Post-remission Survival Research Articles

Impact of Choice of Induction Regimen on Overall Survival and Post-Remission Survival Among Older Adults with Acute Myeloid Leukemia

Older patients make up the majority of those diagnosed with acute myeloid leukemia (AML), however, many of these patients are not able to tolerate intense induction chemotherapy regimens. The use of lower intensity induction such as hypomethylating agents (HMA) with or without venetoclax or other targeted therapies has widened the scope of patients who are able to receive induction chemotherapy and move towards a hematopoietic stem cell transplant. Recent data from the Center of International Blood and Marrow Transplant research showed that patients aging >64 years accounted for 26% of all allogeneic transplantations in 2019 compared to only 9% in 2009. We have previously published a report showing that induction with FLAG +/- Idarubicin (FLAG+ IDA) results in better post remission survival than '7+3'induction (Solh et al, Leuk res 2020). In order to determine how induction chemotherapy affects post-remission outcomes among older patients with AML, 289 patients over the age of 55 year who received either FLAG±IDA, 7+3, or HMA based induction at a single institution were analyzed. Median follow up was 48 months. Patient and disease characteristics were as follows: Median age 64 (55,83) years, secondary AML (10%), abnormal cytogenetics (49%), and NCCN non-favorable risk (76%). Induction regimens included FLAG+/- Ida (n=208, 72%), 7+3 (n=60, 21%) and HMA based (n=21, 7%). A total of 248 patients (86%) achieved CR/Cri after induction with a median time from induction to CR of 28 days. Patients who received induction with FLAG±IDA reached a higher rate of CR after one cycle (92% vs 75% vs 62%) and had a shorter time to CR (27 vs 33vs 55 days) compared to '7+3' or HMA based therapy (p<0.001 for both). FLAG±IDA had better overall survival and DFS 3 years post-remission compared to '7+3' and HMA OS (50%, 45%, 22%, p=0.021) and DFS (45%, 37%, 8% p=0.01) respectively. A total of 133 patients received allogeneic transplantation. Transplant rate was similar between FLAG+/- IDA (n=100) and 7+3 (n=29) at 48% and was significantly better than HMA-based induction 19% (n=4) (p=0.03). Post-transplant survival and DFS was not significantly different between FLAG+/-Ida and 7+3, however both were better compared to HMA based induction with OS (54%, 44%, 25%) and DFS (51%, 44%, 25%) . On multivariate analysis on post remission survival and disease free survival, NCCN risk and age were both associated with OS ( high risk NCCN vs others HR 3.63, P<0.001; Age per 5 year increment HR 1.16, p=0.049) and NCCN risk was the only factor associated with worse DFS ( high vs others HR 2.4, p<0.0001). The choice of induction regimen did not significantly impact post-remission survival outcomes.In conclusion, Older patients with AML achieve higher rates of complete remission, shorter time to remission and better post-remission survival with FLAG+/-IDA than 7+3 or HMA-based induction. DisclosuresSolh: BMS: Consultancy; Partner Therapeutics: Research Funding; Jazz Pharmaceuticals: Consultancy; ADCT Therapeutics: Consultancy, Research Funding.

Improved Post remission survival of non- favorable risk Acute Myelogenous Leukemia (AML) patients following initial remission induction therapy with FLAG+/-Idarubicin versus 3 + 7 (Anthracycline + Cytarabine)

The fludarabine, high dose cytarabine and G-CSF with or without idarubicin combination regimen, referred to as FLAG+/-Ida, is commonly used as a salvage regimen for relapsed/refractory AML but its use as initial induction therapy has been more limited. The impact of choice of induction regimen on post remission survival remains unclear. We retrospectively analyzed 304 consecutive AML patients, with non-favorable NCCN risk who received initial treatment at our center with either 7 + 3 (n = 86) or FLAG+/-Ida (n = 218). Patients in the FLAG+/-Ida group were more likely to achieve remission after one course of induction (74 % vs 62 %, p < 0.001) and had a faster time to achieve CR (30 days vs 37.5, p < 0.001) compared to 7 + 3. The time from diagnosis to transplant was shorter among CR patients after FLAG+/-Ida compared to 7 + 3 (115 vs. 151 days, p < 0.003). The 3-year post-remission OS and DFS was significantly better for patients receiving FLAG-Ida at 54 % and 49 % compared to 39 % and 32 % for 7 + 3 respectively (P = 0.01). Factors associated with post-remission survival included age at CR1, NCCN risk, induction regimen (FLAG+/-Ida vs 3 + 7 h 0.62, p = 0.01) and receipt of HCT. Our data, with the limitations inherent to a retrospective analysis, shows that achieving CR after FLAG+/-Ida has better post remission survival than 7 + 3.

Real-world outcomes of unselected elderly acute myeloid leukemia patients referred to a leukemia/hematopoietic cell transplant program.

Due to perceived intolerance, many elderly AML patients do not receive therapy, and few are considered for hematopoietic cell transplantation (HCT). To better understand "real-world" outcomes, 323 consecutive AML patients ≥ 60 years referred from 2009 to 2017 were evaluated (median age 70 [60-88] years); favorable (fav) in 48 (15%), intermediate (int) in 112 (35%) and poor risk in 161 (50%). Remission induction therapy, either intensive chemotherapy (IC, n = 205) or hypomethylating agents (HMA, n = 57), was given to all but 61 (19%) patients. With median f/u of 34 months, 2-year overall survival (OS) for the whole cohort was 31%; 40 and 33% for IC- and HMA-treated vs. 0% for untreated patients. Early mortality was 14%. Remission (CR/CRi) was achieved in 60% of patients, with approximately half of these surviving 2 years. In transplant-eligible patients (60-75-year-old, int/poor risk, achieving remission), 54 (46%) of 118 received HCT. Transplanted patients had improved 2- and 3-year post-remission survival of 59% and 40% compared to 26% and 18% in similar patients not receiving HCT (HR = 0.59, 95% CI 0.37-0.93, p = 0.023). These results suggest that survival of elderly AML patients may be improved through a coordinated approach of remission induction therapy for most patients followed by HCT when feasible.

The Choice of Induction Regimen Affects Post Remission Survival of Acute Myelogenous Leukemia (AML) Patients with Intermediate or Poor Risk Disease

The fludarabine, high dose cytarabine and G_CSF with or without idarubicin combination regimen, referred to as FLAG+/-Ida, is commonly used as a salvage regimen for relapsed/refractory AML but its use as initial induction therapy has been more limited. The MRC trial 15 compared 2 induction courses of FLAG-Ida regimen to 3+7 (anthracycline plus cytarabine) regimens with etoposide (ADE) and found a higher relapse free survival among patients receiving FLAG-Ida. The findings of the MRC AML 15 trial are not widely applied in the United States as many experts use one course of induction followed by consolidation if patients achieve remission. The impact of choice of induction regimen on post remission survival in non-favorable risk AML patients remains unclear. To address this question, we assessed outcomes of 306 consecutive AML patients between aged 18 to75 years, with non-favorable NCCN risk who were received initial treatment at our center between January of 2009 and July of 2017 with either 3+7 (n=88) or FLAG+/-Ida (n=218). Our center's algorithm is to offer allogeneic HSCT as a consolidative therapy to all AML patients with non-favorable risk in CR1 who are considered transplant candidates. Patient characteristics were as follows: Median age 58(19, 75), male 55%, FLT-3 ITD positive 12%, NCCN risk ( intermediate 49%, poor 51%) and normal cytogenetics 45%. Baseline characteristics were similar between the two treatment groups with FLAG+/-Ida being younger at time of diagnosis (59 vs 66 years, P<0.001). A total of 240 (78%) patients achieved CR 1 after 3+7 (n=67, 76%) or FLAG+/-Ida (n=167, 79%) with no difference in the rate of achieving remission between the two groups. Patients in the FLAG-Ida group were more likely to achieve remission after one course of induction (74% vs 62%, p<0.001) and had a faster time to get into CR (30 days vs 37.5, p<0.001) compared to 3+7. CR was achieved in 84% and 73% of patients with intermediate and poor NCCN risk disease respectively. HSCT was performed in 172 patients accounting for 72% of the 240 patients who achieved CR post induction without any significant difference in transplant rates between FLAG+/-Ida and 3+7. The time from diagnosis to transplant was significantly shorter among CR patients after FLAG+/-Ida compared to 3+7 (FLAG+/- Ida 115 days vs 144 days for 3+7, p<0.001). After a median follow up of 41 months for patients achieving CR, the 3 year post remission OS and DFS was significantly better for patients receiving FLAG-Ida at 54% and 49% compared to 39% and 32% for patients receiving 3+7 respectively( P= 0.01 for both endpoints). In multivariate analysis, we analyzed factors associated with OS and DFS since achieving CR1 including age at CR1 (≤49, 50-64, ≥65), gender, race, NCCN risk, induction regimen, number of cycles to CR1, HSCT (yes, no) and year of CR1. HSCT was modelled as a time dependent covariate. A forward stepwise algorithm was implemented and variables were selected if p value was less than 0.05. Factors associated with r post remission survival included age at CR1 (≤49 vs50-64, HR 0.59, p=.02; ≤49 vs ≥65 HR 0.46, p=0.001), NCCN risk (intermediate vs poor HR 0.54, p<0.001), induction regimen (FlAG+/-Ida vs 3+7 HR 0.62, p=0.01) and receiving HSCT (yes vs no HR 0.68, p=0.02). Factors affecting DFS from time of CR also included age, NCCN risk, induction regimen (FlAG+/-Ida vs 3+7 HR 0.68, p=0.028) and receiving HSCT. This single center analysis shows that among patients with non-favorable risk AML, achieving CR after FLAG+/-Ida has better post remission survival than 3+7. This may be partially explained by the faster time to achieve CR and faster time to HSCT in the FLAG+/- Ida group. DisclosuresSolh:Amgen: Speakers Bureau; Celgene: Speakers Bureau; ADC Therapeutics: Research Funding.

Timed sequential therapy for acute myelogenous leukemia: Results of a retrospective study of 301 patients and review of the literature

Timed sequential therapy (TST) aims to improve outcomes in acute myelogenous leukemia (AML) by harnessing drug-induced cell cycle kinetics of AML, where a second drug is timed to coincide with peak leukemia proliferation induced by the first drugs. We analyzed outcomes in 301 newly diagnosed AML patients treated from 2004–2013 with cytarabine, anthracycline, and etoposide TST induction. Median age was 52 (range 20–74) and complete remission rate 68%. With median follow-up 5.8 years, 5-year DFS and overall survival (OS) were 37% (95% CI 31–45%) and 32% (95% CI 27–38%), respectively. In multivariate analysis, older age, unfavorable cytogenetics, and WBC≥50×109/L resulted in worse OS. Among patients not undergoing blood and marrow transplant, a propensity score analysis, which reduces imbalance in baseline characteristics, showed consolidation with TST compared with 1 or more cycles high-dose cytarabine trended toward lower DFS and post-remission survival with hazard ratio (HR) 1.9 (95% CI 0.9–4.0), and 1.6 (95% CI 0.7–3.6), respectively. Our results demonstrate the efficacy and feasibility of TST induction for newly diagnosed patients with AML, with results comparable to that seen in clinical trials with other TST therapies and 7+3.

No survival benefit associated with routine surveillance imaging for Hodgkin lymphoma in first remission: a Danish-Swedish population-based observational study.

The use of routine imaging for patients with classical Hodgkin lymphoma (HL) in complete remission (CR) is controversial. In a population-based study, we examined the post-remission survival of Danish and Swedish HL patients for whom follow-up practices were different. Follow-up in Denmark included routine imaging, usually for a minimum of 2years, whereas clinical follow-up without routine imaging was standard in Sweden. A total of 317 Danish and 454 Swedish comparable HL patients aged 18-65years, diagnosed in the period 2007-2012 and having achieved CR following ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine)/BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) therapy, were included in the study. The cumulative progression rates in the first 2years were 4% (95% confidence interval [CI] 1-7) for patients with stage I-II disease vs. 12% (95% CI 6-18) for patients with stage III-IV disease. An imaging-based follow-up practice was not associated with a better post-remission survival in general (P=0·2) or in stage-specific subgroups (P=0·5 for I-II and P=0·4 for III-IV). Age ≥45years was the only independent adverse prognostic factor for survival. In conclusion, relapse of HL patients with CR is infrequent and systematic use of routine imaging in these patients does not improve post-remission survival. The present study supports clinical follow-up without routine imaging, as encouraged by the recent Lugano classification.

Prediction of post-remission survival in acute myeloid leukaemia: a post-hoc analysis of the AML96 trial

The optimum post-remission treatment (PRT) in acute myeloid leukaemia (AML) is still a matter of debate. Consolidation treatments include chemotherapy with high-dose cytarabine, or allogeneic or autologous haemopoietic stem cell transplantation (HSCT). In a post-hoc analysis of the AML96 trial (NCT00180115), our aim was to differentiate groups of patients according to the treatments that would provide them optimum benefit. In the multicentre AML96 trial, 586 patients (aged 15-60 years) with AML--excluding those with t(8;21)--who were in complete remission after double induction treatment were consolidated with allogeneic HSCT, autologous HSCT, or chemotherapy containing high-dose cytarabine in a priority-based and risk-adapted manner. We assessed the association between potentially prognostic variables and overall survival after complete remission by use of a stratified Cox regression analysis. With the significant variables of the resulting model, we developed a PRT score in 452 patients with a complete dataset. This score was then validated by use of data from 407 patients from the AML2003 trial (NCT00180102). Age, percentage of CD34-positive blasts, FLT3-ITD mutant-to-wild-type ratio, cytogenetic risk, and de-novo or secondary AML were identified as independent prognostic factors, and included in the PRT score. The PRT score separated patients in AML96 into three groups: favourable (n=190; 3-year survival 68%, 95% CI 60-74), intermediate (n=198; 49%, 42-56), and unfavourable (n=64; 20%, 12-31). All pair-wise comparisons of two of three PRT score groups were significant in the log-rank test (p<0·0001). Similar results were noted when data from AML2003 were used: 3-year survival for the favourable group (n=265) was 69% (62-76), for the intermediate group (n=114) it was 61% (50-71), and for the unfavourable group (n=28) it was 46% (24-65). The overall comparison between the three risk groups resulted in significantly different survival probabilities (p=0·015). We also analysed response to treatment in AML96 in each of the PRT score groups. In the favourable group, patients given allogeneic HSCT (n=60) had higher survival probabilities (82%, 69-89) than did those given chemotherapy (n=56, 55%, 41-67; p=0·0012) or autologous HSCT (n=74, 66%, 54-76; p=0·044). In the intermediate PRT score group, patients given autologous HSCT (n=69) had the best survival probabilities (62%, 50-72) compared with those given chemotherapy (n=72, 41%, 30-52; p=0·0006) or allogeneic HSCT (n=57, 44%, 31-56; p=0·0045). The PRT score groups could help physicians to tailor treatment for patients with AML and our results lend support to the use of autologous HSCT in patients aged 60 years or younger with an intermediate PRT score. Deutsche Krebshilfe.

Outcomes in CCG-2961, a Children's Oncology Group Phase 3 Trial for untreated pediatric acute myeloid leukemia: a report from the Children's Oncology Group

AbstractCCG-2961 incorporated 3 new agents, idarubicin, fludarabine and interleukin-2, into a phase 3 AML trial using intensive-timing remission induction/consolidation and related donor marrow transplantation or high-dose cytarabine intensifi-cation. Among 901 patients under age 21 years, 5-year survival was 52%, and event-free survival was 42%. Survival improved from 44% between 1996 and 1998 to 58% between 2000 and 2002 (P = .005), and treatment-related mortality declined from 19% to 12% (P = .025). Partial replacement of daunomycin with idarubicin in the 5-drug induction combination achieved a remission rate of 88%, similar to historical controls. Postremission survival was 56% in patients randomized to either 5-drug reinduction or fludarabine/cytarabine/idarubicin. For patients with or without a related donor, respective 5-year disease-free survival was 61% and 50% (P = .021); respective survival was 68% and 62% (P = .425). Donor availability conferred no benefit on those with inv(16) or t(8;21) cytogenetics. After cytarabine intensification, patients randomized to interleukin-2 or none experienced similar outcomes. Factors predictive of inferior survival were age more than 16 years, non-white ethnicity, absence of related donor, obesity, white blood cell count more than 100 000 × 109/L, −7/7q−, −5/5q−, and/or complex karyotype. No new agent improved outcomes; experience may have contributed to better results time.

CD7 expression predicts poor disease free survival and post-remission survival in patients with acute myeloid leukemia and normal karyotype

AML patients with normal karyotype comprise the largest subgroup (∼50%) but have a highly heterogeneous clinical course. By multi-parameter flow cytometry we analyzed CD7 expression along with other phenotypic markers in 185 patients with normal-karyotype AML. CD7 was expressed in 68 (37%) patients. CD7 expression was associated with younger age ( P = 0.024) but not with sex, WBC count, or extramedullary disease. Patients expressing CD7 had significant shorter disease free (DFS) and post-remission survivals (PRS) than patients without CD7 (DFS of 12 months versus 42 months, P = 0.005; PRS of 15 months versus 33 months, P = 0.013). We also found that expression of CD34 or HLA-DR was associated with lower CR rate ( P = 0.0007 and P = 0.019, respectively) but did not affect DFS or OS. Furthermore, as for all AML patients, we demonstrated that in the normal karyotypic subgroup, patients with higher WBC counts (>50) and older age (>60 years) had lower CR rate ( P = 0.003 and P = 0.0157, respectively) and shorter OS ( P ≤ 0.001 and P = 0.007, respectively). Multivariate analysis of age, WBC, CD34, HLA-DR and CD7 showed that CD7 expression was an independent risk factor for DFS ( P = 0.01) and PRS ( P = 0.02).

Internal Tandem Duplications of Flt3 Gene (Flt3/ITD) Predicts a Poor Post-Remission Outcome in Adult Patients with Acute Non-Promyelocytic Leukemia

Despite progress in AML therapy, most patients eventually relapse, even the ones with normal or favorable karyotype. Since survival is poor once relapse occurs, new genetic tools above karyotype at diagnosis are needed to predict leukemia free survival. Recently, Flt3/ITD has been reported as an independent marker for clinical outcome in most studies concerning adult AML patients. To assess the prognostic relevance of activating mutations of Flt3, pretreatment samples of 100 not-M3 AML patients, all of them subjected to an intensive chemotherapy regimen, were analyzed for Flt3/ITD; 25/100 patients had one or more Flt3-ITD. Flt3/ITD patients had higher WBC count (P = 0.005), a lower incidence of a preceding MDS (P = 0.004) and most of them had a normal karyotype. Flt3/ITD had no impact on CR achievement while karyotype remained the most powerful prognostic factor (HR 2.8 95% CI 1.2 – 6.3). However, post-remission outcome was significantly worsened by the presence of Flt3/ITD. Median RFS of the Flt3/ITD patients was 5 vs. 27 months compared to the patients with wild-type Flt3 (P = 0.0002); moreover, Flt3/ITD patients had a significantly poorer post-remission survival (11 vs. 38 months, P = 0.01). On multivariate analysis, the presence of Flt3-ITD significantly affected relapse free survival and post-remission survival (HR 3.1 and 2.1, respectively). Thus, post-remission outcome highly depends on Flt3 status. Flt3 mutations identify patients at high risk of relapse, who should prospectively receive, according to age, either more aggressive or alternative therapeutic approaches.