Myeloid Leukemia In First Relapse Research Articles

Poor Outcome of Patients with Acute Myeloid Leukemia in First Relapse Underscores the Need for Effective Initial Treatment

Introduction: The incorporation of novel targeted agents into combination regimens used in the treatment of patients with acute myeloid leukemia (AML) has improved their outcomes. However, disease relapse is still challenging and associated with a poor response rate, limited therapeutic options and poor outcome. Predictors of outcome for patients in first relapse include the duration of first remission, cytogenetic risk at diagnosis, age and whether they underwent an allogeneic stem cell transplantation (alloSCT) in first remission. The incorporation of genetic aberrations detectable at diagnosis has been useful in further stratifying prognosis, but their predictive value at the time of relapse is not well established. Herein we analyze a large cohort of frontline-treated AML patients, focusing on the outcomes of patients presenting a first disease relapse. Methods: This is a retrospective single-center study including patients diagnosed with AML from April 2017 to October 2022. Risk assessment and response to treatment were defined according to the ELN 2022 guidelines. Mutations were assessed using an 81-gene NGS panel. Survival analyses were estimated with the Kaplan-Meier method, using the log-rank test for comparison. Univariate and multivariate analysis were performed using Cox proportional hazards regression. Results: A total of 875 patients with AML were included in the study, with a median age of 65 years old (range,18-95). According to the ELN risk category, 171 (20%) patients had favorable disease, 200 (23%) patients intermediate and 473 (54%) adverse. Patients received intensive treatment (IT; 40% of patients, 41% of whom with the addition of venetoclax) or low intensity treatments (LIT; 60% of patients, 72% with venetoclax). The overall response rate including complete remission (CR)/CR with incomplete hematologic recovery (CRi) was 73%. Among responding patients, 201 (32%) underwent alloSCT in first remission. After a median follow-up of 25 months, the median OS was 53 months for patients receiving IT and 11 months for patients receiving LIT (Figure 1). The median OS for favorable, intermediate and adverse risk patients was not achieved, 24 and 11 months, respectively. During this follow up time, 337 patients were alive and maintaining CR. 197 patients have relapsed after having achieved CR/CRi, 36 of them after undergoing alloSCT. Available data for analysis was available in 164 of these patients. The median age at relapse was 67 (21-95) and 57 (35%) received prior IT whereas 107 (65%) received LIT. At diagnosis, 15%, 16% and 69% were favorable, intermediate and adverse risk, respectively. The median time from best response to relapse was 7.5 (range,1-35) and 6.3 (range, 1-49) months for patients treated with IT and LIT, respectively. At the time of relapse, 36% of patients had a complex karyotype, 4% had MECOM gene rearrangement and 3% had KMT2A gene rearrangement. The most common mutations at time of relapse were TP53 (34%), DNMT3A (34%), TET2 (23%) and RUNX1 (19%). After relapse, 32 (20%) and 132 (80%) received salvage IT and LIT treatment, respectively. The CR/CRi rate for IT and LIT were 31% and 27%, respectively. The mOS from relapse was 3.4 and 5.5 months for patients with salvage IT and LIT, respectively (p=0.6). Age at relapse (mOS of 6.5 vs 5.1 months for patients age <60 and ≥60, respectively [p=0.1]), type of induction therapy (mOS of 6.6 vs 4.9 for patients receiving IT and LIT, respectively [p=0.07]), or risk classification at relapse (mOS of 4.9, 6.3 and 5.1 months for favorable, intermediate and adverse risk, respectively [p=0.7]) did not stratify patients. Duration of first remission longer than 12 months was associated with a better OS (mOS 8.1 vs 4.3 months, p=0.008). Univariate and multivariate analysis was performed, including clinical and biological variables at diagnosis and relapse (Table 1). Importantly, high white blood cell count at relapse (HR 2.1), short first remission (HR 1.6), complex karyotype at relapse (HR 1.7) and KMT2A rearrangement at relapse (HR 3.8) were independent predictors of outcome after relapse. Conclusion: Although outcomes of patients with AML have improved, disease relapse remains a major obstacle with poor outcomes despite the availability of new salvage strategies. Highly effective induction and maintenance regimens are needed to reduce the risk of relapse.

A Novel Prognostic Model for Patients with Acute Myeloid Leukemia in First Relapse with Improved Prognostic Accuracy

Introduction Despite high rates of complete remission (CR) after intensive induction chemotherapy in newly diagnosed AML, relapse is frequent and associated with poor outcome with a median overall survival (OS) of 3-5 months. While cytogenetic and molecular markers are associated with outcome in newly diagnosed patients, the prognostic value in the relapsed setting is unclear, even though it may facilitate therapeutic decision making. Genetic data was only limitedly available when earlier models for relapsed patients were developed, such as reported by HOVON-SAKK (Breems, JCO 2005) and GOELAMS (Chevallier, Leukemia, 2011). Therefore, a comprehensive analysis of clinical, cytogenetic and molecular variables in a prognostic model for outcome after relapse is needed. We set out to evaluate the impact of these variables on outcome after first relapse in the current therapeutic era, and develop a new prognostic model and compare that model with earlier models. Methods A total of 946 (44%) relapsing patients out of 2127 newly diagnosed AML patients who participated in prospective HOVON-SAKK trials of intensive induction chemotherapy between 2000-2018 were included in this analysis. A random survival forest machine learning algorithm was used to identify top markers impacting 1 year survival after relapse among 45 candidate predictors, including 7 clinical parameters, and 9 cytogenetic and 29 molecular abnormalities present at diagnosis. Cox regression with backward selection was performed to obtain hazard ratios (HRs) from relevant predictors identified by the random survival forest algorithm. A clinical prognostic tool was developed with points assigned to each marker based on the rounded logarithm of HR. Four groups were defined based on quartiles of the individual predictions. Prognostic accuracy of risk models was assessed using Harrel's C-index. Results The median age of relapsed patients was 58 years (range: 18-81), with 56% being male. Adverse risk AML according to ELN2022 risk was found in 48% of patients, whereas favorable and intermediate risk were classified in 22% and 31%, respectively. Prior allogeneic stem cell transplantation (SCT) in first CR was performed in 33% of patients, while 14% received autologous SCT. The median time between CR and relapse was 14 months (range: 0-124). The median follow-up time after relapse for patients alive was 49 months (range: 0-124). The random survival forest identified 16 parameters that were associated with 1 year OS based on variable importance, including: age at relapse ≥60 years, relapse-free interval ≤1 year, white blood cell count ≥10 x 10e9/L at diagnosis, prior allogeneic SCT, absence of t(8;21)/inv16, and presence of complex or monosomal karyotype (CK/MK), -5 or del(5q), -7, t(v;11q23), chromosome 17 alterations (-17, del(17p) or abn(17p)), FLT3-ITD, and mutations found in either TP53 with VAF ≥10%, DNMT3A, EZH2, NPM1, or NRAS. From these parameters, nine remained significant with Cox regression: age (HR 1.48, p<0.01), relapse free interval ≤1 year (HR 1.74, p<0.01), white blood cell count ≥10 x 10e9/L at diagnosis (HR 1.23, p=0.02), prior allogeneic SCT (HR 1.58, p<0.01), CK/MK (HR 1.53, p<0.01), no t(8;21)/inv(16) (HR 2.34, p<0.01), t(v;11q23) (HR 1.51, p=0.02), mutated TP53 with VAF ≥10% (HR 1.70, p<0.01), FLT3-ITD (HR 1.32, p<0.01). Next, weights were assigned to these variables based on the multivariate HRs (Figure 1A). Scores were calculated for individual patients and four groups were defined. OS at 1 year estimated 54±3% in the favorable risk group (≤5 points), 35±3% in the intermediate group (6-7 points), 18±3% in the high risk group (8-9 points), and 8±2% in the very high risk group (≥10 points) (Figure 1B). The prognostic accuracy for 1 year OS as measured by the C-index was 0.70. In contrast, in this cohort C-indices for the HOVON-SAKK and GOELAMS models were 0.65 and 0.64, respectively. In addition, comparing the earlier models with the new model, 50% of patients in the adverse group of the HOVON-SAKK model were classified to the favorable (14%) and intermediate group (36%) in the new model. In the GOELAMS model, 42% of intermediate risk patients were considered high (10%) or very high risk (32%) in the new model. Conclusion Analysis of clinical, cytogenetic and molecular variables identified nine variables for a new prognostic model which was associated with distinct OS at 1 year after first AML relapse and improved prognostic accuracy.

Identifying Prognostic Factors That Influence Outcome of Childhood Acute Myeloid Leukemia in First Relapse in Saudi Arabia: Results of the Multicenter SAPHOS Study

BackgroundThe outcome of childhood acute myeloid leukemia (AML) in first relapse (rAML) remains poor. Reported overall survival (OS) rates vary between high-income developed countries and those with fewer resources. The OS of rAML in high-income developing countries (HIDCs) has not been reported. Patients and MaterialsA multicenter study was performed in an HIDC. The outcome of patients with relapsed non-M3/non-Down syndrome AML was evaluated. Three-year OS was computed using the Kaplan-Meier method, and predictors of OS were analyzed using a Cox proportional hazards model. ResultsA total of 88 patients with non-M3/non-Down syndrome AML diagnosed between January 2005 and December 2012 with a first relapse were identified. Their 3-year OS was 22.6% ± 5.4%. Patients with inv(16) and t(8;21) had an OS of 75.0% ± 21.7% and 36.0% ± 16.1%, respectively. Worse outcomes were associated with “other intermediate” and 11q23 rearrangement AML (OS of 9.4% ± 8.7% and 10.7% ± 9.6%, respectively). Patients experiencing time to relapse (TTR) less than 1 year had shorter OS than those with a longer TTR (14.6% ± 5.4% vs. 41.1% ± 11.5%; P = .006). The outcome of patients after stem cell transplantation (SCT) in second complete remission (CR2) was superior compared with no SCT (50.9% ± 11.2% vs. 7.7% ± 4.6%; P = .001). TTR, risk group, CR2, and SCT in CR2 were the most significant predictors for survival. ConclusionsrAML remains a clinical challenge. Genetic variability in outcomes was observed. A majority of patients with inv(16) were successfully salvaged post-relapse, whereas patients with 11q23 rearrangement had a poor prognosis. Only one-third of those with t(8;21) rAML survived. Better access to SCT in HIDCs is needed.

Improving outcomes for patients with acute myeloid leukemia in first relapse: a single center experience.

The outcome of patients with relapsed acute myeloid leukemia (AML) remains unsatisfactory, with few available effective therapies. Increased understanding of the biology of the disease has led to the identification of novel therapeutic agents, several of which have been evaluated in recently conducted clinical trials. We sought to determine whether the introduction of these agents as well as modern supportive care measures has already translated to better outcomes. We examined the outcomes of 1,056 patients with AML in first relapse treated between January 1993 and December 2013 at our institution. As previously reported, the independent prognostic factors for survival after first relapse included age at relapse, cytogenetics, and duration of first complete remission. Upon multivariable analysis, treatment era was an independent predictor of survival, with significant improvement in overall survival between 2008 and 2013 as compared to prior time periods. Modern supportive care measures as well as participation in clinical trials of novel agents are already improving the outcomes in first relapse.

Core-binding factor acute myeloid leukemia in first relapse: a retrospective study from the French AML Intergroup

AbstractAlthough core-binding factor-acute myeloid leukemia (CBF-AML) (t[8;21] or inv[16]/t[16;16]) represents a favorable cytogenetic AML subgroup, 30% to 40% of these patients relapse after standard intensive chemotherapy. The encouraging results of gemtuzumab ozogamicin (GO) in newly diagnosed AML, and particularly in CBF-AML, incited us to retrospectively investigate the impact of GO-based salvage in these patients. We retrospectively analyzed the outcome of 145 patients with CBF-AML (59 t[8;21], 86 inv[16]/t[16;16]) in first relapse. As salvage, 48 patients received GO-based chemotherapy and 97 patients received conventional chemotherapy. Median age was 43 years (range, 16-76). Median first complete remission duration was 12.1 months (range, 2.1-93.6). Overall, second complete remission (CR2) rate was 88%. With a median follow-up from relapse of 3.5 years, the estimated 5-year disease-free survival (DFS) was 50% and 5-year overall survival (OS) was 51%. Older age and shorter first complete remission duration was associated with a shorter OS. Patients treated with GO had similar CR2 rate but significantly higher 5-year DFS (68% vs 42%; P = .05) and OS (65% vs 44%; P = .02). In multivariate analysis, GO salvage was still associated with a significant benefit in DFS and OS. In the 78 patients who received allogeneic hematopoietic stem cell transplantation in CR2, GO before transplant significantly improved posttransplant DFS and OS without excess of treatment-related mortality.

Outcome of older patients with acute myeloid leukemia in first relapse

To provide data for future drug evaluation, we analyzed the outcome of 393 patients aged 50 years or older (median, 64 years) with AML in first relapse after treatment in recent ALFA trials. Salvage options were retrospectively classified as follows: best supportive care (BSC), low-dose cytarabine (LDAC), gemtuzumab ozogamicin (GO), intensive chemotherapy (ICT), or ICT combined with GO. Second complete remission (CR2) rate was 31% and median post-relapse survival was 6.8 months (0, 17, 42.5, 53, and 80% and 3.2, 5.6, 8.9, 9, and 19.8 months in BSC, LDAC, GO, ICT, and ICT + GO subsets, respectively). Age, performance status, WBC, CR1 duration, and favorable AML karyotype, but not other cytogenetic or molecular features, influenced post-relapse outcome. Multivariate adjustment and propensity score matching showed that intensive salvage (ICT/ICT+GO/GO versus LDAC/BSC) was associated with longer post-relapse survival, at least in patients with CR1 duration ≥12 months (P = 0.001 and 0.0005, respectively). Of interest, GO appeared to be as effective as standard ICT, and ICT + GO combination more effective than standard ICT. In conclusion, older patients with CR1 duration ≥12 months appeared to benefit from intensive salvage and results observed with GO-containing salvage suggest that GO combination studies should be actively pursued in this setting.

Fractionated doses of gemtuzumab ozogamicin combined with 3 + 7 induction chemotherapy as salvage treatment for young patients with acute myeloid leukemia in first relapse

Current salvage therapies for relapsed acute myeloid leukemia (AML) are unsatisfactory. We retrospectively evaluated the efficacy and toxicity of fractionated doses of gemtuzumab ozogamicin (GO) combined with a standard 3 + 7 induction regimen in young patients with AML in first relapse. Salvage regimen consisted of GO 3 mg/m² on days 1, 4, and 7; cytarabine, 200 mg/m² on days 1-7; and daunorubicine, 60 mg/m²; or idarubicine, 12 mg/m² on days 1-3. Fourteen patients were treated between April 2008 and April 2011. Median age was 46 years (29-58), median white blood cell count is 3.4 10⁹/L (0.9-19), and median first complete remission (CR) duration is 11 months (1-42). All the patients had previously received high or intermediate doses of cytarabine as consolidation therapy. Salvage treatment was performed as scheduled for the 14 patients, using daunorubicine in 12 patients and idarubicine in two. Overall response rate was 79 % with six CR and five CR with incomplete platelet recovery. Median times to neutrophil (>0.5 10⁹/L) and platelet (>20 10⁹/L) recovery were 29 days (23-32) and 36 days (28-48), respectively. Allogeneic transplantation was performed in the 11 responding patients within a median time of 4 months (3-10). Three mild and one moderate veno-occlusive disease (VOD) occurred after salvage and two moderate VOD after transplantation. Median and 2-year overall survival (OS) were 10 months and 42 %, respectively. For responders, estimated 2-year OS was 53 % (median OS not reached). This salvage regimen seems safe and effective in younger patients with AML in first relapse allowing allogeneic transplantation in CR2 for most patients.

Mitoxantrone and etoposide for acute myeloid leukemia in first relapse.

6563 Background: Achievement of complete remission (CR) for relapsed acute myeloid leukemia (AML) is crucial for improving prognosis and survival. However, there are no established standard therapies for AML in first relapse. Our purpose was to evaluate the efficacy and toxicity of a regimen of mitoxantrone and etoposide for relapsed AML and assess factors that may be predictive of response. Methods: Patients were identified from a database of patients with AML treated at the University of Pittsburgh Cancer Institute from 1999-2011. Subjects were patients with AML in first relapse treated with mitoxantrone 10mg/m2 and etoposide 100mg/m2 daily on days 1-5. An exploratory analysis was performed to determine CR rate, overall survival, toxicities, and predictive factors. Results: The study cohort consisted of 66 patients with AML in first relapse, median age 56.5 years (range 21-75). At time of relapse, 12 were classified as having poor cytogenetics, 39 had intermediate cytogenetics, and 5 had favorable cytogenetics (9 patients did not have karyotype analysis). 34.8% (23/66) of patients achieved CR, and 16 went on to have allogeneic hematopoietic cell transplantation. Patients with favorable, intermediate, and poor cytogenetics had CR rates of 60% (3/5), 35.9% (14/39) and 50% (6/12), respectively. Median survival was 8.1 months (95% CI 5.1-11.9). Patients who achieved CR had significantly improved survival compared to those who did not (20.0 months vs. 5.2 months, p<0.0001). Median days to neutrophil and platelet recovery were 37.5 (range 19-81) and 40 (range 21-81), respectively. There were no grade 3/4 hepatic toxicities. The 4-week and 8-week mortality rates were 4.5% and 13.6%, respectively. Duration of first remission greater than 12 months was predictive of CR (p<0.001), whereas age, cytogenetics, bone marrow blast percentage, and white blood cell count at relapse were not. Conclusions: In an unselected heterogeneous patient population with relapsed AML, mitoxantrone and etoposide was an effective regimen with acceptable toxicity, and those who achieved CR had significantly improved overall survival. Duration of first remission greater than 12 months was the only predictive factor, and response was seen among all cytogenetic risk groups.

Predictors of Outcome In Adult Patients with Acute Myeloid Leukemia In First Relapse,

Abstract 3569Treatment of patients with acute myeloid leukemia (AML) in first relapse has remained challenging and although relatively high response rates have been reported using selected combination chemotherapy regimens, long term leukemia-free survival has been less than 20% in most studies. A number of predictors of outcome have been reported of which the most significant are duration of first CR (CR1), cytogenetics at diagnosis, age at relapse, and whether allogeneic stem cell transplant (SCT) was performed in CR1 (Breems, DA, JCO, 2005). We sought to examine predictors of outcome after first relapse of AML incorporating some of the more recent relevant covariates such as molecular data, when available. From January 2000 to March 2010, 447 patients with AML (excluding acute promyelocytic leukemia) in first relapse were seen at the University of Texas – MD Anderson Cancer Center (MDACC) and have available survival data; 275 received therapy at MDACC and 66 (24%) achieved a second CR (CR2), with 14 (5%) patients achieving CR without platelet recovery (CRp2). For the overall population, the median survival from relapse is 5 months (range, 1 to 103+) and the median follow-up in surviving patients is 34.3 months (range, 5 to 103+). On univariate analysis, the following factors predicted survival in first relapse: the duration of CR1 (p<0.001), unfavorable cytogenetics at diagnosis (p<0.001) and having NPM1+/FLT3- status at diagnosis (p=0.001), as well as the following variables at relapse: age (p< 0.001), WBC (p<0.001), platelets (p=0.005), peripheral blood blast % (p<0.001), bone marrow blast % (p<0.001), performance status (p<0.001), creatinine (p<0.001), LDH (p<0.001) and albumin (p<0.001). Having FLT3-ITD at diagnosis and undergoing allogeneic stem cell transplant in CR1 were of borderline significance (p value for both =0.08). On multivariate analysis, taking into account only variables with a p<0.1, duration of CR1, age at relapse, unfavorable cytogenetics at diagnosis, and LDH as well as bone marrow blast % at relapse were significant (p<0.001). Positive FLT3-ITD at diagnosis was also significant (p=0.04). When multivariate analysis was conducted in the subset of 121 patients with complete FLT3 and NPM1 mutational status at diagnosis, neither the NPM1+/FLT3- status, nor having FLT3-ITD at diagnosis remained significant. In conclusion, we confirm that the most important predictors for survival in first relapse are duration of CR1, age at relapse, unfavorable cytogenetics, and possibly FLT3-ITD at diagnosis, as well as percentage of bone marrow blasts and LDH at relapse. Disclosures:No relevant conflicts of interest to declare.

Fractionated doses of gemtuzumab ozogamicin with escalated doses of daunorubicin and cytarabine as first acute myeloid leukemia salvage in patients aged 50–70‐year old: A phase 1/2 study of the acute leukemia French association

This Phase 1/2 study aimed to determine optimal doses of daunorubicin (DNR; mg/m(2)) and cytarabine (mg/m(2)) to be combined with fractionated doses of gemtuzumab ozogamicin (GO, Mylotarg(®); 3 mg/m(2) on day 1, 4, and 7) satisfying safety requirements. Three dose levels of DNR/AraC were investigated namely (45, 100), (60, 100), and (60, 200). Patients included were acute myeloid leukemia in first relapse, aged 50-70 years. Hematological recovery was 31 days for neutrophil and 32 days for platelet counts. A documented infectious episode > Grade 2 occurred in 11/20 patients (55%). None of the 20 patients had signs of veno-occlusive disease. Overall, eleven patients reached complete remission (CR), two CR with incomplete platelets recovery. The results showed that combination of fractionated GO doses with DNR at 60 mg/m(2)/d for 3 days and cytarabine at 200 mg/m(2)/d for 7 days is tolerable and could be further investigated in the front-line therapy.

Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse

AbstractIn a randomized trial of therapy for FMS-like tyrosine kinase-3 (FLT3) mutant acute myeloid leukemia in first relapse, 224 patients received chemotherapy alone or followed by 80 mg of the FLT3 inhibitor lestaurtinib twice daily. Endpoints included complete remission or complete remission with incomplete platelet recovery (CR/CRp), overall survival, safety, and tolerability. Correlative studies included pharmacokinetics and analysis of in vivo FLT3 inhibition. There were 29 patients with CR/CRp in the lestaurtinib arm and 23 in the control arm (26% vs 21%; P = .35), and no difference in overall survival between the 2 arms. There was evidence of toxicity in the lestaurtinib-treated patients, particularly those with plasma levels in excess of 20μM. In the lestaurtinib arm, FLT3 inhibition was highly correlated with remission rate, but target inhibition on day 15 was achieved in only 58% of patients receiving lestaurtinib. Given that such a small proportion of patients on this trial achieved sustained FLT3 inhibition in vivo, any conclusions regarding the efficacy of combining FLT3 inhibition with chemotherapy are limited. Overall, lestaurtinib treatment after chemotherapy did not increase response rates or prolong survival of patients with FLT3 mutant acute myeloid leukemia in first relapse. This study is registered at www.clinicaltrials.gov as #NCT00079482.

A Phase II Trial of Gemcitabine and Mitoxantrone for Patients With Acute Myeloid Leukemia in First Relapse

We evaluated the complete remission (CR) rate in patients with acute myeloid leukemia (AML) in first relapse treated with fixed-dose-rate gemcitabine and mitoxantrone. In addition, we measured multidrug resistance (MDR) proteins on pretreatment bone marrows and correlated expression with outcome. The study was performed in a 2-stage design. Pretreatment bone marrows were assayed for the MDR proteins (LRP, MDR1, MRP1, SLC28-29A1/A2, ABCC4/C5, and GSTP1) by immunohistochemistry and reverse-transcriptase polymerase chain reaction (RT-PCR). Only 5 of the first 24 patients (21%) achieved CR; therefore, the study was terminated. Eleven patients (46%) had poor-risk cytogenetics and the median duration of first CR was 7.3 months. Patients had significant expression of the various MDR genes, with 70% of patients expressing moderate to high levels of GSTP1 by immunohistochemistry. Higher sum total of ABCC4 and SLC29A2 expression measured by RT-PCR was associated with not achieving CR (20.6 vs. 12.1; P = .006). In addition, there was a trend for higher expression of the sum total of the 10 MDR genes (measured by RT-PCR) and not achieving CR (P = .06). The CR rate in this study was comparable to other regimens used in poor-risk patients. Of interest, ABCC4 and SLC29A2 expression were predictive of achieving CR. The high expression of GSTP1 suggests that this may be a therapeutic target for relapsed AML. Finally, the rapidity and ease of using RT-PCR to quantify MDR in this study may have clinical utility in future trials.

Prognostic factors and outcomes of adult patients with acute myeloid leukemia after first relapse

Patients with acute myeloid leukemia who are treated with conventional chemotherapy still have a substantial risk of relapse; the prognostic factors and optimal treatments after relapse have not been fully established. We, therefore, retrospectively analyzed data from patients with acute myeloid leukemia who had achieved first complete remission to assess their prognosis after first relapse. Clinical data were collected from 70 institutions across the country on adult patients who were diagnosed with acute myeloid leukemia and who had achieved a first complete remission after one or two courses of induction chemotherapy. Among the 1,535 patients who were treated with chemotherapy alone, 1,015 relapsed. Half of them subsequently achieved a second complete remission. The overall survival was 30% at 3 years after relapse. Multivariate analysis showed that achievement of second complete remission, salvage allogeneic hematopoietic cell transplantation, and a relapse-free interval of 1 year or longer were independent prognostic factors. The outcome after allogeneic transplantation in second complete remission was comparable to that after transplantation in first complete remission. Patients with acute myeloid leukemia and cytogenetic risk factors other than inv(16) or t(8;21) had a significantly worse outcome when they did not undergo salvage transplantation even when they achieved second complete remission. We found that both the achievement of second complete remission and the application of salvage transplantation were crucial for improving the prognosis of patients with acute myeloid leukemia in first relapse. Our results indicate that the optimal treatment strategy after first relapse may differ according to the cytogenetic risk.

Decitabine-Based Salvage Therapy in Adults with Acute Myeloid Leukemia.

Abstract 2063Poster Board II-40 Introduction:Adults with primary refractory or relapsed acute myeloid leukemia (AML) have a poor prognosis with complete responses to salvage therapy from 13-15% and a median survival of 1.5-6 months[1, 2]. From 2006-2009, 79 patients with relapsed or refractory acute myeloid leukemia were given salvage chemotherapy with decitabine 20mg/m2 daily for 10 days or decitabine 20mg/m2 × 5 days with gemtuzumab ozogamicin (GO) 3mg/m2 on day 5 at Weill Cornell Medical Center. Methods:Medical records of 79 patients who received decitabine-based salvage therapy were reviewed from September 2006 through July 2009 at Weill Cornell Medical College. Survival was calculated by the Kaplan Meir method and differences in survival calculated by the log-rank test using STATA software. Results:Twenty-five patients received decitabine-based therapy as first salvage, 32 patients as second salvage, and 22 patients as third or greater salvage. Fifty-one patients were treated with decitabine/GO and 29 patients received decitabine alone. Median age of patients was 65.5 years with a range of 24 -89 years (first salvage 75 years, second salvage 62 years, and third or greater salvage 64 years). Median survival of all patients was 205 days, range 7-732 days. Overall 34% patients responded: 16% CR (<5% blasts in bone marrow, recovery ANC >1000 and Plts > 100,000) with median survival not yet reached; 5% CRp (< 5% blasts in bone marrow, ANC >1000 and plts < 100,000) with median survival 223 days; 13% PR (blasts 6-11%) with median survival 205 days; and 66% no response with median survival 118 days. Patients receiving first salvage had median survival 181 days with CR 13%, CRp 6%, PR 17%. Patients receiving second salvage had median survival 207 days with CR 9%, CRp 4%, PR 9%. Patients with third or greater salvage had median survival 209 days with CR 23%, CRp 0%, PR 14%. Patients receiving decitabine alone had a median survival of 209 days and those receiving decitabine/GO had a median survival of 177 days but the difference was not significant. Median survival for normal, favorable, intermediate and unfavorable cytogenetics was 282, 224, 157 and 176 days respectively (p=0.06). Conclusions: Decitabine-based treatment for relapsed and refractory AML is a low intensity alternative that has activity rivaling more intensive regimens. This retrospective study suggests that further investigation of decitabine-based salvage is warranted.1. Sievers, E.L., et al., Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol, 2001. 19(13): p. 3244-54.2. Giles, F., et al., Outcome of patients with acute myelogenous leukemia after second salvage therapy. Cancer, 2005. 104(3): p. 547-54. Disclosures:Off Label Use: Phase I trial of decitabine in AML is off-label .

Phase 3 randomized, placebo-controlled, double-blind study of high-dose continuous infusion cytarabine alone or with laromustine (VNP40101M) in patients with acute myeloid leukemia in first relapse

AbstractLaromustine is a sulfonylhdrazine alkylator with significant antileukemia activity. An international, randomized (2:1), double-blind, placebo-controlled study was conducted to compare complete remission (CR) rates and overall survival (OS) in patients with first relapse acute myeloid leukemia (AML) treated with laromustine and high-dose cytarabine (HDAC) versus HDAC/placebo. Patients received 1.5 g/m2 per day cytarabine continuous infusion for 3 days and laromustine 600 mg/m2 (n = 177) or placebo (n = 86) on day 2. Patients in CR received consolidation with laromustine/HDAC or HDAC/placebo as per initial randomization. After interim analysis at 50% enrollment, the Data Safety Monitoring Board (DSMB) expressed concern that any advantage in CR would be compromised by the observed on-study mortality, and enrollment was held. The CR rate was significantly higher for the laromustine/HDAC group (35% vs 19%, P = .005). However, the 30-day mortality rate and median progression-free survival were significantly worse in this group compared with HDAC/placebo (11% vs 2%; P = .016; 54 days vs 34; P = .002). OS and median response durations were similar in both groups. Laromustine/HDAC induced significantly more CR than HDAC/placebo, but OS was not improved due to mortality associated with myelosuppression and its sequelae. The DSMB subsequently approved a revised protocol with laromustine dose reduction and recombinant growth factor support. The study was registered as NCT00112554 at http://www.clinicaltrials.gov.

Outcome of patients with FLT3-mutated acute myeloid leukemia in first relapse

Mutations of Fms-like tyrosine kinase-3 (FLT3) have been described in about 30% of patients with acute myeloid leukemia (AML) and are associated with a shorter disease-free and overall survival after initial therapy. We sought to examine whether the presence of these mutations in relapsed disease was also associated with a poor response to salvage chemotherapy by comparing the outcome of 34 patients with diploid cytogenetics and mutated FLT3 (internal tandem duplication mutation, ITD) to 69 patients with normal karyotype and wild-type FLT3 (FLT3-WT) in first relapse. On univariate analysis, patients with mutated FLT3 were less likely to achieve a CR to first salvage compared to FLT3-WT patients (24% vs. 41%; P = 0.09). Furthermore, survival was longer for the FLT3-WT patients achieving a second CR after salvage compared to FLT3-mutated patients ( P = 0.017). Overall, patients with mutated FLT3 had a shorter survival from the time of relapse compared to those with FLT3-WT ( P < 0.001). The adverse prognostic impact of FLT3 mutations appears to persist beyond the initial treatment.

Decitabine as “bridge therapy” to a MUD transplant in relapsed AML postautologous stem cell transplantation

American Journal of HematologyVolume 83, Issue 10 p. 825-827 LetterFree Access Decitabine as “bridge therapy” to a MUD transplant in relapsed AML postautologous stem cell transplantation Celalettin Ustun, Celalettin Ustun Medical College of Georgia, Section of Hematology-Oncology, Augusta, GeorgiaSearch for more papers by this authorAbhishek Kalla, Abhishek Kalla Medical College of Georgia, Department of Medicine, Augusta, GeorgiaSearch for more papers by this authorStephanie Farrow, Stephanie Farrow Medical College of Georgia, Section of Hematology-Oncology, Augusta, GeorgiaSearch for more papers by this authorDavid L. Deremer, David L. Deremer Medical College of Georgia, University of Georgia College of Pharmacy, Augusta, GeorgiaSearch for more papers by this authorAnand Jillella, Anand Jillella Medical College of Georgia, Section of Hematology-Oncology, Augusta, GeorgiaSearch for more papers by this author Celalettin Ustun, Celalettin Ustun Medical College of Georgia, Section of Hematology-Oncology, Augusta, GeorgiaSearch for more papers by this authorAbhishek Kalla, Abhishek Kalla Medical College of Georgia, Department of Medicine, Augusta, GeorgiaSearch for more papers by this authorStephanie Farrow, Stephanie Farrow Medical College of Georgia, Section of Hematology-Oncology, Augusta, GeorgiaSearch for more papers by this authorDavid L. Deremer, David L. Deremer Medical College of Georgia, University of Georgia College of Pharmacy, Augusta, GeorgiaSearch for more papers by this authorAnand Jillella, Anand Jillella Medical College of Georgia, Section of Hematology-Oncology, Augusta, GeorgiaSearch for more papers by this author First published: 19 August 2008 https://doi.org/10.1002/ajh.21267Citations: 6AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat References 1 Kantarjian H,Issa JP,Rosenfeld CS, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: Results of a phase III randomized study. Cancer 2006; 106: 1794– 1803. 2 Silva LD dM,Kantarjian H,Champlin R, et al. Outcome of allogeneic stem cell transplantation after hypomethylating therapy with 2′-deoxy-5 azacytidine for patients with myelodysplastic syndrome. Blood 2007; 110: 1468a. 3 Lubbert MRB,Schmid M,Knipp S, et al. Continued low-dose decitabine (DAC) is an active first-line treatment of older AML patients: First results of a multicenter Phase II study. Blood 2005; 106: 1852a. 4 Ravandi FIJ,Faderl S,Garcia-Manero G, et al. Randomized study of decitabine versus observation or continued cytotoxic chemotherapy in patients with intermediate and poor risk acute myeloid leukemia in first or subsequent complete remission. Blood 2007; 110: 2859a. 5 Graef T,Kuendgen A,Fenk R, et al. Successful treatment of relapsed AML after allogeneic stem cell transplantation with azacitidine. Leuk Res 2007; 31: 257– 259. 6 Rossetti JM,Shadduck RK,Chandana Thatikonda C, et al. Low-dose azacitidine for relapse of MDS/AML after unrelated donor peripheral blood stem cell transplantation. Blood 2007; 110: 5034a. 7 Cashen AF,Devine H,DiPersio J. Second complete remission in an elderly patient with acute myeloid leukemia retreated with decitabine. Am J Hematol 2006; 81: 543– 545. 8 Estey E. Treatment of refractory AML. Leukemia 1996; 10: 932– 936. 9 Lee S,Tallman MS,Oken MM, et al. Duration of second complete remission compared with first complete remission in patients with acute myeloid leukemia. Eastern Cooperative Oncology Group. Leukemia 2000; 14: 1345– 1348. 10 Levy V,Marjanovic Z,Vekhoff A, et al. Relapse after autologous hematopoietic stem cell transplantation in acute myeloid leukemia, a single center experience over 13 years. Am J Hematol 2000; 64: 232– 233. 11 Breems DA,Van Putten WL,Huijgens PC, et al. Prognostic index for adult patients with acute myeloid leukemia in first relapse. J Clin Oncol 2005; 23: 1969– 1978. 12 Breems DA,Boogaerts MA,Dekker AW, et al. Autologous bone marrow transplantation as consolidation therapy in the treatment of adult patients under 60 years with acute myeloid leukaemia in first complete remission: A prospective randomized Dutch-Belgian Haemato-Oncology Co-operative Group (HOVON) and Swiss Group for Clinical Cancer Research (SAKK) trial. Br J Haematol 2005; 128: 59– 65. 13 Bug G,Atta J,Klein SA, et al. High-dose melphalan is an effective salvage therapy in acute myeloid leukaemia patients with refractory relapse and relapse after autologous stem cell transplantation. Ann Hematol 2005; 84: 748– 754. 14 Diaconescu R,Flowers CR,Storer B, et al. Morbidity and mortality with nonmyeloablative compared with myeloablative conditioning before hematopoietic cell transplantation from HLA-matched related donors. Blood 2004; 104: 1550– 1558. Citing Literature Volume83, Issue10October 2008Pages 825-827 ReferencesRelatedInformation

T-Cell Large Granular Lymphocyte Leukemia of Donor Origin Following Myeloablative Allogeneic Peripheral Blood Stem Cell Transplantation for Acute Myeloid Leukemia.

Lymphoproliferative disorders are a recognized complication of allogeneic hematopoietic cell transplantation (HCT). Most are B-cell disorders, often associated with Epstein-Barr virus infection. We report the fourth case of T-cell, large granular lymphocyte leukemia. In May 2005, a 63-year-old woman with acute myeloid leukemia in first relapse underwent reduced intensity, myeloablative, allogeneic peripheral blood HCT from her HLA-genotypically matched brother. Three months later, she received a donor-lymphocyte infusion (DLI) for recurrent leukemia. She developed acute graft-versus-host disease (GvHD) and remission of leukemia. GvHD was controlled with high-dose steroids. Multiple episodes of asymptomatic cytomegalovirus viremia were treated with pre-emptive valganciclovir. In June 2006, 10 months post-DLI, PCR-based chimerism studies revealed 100% donor peripheral blood cells. One month later, immunophenotyping of peripheral blood to evaluate neutropenia and lymphocytosis, revealed expansion of CD3+, CD8+, CD2+, CD11c+ and HLA-DR+ lymphocytes with clonally rearranged T-cell receptor genes, consistent with the diagnosis of large granular lymphocyte (LGL) leukemia. Evaluation of her donor, including bone marrow aspiration and biopsy, showed normal hematopoiesis with no evidence of LGL expansion. PCR of donor peripheral blood mononuclear cells was negative for TCRγ rearrangements. During the year since diagnosis of T-cell LGL leukemia the CBC has been stable, without specific treatment, and AML remains in remission.Discussion: lymphocytosis due to expansion of T-cell large granular lymphocytes is a rare occurrence after allogeneic HCT. Non-clonal expansion is more common, with 6 cases described in a series of 201 patients (Mohty et al. Leukemia 2002; 16:2129–33). To our knowledge, this is the fourth documented case of donor-derived T-cell LGL leukemia (clonal expansion) after allogeneic HCT. The course of post-transplant LGL leukemia appears to resemble de novo disease. Of the previously reported cases, 2 patients were alive 6 and 18 months (Chang et al. Am J Clin Pathol 2005; 123:196–9), and 1 died 7 months post-LGL leukemia diagnosis (Au et al. Am J Clin Pathol 2003; 120:626–30). Our patient is 12 months since diagnosis without therapy. Etiologic factors responsible for post-transplant LGL leukemia have not been identified. In all cases tested, the leukemia arose in donor cells, but was not transmitted from the donor. An association between long-term antigenic stimulation due to GvHD or viral infection has been proposed. Our patient had both GvHD and recurrent CMV viremia before developing T-cell LGL leukemia. Of interest, our patient experienced long-lasting complete remission of AML after DLI. Whether the T-cell LGL leukemia, which developed almost one year after DLI, has any impact on maintaining remission (graft-versus-leukemia effect) is unknown, but has been suggested by other authors.

A Phase II study of Bcl-2 antisense (oblimersen sodium) combined with gemtuzumab ozogamicin in older patients with acute myeloid leukemia in first relapse

Oblimersen selectively targets Bcl-2 mRNA and has been shown to enhance the apoptotic activity of various antileukemic agents, including gemtuzumab ozogamicin (GO), in preclinical studies. We evaluated the efficacy and safety of oblimersen combined with GO in patients ≥60 years of age in first relapse with CD33+ acute myeloid leukemia. Oblimersen 7 mg/kg/day was given as a continuous intravenous infusion on days 1–7 and 15–21. GO 9 mg/m 2 was given intravenously on days 4 and 18. Twelve of 48 patients (25%) achieved a major response (five, complete response and seven, complete response without platelet recovery). Ten of the 12 patients who achieved a major response survived >6 months compared with six of 36 non-responders. Serious adverse events for the oblimersen/GO combination were qualitatively similar to those reported for GO alone. Oblimersen can be safely combined with GO. Assessment of incremental benefit will require a randomized trial.

Prognostic Index for Adult Patients With Acute Myeloid Leukemia in First Relapse

The treatment of acute myeloid leukemia (AML) in first relapse is associated with unsatisfactory rates of complete responses that usually are short lived. Therefore, a clinically useful prognostic index can facilitate therapeutic decision making and evaluation of investigational treatment strategies at relapse of AML. A prognostic score is presented based on the multivariate analysis of 667 AML patients in first relapse among 1,540 newly diagnosed non-M3 AML patients (age 15 to 60 years) entered onto three successive Dutch-Belgian Hemato-Oncology Cooperative Group and the Swiss Group for Clinical Cancer Research Collaborative Group trials. Four clinically relevant parameters are included in this index (ie, length of relapse-free interval after first complete remission, cytogenetics at diagnosis, age at relapse, and whether previous stem-cell transplantation was performed). Using this stratification system, three risk groups were defined: a favorable prognostic group A (overall survival [OS] of 70% at 1 year and 46% at 5 years), an intermediate-risk group B (OS of 49% at 1 year and 18% at 5 years), and a poor-risk group C (OS of 16% at 1 year and 4% at 5 years). The prognostic index estimates the outcome of AML patients in first relapse using four commonly applied clinical parameters and might identify patients who are candidates for salvage and investigational therapy.