, 0% to 24%), respectively. Conclusion At disease recurrence after nephrectomy for localized disease, a scoring system based on objective clinical and laboratory data provides meaningful risk stratification for both patient counseling and clinical trial entry.

Download Full-text

Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia

Blood ◽

10.1182/blood-2005-10-4006 ◽

2006 ◽

Vol 107 (9) ◽

pp. 3469-3473 ◽

Cited By ~ 259

Author(s):

Elihu Estey ◽

Guillermo Garcia-Manero ◽

Alessandra Ferrajoli ◽

Stefan Faderl ◽

Srdan Verstovsek ◽

...

Keyword(s):

Retinoic Acid ◽

High Risk ◽

Arsenic Trioxide ◽

Promyelocytic Leukemia ◽

Low Risk ◽

High Risk Patients ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Risk Patients

We examined whether combining all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) might be an alternative to ATRA plus chemotherapy in untreated acute promyelocytic leukemia (APL). Twenty-five low-risk patients (white blood cell [WBC] count less than 10 × 109/L [10 000/μL]) received ATRA (45 mg/m2 daily) and ATO (0.15 mg/kg daily, beginning day 10 of ATRA), and in complete remission (CR) received ATO plus ATRA, without chemotherapy, unless they were reverse transcriptase–polymerase chain reaction (RT-PCR)–positive 3 months from CR date or had molecular relapse. Nineteen high-risk patients were treated identically, but received chemotherapy, generally 9 mg/m2 gemtuzumab ozogamycin (GO) on day 1 of induction. The CR rate was 39 of 44 (24 of 25 in low-risk, 15 of 19 in high-risk). Disease recurred at 9, 9, and 15 months, respectively, in 3 high-risk patients. The median follow-up time from CR date in the 36 patients alive in first CR is 16 months (15 months in low-risk, 20 months in high-risk), with 9 patients followed for at least 24 months. Each of the 36 patients was PCR-negative at last follow-up. Thus, none of the low-risk patients has received chemotherapy, and only 3 high-risk patients (the 3 with relapsed disease) have received chemotherapy past induction. ATRA plus ATO may serve as an alternative to chemotherapy in low-risk untreated APL (eg, in older patients) and, when combined with GO, may improve outcome in high-risk patients.

Download Full-text

Low Von Willebrand Factor: Cut-Off Value for Diagnosis and Risk Score to Predict Bleeding Incidence

Blood ◽

10.1182/blood-2020-142375 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 18-19

Author(s):

Ferdows Atiq ◽

Esmee Wuijster ◽

Moniek P.M. de Maat ◽

Marieke J.H.A. Kruip ◽

Marjon H. Cnossen ◽

...

Keyword(s):

High Risk ◽

Risk Score ◽

Research Funding ◽

Low Risk ◽

Intermediate Risk ◽

Spontaneous Bleeding ◽

High Risk Patients ◽

Risk Patients ◽

Surgical Bleeding

Introduction Although large studies have recently provided valuable insights on the diagnosis, bleeding phenotype, and treatment outcomes of VWD patients, these aspects remain poorly understood in individuals with low VWF. Firstly, there is no clear evidence which cut-off value should be used to diagnose low VWF. Although 0.50 IU/mL is the most recommended cut-off value, some centers use the lower limit of normal (0.60 IU/mL). Secondly, the incidence of post-surgical bleeding, postpartum hemorrhage (PPH) and traumatic- or spontaneous bleeding after diagnosis of low VWF are still unknown. Lastly, it is hard to predict which individuals with low VWF have an increased bleeding risk. Therefore, we investigated the bleeding phenotype of individuals with historically lowest VWF levels of 0.31-0.50 IU/mL and 0.51-0.60 IU/mL, and the incidence of post-surgical bleeding, PPH and traumatic- and spontaneous bleeding after their initial diagnosis of "low VWF". Methods We performed a retrospective cohort study from January 2007 to November 2019 at the Erasmus MC, University Medical Center Rotterdam. All patients evaluated for the presence of a bleeding disorder with VWF antigen (VWF:Ag) and/or VWF activity (VWF:Act) and/or VWF collagen binding (VWF:CB) levels between 0.31-0.60 IU/mL, were included. Patients with VWF:Ag and/or VWF:Act and/or VWF:CB ≤0.30 IU/mL, acquired VWD and those with a concomitant bleeding disorder were excluded. For each individual we collected data from electronic patient files on baseline characteristics, reason for referral, family history of bleeding disorders, ISTH-BAT and laboratory measurements at diagnosis. Retrospective follow-up started from initial date of low VWF diagnosis through November 2019, during which we collected data on surgical procedures, pregnancies, and incidence of spontaneous- and traumatic bleeding. Results We included 439 patients; 269 patients with historically lowest VWF levels 0.31-0.50 IU/mL and 170 patients 0.51-0.60 IU/mL. Mean age at diagnosis was 28.8 ±17.7 years. Most patients were female (74.3%) and had blood group O (76.4%, Table 1). The bleeding score (BS) was similar in patients with historically lowest VWF levels of 0.31-0.50 IU/mL (3.7 ±3.0) and 0.51-0.60 IU/mL (4.0 ±2.9, p=0.209, Table 1). During the mean follow-up period of 6.3 ±3.7 years, 259 surgical procedures were performed in 146 patients, 81 deliveries in 56 women, and 109 spontaneous- or traumatic bleedings in 71 patients. The incidence of post-surgical bleeding was 7 (2.7%) during follow-up, whereas 8 deliveries (10%) were complicated by PPH. Overall, 65 out of 439 patients (14.8%) had a bleeding episode requiring treatment during follow-up, resulting in an incidence of bleeding requiring treatment of 0.5 ±1.9 per patient per decade. No difference was found in the incidence of bleeding requiring treatment between patients with historically lowest VWF levels of 0.31-0.50 IU/mL and 0.51-0.60 IU/mL (Figure 2A, p=0.154). We found that referral for a personal bleeding diathesis, a younger age at diagnosis and an abnormal BS at diagnosis were strong and independent risk factors for bleeding requiring treatment during follow-up, respectively HR=2.32 (95%CI: 1.16-4.63), HR=1.18 (95%CI: 1.01-1.38) and HR=1.77 (95%CI: 1.04-3.01). These risk factors were combined to develop a risk score to identify low VWF patients with an increased risk for bleeding requiring treatment (Figure 2B). The risk score performed excellent to differentiate in bleeding requiring treatment between low risk, intermediate risk and high risk patients (p<0.001, Figure 2C). The number of patients with bleeding requiring treatment was 8/126 (6.3%) in patients with low risk, 18/143 (12.6%) in intermediate risk and 39/170 (22.9%) in high risk patients (p<0.001). Likewise, the incidence of bleeding requiring treatment per patient per decade was 0.22 ±1.08 in low risk, 0.28 ±1.25 in intermediate risk and 0.87 ±2.61 in high risk patients (p=0.004, Figure 2D). Conclusion To conclude, there is no difference in the bleeding phenotype of individuals with historically lowest VWF levels of 0.31-0.50 IU/mL and 0.51-0.60 IU/mL. Therefore, the cut-off value to diagnose low VWF should be set at 0.60 IU/mL. Furthermore, the risk score developed in the current study may assist to identify low VWF patients with low, intermediate and high risk for future bleeding. Disclosures Atiq: SOBI: Other: travel grant; CSL Behring: Research Funding. Kruip:Boehringer Ingelheim: Research Funding; Pfizer: Research Funding; Bayer: Research Funding; Daiichi Sankyo: Research Funding; SOBI: Research Funding; Bayer: Speakers Bureau. Cnossen:Takeda: Research Funding; Shire: Research Funding; Baxter: Research Funding; Bayer: Research Funding; Sobi: Research Funding; CSL behring: Research Funding; Nordic Pharma: Research Funding; Novo Nordisk: Research Funding; Pfizer: Research Funding. Leebeek:CSL Behring: Research Funding; Shire/Takeda: Research Funding; Uniqure: Consultancy; Shire/Takeda: Consultancy; Novo Nordisk: Consultancy; SOBI: Other: Travel grant; Roche: Other: DSMB member for a study.

Download Full-text

Risk-adapted combined therapy with arsenic trioxide and all-trans-retinoic acid for de novo acute promyelocytic leuкaemia

Hematology and Transfusiology ◽

10.35754/0234-5730-2021-66-2-168-191 ◽

2021 ◽

Vol 66 (2) ◽

pp. 168-191

Author(s):

V. V. Troitskaya ◽

E. N. Parovichnikova ◽

A. A. Semenova ◽

Z. T. Fidarova ◽

A. N. Sokolov ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

De Novo ◽

Early Mortality ◽

Low Risk ◽

Molecular Remission ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Risk Patients ◽

High Risk Cohort

Introduction. Non-chemotherapy for acute promyelocytic leukaemia (APL) with a combination of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) provides for a high patient survival rate at lesser toxicity as effectively or superior to standard chemotherapy programmes.Aim — assessment of the ATO–ATRA risk-adapted exposure protocol in management of de novo acute promyelocytic leucaemia.Materials and methods. A prospective study included 51 primary APL patients aged 18–76 years. The program included remission induction (ATO 0.15 mg/kg intravenously, ATRA 45 mg/m2 orally) for 30–60 days in a low-risk (until remission) and 60 days — in a high-risk cohort that had idarubicin therapy added on days 2 and 4. Remission consolidation was attained with four (low-risk) or five (high-risk) courses. Minimal residual disease was monitored with real-time PCR at all phases.Results. The high-risk cohort was assigned 15 (29.4 %), the low-risk cohort — 36 (70.6 %) patients. Therapy induction till APL morphological remission was performed in 48/51 (94 %) patients. Molecular APL remission was achieved in 47 (92 %) patients, 100 % in the low-risk and 80 % in high-risk cohort. Early mortality was 6 % (n = 3), death in remission — 2 % (n = 1). Differentiation syndrome (DS) occurred in 16 (31.7 %) patients, more frequently in the high-risk vs. low-risk cohort (53.3 % and 22.2 %, respectively, p = 0.05; odds ratio 4.0 [1.1–14.4]). DS developed on days 1–20 (3 days median) of therapy. DS risk factors: a high-risk status, haemorrhagic syndrome and infection at the disease onset. A median follow-up time in survivors was 12.9 months (2.5–34.3), a six-month overall survival — 92 % (95 % CI: 85–100 %). A six-month overall survival was 100 and 73 % in the low- and high-risk cohorts, respectively (95 % CI: 54–100 %, p = 0.001). APL relapse not registered, 47 (92 %) patients survived and achieved the first molecular remission.Conclusion. A differentiated risk-adapted approach to APL therapy with cytostatic treatment added in high-risk patients only provided for a 100 % molecular remission and relapse-free survival. Therapy failures (early mortality and death in remission) affected high-risk patients due to a severe individual condition at the time of APL diagnosis.

Download Full-text

Real-World Ibrutinib Validation of the Ball Score to Predict Overall Survival: A Filo Group Study in RR CLL Patients

Blood ◽

10.1182/blood-2019-122318 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1741-1741

Author(s):

Loic Ysebaert ◽

Anne-Sophie Michallet ◽

Fontanet Bijou ◽

Aline Clavert ◽

Anne Quinquenel ◽

...

Keyword(s):

Overall Survival ◽

Clinical Trials ◽

High Risk ◽

Risk Score ◽

Real World ◽

Low Risk ◽

The Other ◽

Intermediate Risk ◽

Second Cancer ◽

Other Hand

Abstract Ibrutinib has revolutionized the management of RR CLL in the past 5 years, improving overall survival (OS) over standard chemo-immunotherapies (CIT) in the registration trials HELIOS and RESONATE. Recently, based on these two studies, a score has been validated able to predict 3 groups with different OS (acronym BALL, further validated in cohorts of patients treated with CIT or other targeted agents) (1). The BALL model consists of four factors with 1 point each (serum ß2-microglobulin>5mg/dL, lactate dehydrogenase >upper limit of normal, hemoglobin <110g/L for women or <120g/L for men, and time from initiation of last therapy <24 months). It separates patients into low (score 0-1), intermediate (score 2-3), and high risk (score 4) groups. Yet, BALL score has never been validated in large cohorts of ibrutinib patients. Methods We collected survival data and causes of death across 10 FiLO centers, in patients treated with ibrutinib monotherapy as per label for RR disease. We included patients across performans statuses, irrespective of previous line of therapies (LOT) or age, with 3 (n=329) or 4 (n=250) available BALL criteria at the time of initiation. Results Median FU was 29.3 months. Stratification of BALL scores in 250 patients (with 4 parameters known) was as follows: low risk (n=88, 35.2%), intermediate risk (n=122, 48.8%), and high risk (n=40, 16%), with estimated 2-years OS rates of 87.3%, 82.3% and 58.8%, respectively (Figure 1A, C-statistics index 0.64). These results are very similar (all 3 groups) to what Soumerai J et al.reported in their ibrutinib/CIT training dataset of 581 patients (1). Causes of 60/250 deaths were as follows: CLL 28.3%, Richter transformation 15%, infectious (33.3%) or cardiovascular (18.3%) toxicity, second cancer (5%). High risk score was significantly associated to deletion 17p/TP53 mutational status (69.4% vs47%, p<0.001), LOT3+ (65.8% vs33.8%, p=0.02), but not age or gender. We also calculated a "worse BALL score" by adding 1 point to 79 more patients with 3 known parameters (n=329 in total). Stratification was as follows: low risk (6.7%, 2y-OS 100%), intermediate risk (45.6%, 2y-OS 82.9%), and high risk (47.7%, 2y-OS 74.6%) (Figure 1B). The latter results were very comparable to the internal validation dataset of ibrutinib/CIT in 242 patients. Causes of 79/329 deaths were as follows: CLL 27.8%, Richter transformation 17.7%, infectious (35.4%) or cardiovascular (15.2%) toxicity, second cancer (3.8%). Altogether, the BALL score was useful to delineate 3 risk-groups with statistically different survivals in real-world ibrutinib patients, despite 50% of deaths were due to toxicity. By Cox univariate analysis for OS (n=227, events=57), variables with significant impact on prognosis were: age>79y (HR 2.09, p=0.003), male gender (HR 1.5, p=0.046), del17p/TP53 mutation (HR 1.45, p=0.049), previous lines of therapy (LOT1-2 vs 3+, HR 2.17, p<0.0001), and BALL score (2-3 vs0-1 HR 1.8, and 4 vs0-1 HR 5.69, p<0.0001). By multivariate analysis, only LOT3+ (HR 2.6, p=0.003) and BALL score (2-3 vs0-1 HR 2.16, p=0.05, and 4 vs0-1 HR 5.2, p<0.001) were shown as independent factors significantly associated with shorter OS. These results further advocated for the use of BALL score in our practice, because we validated its use even in elderly RR patients. In the clinical trials used for model building, median age was <65y, and we included 23.1% of patients >79y. On the other hand, LOT was excluded from the model, and so its impact left unanswered by the first publication. Our data suggested that OS of multi-relapsing patients (3 or more previous lines of therapy) was not adequately predicted by the BALL score. On the other hand, we confirmed that deletion 17p/TP53mutational status was not an independent factor for OS, because predicted by the BALL score parameters (1). Conclusions In our series, the BALL score also identified a well-defined cohort of real-world RR CLL patients with an unmet clinical need despite the use of ibrutinib (median OS 27 months). We suggest that patients in the high-risk group should be thoroughly monitored, or even proposed clinical trials with drug combinations, or even cellular therapies approaches (CAR-T cells, bispecific antibodies) due their shorter OS. (1) Soumerai J, et al. Risk Model for Overall Survival in Relapsed or Refractory Chronic Lymphocytic Leukaemia in the Era of Targeted Therapies. Lancet Haematol 2019. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Risk Stratification in Acute Promyelocytic Leukemia Based on Elevated White Cell Count and Reduced Platelet Count Does Not Identify Subsequent Relapses: A Retrospective Review of 60 Patients.

Blood ◽

10.1182/blood.v104.11.4522.4522 ◽

2004 ◽

Vol 104 (11) ◽

pp. 4522-4522

Author(s):

Richard T. Doocey ◽

Stephen H. Nantel ◽

Michael J. Barnett ◽

Donna L. Forrest ◽

Donna E. Hogge ◽

...

Keyword(s):

High Risk ◽

Complete Remission ◽

Maintenance Therapy ◽

Risk Group ◽

White Cell Count ◽

High Risk Group ◽

Low Risk ◽

Intermediate Risk ◽

Risk Patients

Abstract Acute promyelocytic leukemia (APL) has become one of the more readily treatable subtypes of acute myeloid leukemia on the basis of its particular sensitivity to anthracyclines and the introduction of the differentiating agent all-trans retinoic acid (ATRA). Unfortunately some patients will ultimately relapse after achievement of complete remission. A PETHEMA and GIMEMA (PETH/GIM) cooperative group joint study sought to identify risk factors associated with relapse and developed a predictive model based on white cell count (WCC) and platelet count (Plt) at diagnosis. This model for relapse free survival was capable of segregating patients into low risk (WCC < 10 x 109/L / Plt > 40 x 109/L), intermediate risk (WCC < 10 x 109/L / Plt < 40 x 109/L), and high risk (WCC > 10 x 109/L). A subsequent follow up study demonstrated improved outcomes for intermediate and high risk group patients treated with an anthracycline and ATRA based risk adapted strategy. We reviewed 60 cases of adult de novo APL treated at Vancouver General Hospital from August 1995 to December 2003. Thirty five females (58%) and 25 males (42%) were treated with a standard induction and consolidation protocol consisting of 3 cycles of Daunorubicin (60 mg/m2 OD for 3 days), Cytosine arabinoside (100 mg/m2 BID for 7 days), and ATRA (45 mg/m2/day until complete remission or a maximum of 60 days). In 2000 maintenance therapy was introduced and ATRA and/or varying doses of Methotrexate and 6-Mercaptopurine were then instituted for up to 2 years duration. At the completion of induction chemotherapy complete morphological and cytogenetic remission was achieved in 55/60 patients (92%) with 4 induction failures and only 1 death during induction treatment. Subsequently during and after consolidation and maintenance therapy at a median follow up of 34 months there were a total of 10 episodes of relapse (18%) in these 55 patients. When the 55 patients in complete remission were stratified at diagnosis by the PETH/GIM risk group there were 18 low risk patients (33%), 26 intermediate risk patients (47%), and 11 high risk patients (20%). The number of relapses was 6 in the low risk group (33%), 4 in the intermediate risk group (15%) and no relapses were identified in the high risk group. In our experience the predictive model for relapse free survival developed by the PETH/GIM cooperative group does not identify those at most likelihood for subsequent relapse after achieving an initial complete remission. The greatest number of relapse was seen in the low risk group with no relapses in the high risk group. These variations may be explained in part by the different chemotherapy treatment protocols with variable maintenance therapy. Future investigation will focus on the prognostic role of immunophenotype, additional cytogenetic abnormalities and molecular isoforms in determining outcome in APL.

Download Full-text

Gastrointestinal Acuity Score (GAS): A Comprehensive Risk Score Incorporating Histologic Grade and Clinical Factors to Predict Need for Second Line Therapy, Non-Relapse Mortality, and Overall Survival in Lower Gastrointestinal Graft Vs. Host Disease

Blood ◽

10.1182/blood.v126.23.3128.3128 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3128-3128

Author(s):

Jin S. Im ◽

Rima M Saliba ◽

Susan C Abraham ◽

Asif Rashid ◽

William Ross ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Risk Group ◽

Low Risk ◽

Intermediate Risk ◽

Second Line ◽

Second Line Therapy ◽

Cart Analysis ◽

Line Therapy ◽

Risk Patients

Abstract Lower Gastrointestinal Graft versus Host Disease (GI GVHD) is a major cause for GVHD related non-relapsed mortality (NRM). High dose corticosteroid is the initial therapy for suspected lower GI GVHD, and additional therapy is often required for steroid refractory cases. The identification of high-risk patients is critical as timely intensification of treatment through early institution of second line therapy improves outcomes. To develop a reliable lower GI GVHD risk scoring system, Gastrointestinal Acuity Score (GAS), we evaluated 210 consecutive patients who underwent endoscopic biopsy for suspected lower GI GVHD within 6 months from the transplant from 2009 to 2012 at M.D. Anderson Cancer Center. We first identified 5 significant prognostic factors that accounted for the increased NRM in lower GI GVHD using univariate analysis: histologic grade, clinical stage, age, multi-organ GVHD, and donor type (Table 1). Gender, donor cell type, conditioning regimen (myeloablative vs non-myeloablative), time of diagnosis, disease status did not significantly influence NRM. Next, we performed multivariate Classification and Regression Tree (CART) analysis that utilizes sequential binary decision nodes to categorize 197 patients into subgroups according to their risk profile and outcome (Figure 1). The decision tree identified 7 subgroups starting with the presence of multi-organ GVHD as the first major decision node. This was followed by clinical stage 3/4, Age > 40 years, histology grade 3/4, and histology grade 1. We then consolidated subgroups with comparable risk profiles into low, intermediate, and high NRM risk groups (Figure 1). The 3 NRM risk groups correlated with day 28 response, the need for second line therapy and overall survival (Figure 2). The complete response rates at day 28 from the initiation of steroid therapy were significantly lower in the high (15%, p<0.001) and intermediate (43%, p=0.003) risk group compared to the low-risk group (70%). Accordingly, the high-risk patients were 4.3 (p < 0.001) and 1.6 (p=0.02) folds more likely to need second line therapy compared to low and intermediate risk patients, respectively. The intermediate risk patients were 2.7 (p=0.02) folds more likely to need second line therapy compared to the low risk group. In addition, the high-risk group was associated with the highest NRM (HR 5.4, p<0.001), followed by the intermediate risk (HR 3.8, p<0.001) compared to the low risk group. This translated into worse overall survival at 1 year for the high-risk patients. Lastly, there was a trend towards a lower chronic GVHD rate in the low risk group (25%, HR=0.6, p 0.06) compared to the high and intermediate risk groups (37%). In conclusion, we developed a novel risk scoring system, Gastrointestinal Acuity Score (GAS), incorporating histologic grades and clinical factors through multivariate CART analysis, and demonstrated that GAS predicts both early outcomes (day 28 CR rate and need for second line therapy) and late outcomes (NRM and overall survival) in patients with lower GI GVHD. Once prospectively validated in a larger cohort of lower GI GVHD patients, it will be of great use for clinicians with limited access to GVHD biomarker analysis in making treatment decisions as our new risk scoring system utilizes readily available variables. Figure 1. Univariate Analysis of risk factors for NRM at 1 year in Lower GI GVHD Figure 1. Univariate Analysis of risk factors for NRM at 1 year in Lower GI GVHD Figure 2. CART Analysis: Decision Tree for Risk Assessment Figure 2. CART Analysis: Decision Tree for Risk Assessment Figure 3. Need for second line therapy, NRM and OS Figure 3. Need for second line therapy, NRM and OS Disclosures Alousi: Therakos, Inc: Research Funding.

Download Full-text

Inpatient Versus Outpatient Hypomethylating Agent Induction for AML As a Predictor for Survival

Blood ◽

10.1182/blood-2020-133837 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 27-28

Author(s):

Chetan Jeurkar ◽

Benjamin E Leiby ◽

Joshua Banks ◽

Margaret Kasner ◽

Gina Keiffer ◽

...

Keyword(s):

Overall Survival ◽

Logistic Regression ◽

High Risk ◽

Research Funding ◽

Low Risk ◽

Intermediate Risk ◽

Tumor Lysis ◽

Palliative Approach ◽

Co Morbidity ◽

Risk Patients

Introduction The hypomethylating agents (HMA) decitabine (dec) and azacytidine (aza) are used in acute myeloid leukemia (AML) for induction therapy in patients with either newly diagnosed or relapsed disease and who are above the age of 60 or for those who would not tolerate intensive induction chemotherapy. As a result, HMA have been widely used at our institution, on both inpatient (IP) and outpatient (OP) services. The decision to administer IP-HMA vs OP-HMA is complex, but IP-HMA is recommended at our institution for neutropenic infections, debility, or risk of tumor lysis. The prognostic significance of this decision, if any, has not been widely explored. We hypothesized that because patients who receive their first cycle of HMA as an IP were at higher risk for complications, they would have a worse 100-day survival than their OP counterparts. Methods This was a retrospective observational study of patients treated at Thomas Jefferson University Hospital from January 2016-January 2020. Inclusion criteria were patients who had a diagnosis of AML, were above the age of 18 when treated, were treated with an HMA during the course of their disease, and were treated at our institution where electronic medical records (EMR) were complete and readily accessible. Exclusion criteria were patients who had died as a direct result of their hematopoietic stem cell transplant (HSCT) and whose records were incomplete or who had been treated at an outside institution. Logistic regression models were used to analyze data. Survival was calculated from day one of the first cycle of HMA received. Results A total of 68 patients were evaluated. Twenty-nine patients received IP-HMA while 39 received OP-HMA. Mean overall survival from HMA initiation was 252 days (95% CI 164-340) in the IP-HMA group and 430 days (95% CI 269-591) in the OP-HMA group. Mean 100-day survival in the IP-HMA group was 78 days (95% CI 65-91) and 93 days (95% CI 87-99) in the OP-HMA group. The average age at HMA initiation in the IP group was 69 (95% CI 64-74) and was 66 (95% CI 62-70) in the OP group. Average Charlson co-morbidity index was 5.5 (95% CI 5.0-6.0) in the IP group and 5.6 (95% CI 5.0-6.2) in the OP group. In the IP group, there were 1 low risk, 7 intermediate risk, and 21 high risk patients according to the European LeukemiaNet (ELN) risk stratification scale. In the OP group, there were 3 low risk, 8 intermediate risk, and 28 high risk patients. Nineteen of the 29 patients in the IP group and 11 of the 39 patients in the OP group received venetoclax in addition to an HMA as part of their therapy. Using a logistic regression model, location of HMA induction was found to have a significant effect on 100-day survival with IP induction being associated with worse survival (odds ratio=3.94; p=0.028) (see figure 1). Co-variates for this model included age at HMA initiation as this was the only confounder found in Wilcoxon rank sum testing to be significant. Other confounders which were tested but not included in logistic regression due to non-significance included race, gender, ELN risk, and Charlson co-morbidity indices. Discussion In this retrospective study, we found that IP-HMA induction was associated with a worse 100 day and overall survival than its OP counterpart. Though we found that co-morbidity indices and ELN risk scores were similar between the two groups, we postulate the reason the IP group had a significantly worse 100 day survival was that being admitted for neutropenic fever, risk of tumor lysis, etc. inherently put them at higher risk for complications like septic shock and hypoxic respiratory failure. Additionally, we found that patients who received HMA as an IP were far more likely to die shortly after their induction, within 100 days and often within 20 days. This would indicate they were potentially poor candidates for chemotherapy and that a palliative approach may have been more appropriate.. This study describes the survival differences seen in patients receiving IP-HMA versus OP-HMA. Knowledge of these results could spawn a more palliative approach for future patients requiring IP-HMA induction. Figure Disclosures Kasner: Otsuka Pharmaceutical: Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Palmisiano:AbbVie: Research Funding; Genentech: Research Funding.

Download Full-text

Immune Reconstitution-Based Score for Risk Stratification of Chronic Graft-Versus-Host Disease Patients

Frontiers in Oncology ◽

10.3389/fonc.2021.705568 ◽

2021 ◽

Vol 11 ◽

Author(s):

Fabio Serpenti ◽

Francesca Lorentino ◽

Sarah Marktel ◽

Raffaella Milani ◽

Carlo Messina ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Risk Stratification ◽

Immune Reconstitution ◽

Validation Cohort ◽

Multivariate Model ◽

Low Risk ◽

Intermediate Risk ◽

High Risk Patients ◽

Risk Patients

IntroductionAllogeneic stem cell transplantation survivors are at a relevant risk of developing chronic GvHD (cGvHD), which importantly affects quality of life and increases morbidity and mortality. Early identification of patients at risk of cGvHD-related morbidity could represent a relevant tool to tailor preventive strategies. The aim of this study was to evaluate the prognostic power of immune reconstitution (IR) at cGvHD onset through an IR-based score.MethodsWe analyzed data from 411 adult patients consecutively transplanted between January 2011 and December 2016 at our Institution: 151 patients developed cGvHD (median follow-up 4 years). A first set of 111 consecutive patients with cGvHD entered the test cohort while an additional consecutive 40 patients represented the validation cohort. A Cox multivariate model for OS (overall survival) in patients with cGvHD of any severity allowed the identification of six variables independently predicting OS and TRM (transplant-related mortality). A formula for a prognostic risk index using the β coefficients derived from the model was designed. Each patient was assigned a score defining three groups of risk (low, intermediate, and high).ResultsOur multivariate model defined the variables independently predicting OS at cGvHD onset: CD4+ >233 cells/mm3, NK <115 cells/mm3, IgA <0.43g/L, IgM <0.45g/L, Karnofsky PS <80%, platelets <100x103/mm3. Low-risk patients were defined as having a score ≤3.09, intermediate-risk patients >3.09 and ≤6.9, and high-risk patients >6.9. By ROC analysis, we identified a cut-off of 6.310 for both TRM and overall mortality.In the training cohort, the 6-year OS and TRM from cGvHD occurrence were 85% (95% CI, 70-92) and 13% (95% CI, 5-25) for low-risk, 64% (95% CI, 44-89) and 30% (95% CI, 15-47) for intermediate-risk, 26% (95% CI, 10-47), and 42% (95% CI, 19-63) for high-risk patients (OS p<0.0001; TRM p = 0.015).The validation cohort confirmed the model with a 6-year OS and TRM of 83% (95% CI, 48-96) and 8% (95% CI, 1-32) for low-risk, 78% (95% CI, 37-94) and 11% (95% CI, 1-41) for intermediate-risk, 37% (95% CI, 17-58), and 63% (95% CI, 36-81) for high-risk patients (OS p = 0.0075; TRM p = 0.0009).ConclusionsIR score at diagnosis of cGvHD predicts GvHD severity and overall survival. IR score may contribute to the risk stratification of patients. If confirmed in a larger and multicenter-based study, IR score could be adopted to identify patients at high risk and modulate cGvHD treatments accordingly in the context of clinical trial.

Download Full-text