D14 Bone Marrow Research Articles

CPX-351 with Venetoclax in Patients with Relapsed/Refractory Acute Myeloid Leukemia: Results of a Phase Ib Study

Introduction: Relapsed/refractory acute myeloid leukemia (rAML) remains a significant challenge, with low response to therapy and poor long-term survival. Treatments focusing on achieving a response and, in eligible patients (pts), proceeding with an allogeneic stem cell transplantation (alloSCT) offer the best prospect for improved survival. CPX-351 is a liposomal fixed-ratio formulation of cytarabine and daunorubicin, which has demonstrated higher response rates and reduced early mortality in some subsets of AML and has also been shown to be active in rAML. The BCL2 inhibitor venetoclax (Ven) has demonstrated efficacy in AML in combination with other agents, such as hypomethylating agents, low dose cytarabine, and intensive chemotherapy. We conducted a Phase Ib/II dose-finding study to evaluate the combination of CPX-351 with Ven in AML. Herein we present the results of CPX-351 plus Ven in the cohort of rAML pts treated on study (NCT03629171). Methods: The study was designed with a safety lead-in phase to establish the safe dose and schedule in R/R AML, followed by 2 expansion cohorts to explore efficacy in (1) R/R AML and (2) frontline AML. Prior Ven use was allowed for pts with R/R AML. The dose of CPX-351 was fixed : daunorubicin 44 mg/m2 and cytarabine 100 mg/m2 IV on days 1, 3 and 5 of induction, and daunorubicin 29 mg/m2 + cytarabine 65 mg/m IV on days 1 and 3 during consolidation. The starting effective dose of Ven was 300mg (at the -1 dose level) on D2-21 for the safety lead-in cohort with appropriate dose adjustment for concomitant CYP3A inhibitors. First, interruption of Ven after D14 was implemented if a D14 bone marrow was hypocellular and without evidence of leukemia. However, a second de-escalation was required (-2 dose level) with Ven given on day 2-8 of each cycle, and daunorubicin dose reduced to 22 mg/m2 during consolidation. This was found to be the recommended phase 2 dose. Results: Between 11/2018 to 1/2022, 33 pts were enrolled. The median age was 53 yrs (range, 26-72) and 61% were female. Diploid karyotype was present in 7 pts (21%), core binding factor rearrangements in 2 (6%), MECOM rearrangement in 2 (6%) and 13 (39%) had a complex karyotype. The most frequent mutations were DNMT3A (37%), TP53 (21%) and NRAS (21%). 8 (24%) pts had secondary AML including 4 (12%) with prior HMA exposure; the median number of prior lines of myeloid-directed therapies was 1 (1-7), including 58% of them with a previous exposure to Ven. Pts received a median of 1 cycle (1-4), and the median number of cycles to first response was 1 (1-2). The ORR was 45% (15/33), with 5 patient (15%) achieving CR, 8 (24%) achieving CRi and 2 (6%) achieving MLFS. The ORR was higher in those pts with only one prior line of therapy (59%) compared to those with 2 or more previous therapies (31%). The ORR for pts with prior exposure to Ven was 37% (7/19) vs 57% (8/14) for those not previously exposed to Ven (p=0.4). The 4- and 8-week mortality was 9 and 21%. 9/15 pts (60%) underwent alloSCT including 14 with CR/CRi/MLFS and 1 pt with an aplastic bone marrow insufficient for response assessment. The most frequent grade 3 or more adverse events were infections (45%, 30% of them pulmonary), febrile neutropenia (24%), and mucositis/stomatitis (6%). Three deaths occurred on study (2 due to sepsis and 1 due to cardiac arrest), all after one cycle of therapy. Other grade 3-4 events registered included rash (6%), cerebrovascular accident (6%), and intracranial hemorrhage (3%). After a median follow-up time of 20.7 months, the OS at 12 and 24 months was 34% and 25%, respectively. The median OS was 6.4 months. The EFS at 12 and 24 months was 26% and 19%, respectively. The median EFS was 2.8 months. For those who achieved response, the 2-year cumulative incidence of relapse and death without relapse were 41% and 28%, respectively. For those who underwent alloSCT, the median OS after alloSCT was 24 months, with 4 deaths after alloSCT, all following disease relapse. Conclusion: In this phase Ib dose escalation study, standard dose CPX-351 combined with 7 days of Ven was found to safe and tolerable in pts with rAML. The combination produced encouraging response rates in a poor risk population, including those with prior Ven treatment, allowing a significant proportion to undergo allo-SCT and extended survival. The RP2D is being studied in pts with newly diagnosed and less heavily pretreated AML.

A Phase II Study of CPX-351 Plus Venetoclax in Patients with Relapsed/Refractory (R/R) or Newly Diagnosed Acute Myeloid Leukemia (AML)

A Phase II Study of CPX-351 Plus Venetoclax in Patients with Relapsed/Refractory (R/R) or Newly Diagnosed Acute Myeloid Leukemia (AML)

Marrow Hypocellularity, but Not Residual Blast Count, Is Prognostic on Day-14 Assessment in Acute Myeloid Leukemia

Background: Standard induction chemotherapy for acute myeloid leukemia (AML) with “7+3” regimen consisting of cytarabine and daunorubicin (DNR) yields a complete remission (CR) rate of 40-80%. Current practice, endorsed by the National Comprehensive Cancer Network, is to perform a repeat bone marrow assessment on day 14 (D14) of initial induction. A blast count greater than 5-10% with a marrow cellularity of 10-20% at that time suggests residual leukemia and recommendation is for a second round of induction chemotherapy. Most studies only note blast count as the key value in decision making. Large studies have confirmed a prognostic value of D14 bone marrow biopsy based on blast percentage, yet controversy lies in its use as treatment decision point. In this single center retrospective study, we evaluated the role of cellularity on clinical outcomes in patients with residual morphologic blasts on day-14 bone marrow biopsy. Methods: All consecutive patients 18 years or older who received induction chemotherapy for newly diagnosed AML from 1/1/06 to 5/1/13 at the Lifespan Cancer Institute were identified. Outcomes were followed until 5/1/17. On D14 marrow assessment, patients were determined to have residual leukemia if the morphologic blast count was ≥5%, deemed to have an intermediate response (IR) if blasts counts were 5-19%, and considered hypocellular if the cellularity was Results: Of 113 patients identified, 68 underwent D14 bone marrow biopsy and 35 had residual disease on D14 determined by blast count. Sixteen of these patients received reinduction. Nineteen had hypocellular bone marrows and 16 were non hypocellular. Between the hypocellular and non hypocellular groups no demographic or leukemia specific variables were significantly different (Table 1). In terms of outcome data, more patients with hypocellular D14 bone marrows attained an IR (12 of 19, 63%) compared to a non hypocellular marrow (3 of 16, 19%, p=.008). Furthermore, hypocellular D14 marrows showed improved post induction complete response (74% v. 31%, p=0.12) and improved median overall survival (17 v. 8.5 months, p=0.03, Figure 1) compared to non hypocellular D14 marrows. Based on logistic regression, there was no benefit for reinduction based on cellularity for either CR (OR 0.056, 95% CI 0.002-1.47) or OS (HR 1.96, 95% CI 0.4-9.6). Using a blast count of ≥5% on the day-14 marrow assessment as a positive screening test for residual leukemia demonstrated PPV of 42%, NPV of 79%, sensitivity of 53% and specificity of 70% for achieving CR. Using the alternative cutoff of Conclusions: In our single center retrospective review, we found that D14 bone marrow hypocellularity significantly predicted CR and OS in patients with residual morphologic blasts. We found no benefit to additional chemotherapy based on D14 marrow assessment in terms of attaining CR or improvement in OS. Furthermore, there was no benefit for reinduction based on D14 marrow cellularity using logistic regression. There is improved specificity for D14 bone marrow biopsy to detect residual disease when a morphologic blast cutoff of 20% or greater and bone marrow cellularity of 20% or greater is utilized. For those patients with residual blast counts over 20% and non hypocellular marrow, strong consideration should be made for clinical trial or novel therapeutic agent. Although these are relatively small numbers, this data underscores the continued value of D14 bone marrow morphologic assessment for prognostication. Download : Download high-res image (142KB) Download : Download full-size image Figure 1 . Disclosures Reagan: Teva: Membership on an entity's Board of Directors or advisory committees.

Favorable Outcomes with Fludarabine, High Dose Cytarabine and Granulocyte Colony Stimulating Factor (FLAG) As Re-Induction for Residual Acute Myeloid Leukemia on Day 14 Bone Marrow

BACKGROUND: Initial response to standard induction therapy for acute myeloid leukemia (AML) is typically assessed by a bone marrow biopsy on day 14 (D14). However, there does not appear to be a consensus on who should receive re-induction therapy and what regimen to choose if treatment is given. Fludarabine, high dose cytarabine and granulocyte colony stimulating factor (FLAG) regimen has been used at our institution for re-induction in patients with residual disease on D14 marrow evaluation. METHODS: A retrospective chart review was performed to evaluate adult patients with AML who received re-induction with FLAG for residual leukemia on D14 marrow between September 2012 and July 2017 at our institution. All patients included in the analysis received standard induction chemotherapy with cytarabine and an anthracycline. Approval for the study was obtained from the IRB. RESULTS: We identified 27 patients that received FLAG as re-induction (Table 1). The median age at diagnosis was 61 years (range 19-77). Median WBC count at presentation was 5.8 X10^3/ml (range 0.6-132) and bone marrow blast % was 64 (range 30-95). Most patients (63%) had poor risk disease based on cytogenetics and molecular abnormalities (as per NCCN AML guidelines), one patient (4%) had favorable risk disease with the rest of the patients (33%) having intermediate risk disease. The D14 marrow had a minimum cellularity of more than 20% in 14 patients. The median blast % by morphology on the D14 marrow was 60% (range 9-95). The overall response rate (CR/CRp/CRi) was 78% with 17 out of 27 (63%) patients achieving complete remission (CR). Four patients (15%) had resistant disease after FLAG based on a bone marrow evaluation and 2 patients died of indeterminate cause. Of the 4 patients with resistant disease, 1 achieved CR with a second cycle of FLAG. Overall, three patients died in the hospital during re-induction. The median time period for neutrophil count recovery (ANC >500) from re-induction date was 19 days (range 15-33). The median length of hospital stay after re-induction for patients that were discharged was 22.5 days (range 17-41). Fifteen patients (56%) proceeded to hematopoietic stem cell transplant (HSCT). Out of the 15, 14 were in CR1 at the time of HSCT. At the last follow up, 16 patients were in remission. The median follow up time period after re-induction was 224 days (range 11-1,663). The median time to relapse for patients that achieved CR after initiating FLAG re-induction was 233 days (range 152-676). The 1 and 2 year overall survival (OS) rates were 72% and 62% respectively (Figure 1). CONCLUSION: We report favorable outcomes with FLAG as a re- induction regimen for patients found to have residual AML on D14 bone marrow biopsy following standard induction chemotherapy. The median age of our population was > 60 years and 63% of the patients had poor risk AML. Within the limitations of a small retrospective study, FLAG was well tolerated with 3 patients expiring during the initial hospitalization. For AML patients with residual disease 14 days after standard induction therapy and who are able to receive further treatment, FLAG is a reasonable salvage option. Disclosures Erba: Celgene: Consultancy, Other: Chair, Scientific Steering Committee , Speakers Bureau; Incyte: all research support paid to University of Alabama, Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Other: all research support paid to University of Alabama, Research Funding; Daiichi Sankyo: Consultancy, Other: all research support paid to University of Alabama, Research Funding; ImmunoGen: Consultancy, Other: all research support paid to University of Alabama, Research Funding; MacroGen: Consultancy; Ono: Consultancy; Pfizer: Consultancy; Seattle Genetics: Consultancy, Other: all research support paid to University of Alabama, Research Funding; Sunesis: Consultancy; Millennium/Takeda: Consultancy, Other: all research support paid to University of Alabama, Research Funding; Agios: Other: all research support paid to University of Alabama, Research Funding; Juno: Other: all research support paid to University of Alabama, Research Funding; Astellas: Other: all research support paid to University of Alabama, Research Funding; Celator: Other: all research support paid to University of Alabama, Research Funding; Janssen: Other: all research support paid to University of Alabama, Research Funding; Glycomimetics: Other: Chair, Data and Safety Monitoring Committee.

Phase II Study of CPX-351 Plus Venetoclax in Patients with Acute Myeloid Leukemia (AML)

Phase II Study of CPX-351 Plus Venetoclax in Patients with Acute Myeloid Leukemia (AML)

Day 14 Bone Marrow Evaluation During Acute Myeloid Leukemia Induction in a Real-world Canadian Cohort

The 2017 National Comprehensive Cancer Network guidelines for acute myeloid leukemia have recommended performing bone marrow (BM) aspiration and BM trephine biopsy (BMTB) 14 to 21 days after starting induction therapy (commonly referred to as "day 14 [D14] marrow"). Those who do not achieve a hypoplastic marrow, with cellularity< 20% and blasts< 5%, are recommended to undergo 2-cycle induction (2CI). We performed a retrospective analysis to determine the impact of D14 BM characteristics in predicting for remission, association with overall survival (OS), and the effect of 2CI according to the D14 BM results. Patients aged 18 to 70 years undergoing induction therapy with standard "7+ 3" regimens were included. D14 cellularity was determined from BMTB samples and the blast percentage was assessed by morphology on BM aspiration and BMTB samples. The outcomes evaluated included the rates of complete remission (CR) and OS. A total of 486patients with results from D14 BM evaluation were included in the present study. On multivariate analysis, cytogenetic risk and D14 blasts< 5% were predictive of CR/CR with incomplete count recovery (P< .001). Cytogenetic risk (P<.001), age< 60 years (P= .001), and D14 blasts< 5% (P= .045) predicted for OS. 2CI was performed in 131 patients (27%). Patients with hypocellular D14 BM but residual blasts (n= 106) underwent 2CI in 46% of cases, with improved remission rates (43.9% vs. 72.0%; P= .004) but no difference in OS. The results from D14 BM evaluations are predictive of subsequent remission and OS. Our findings did not show a survival benefit with D14 BM-driven 2CI.

Does day 14 bone marrow status predict response to chemotherapy in acute myeloid leukemia? Experience of a hemato-oncology care center from Eastern India

Background: Acute myeloid leukemia (AML), the most common type of acute leukemia in adults, yet continues to have the lowest survival rate of all leukemias. The present study aimed to study ability of Day 14 marrow status to predict the remission status in AML. Materials and Methods: This prospective, observational study conducted in 30 AML patients who received “induction remission” as per standard guidelines and undergone bone marrow (BM) aspiration and biopsy on day 14 and day 28. Complete remission (CR) defined as per standard criteria. SPSS 15.3 was used to perform statistical analysis. Results: Median BM blast count on day14 was 10.6% (range, 1–50). Patients achieving remission in day 28 + BM had mean day 14 BM blast count of 8.52% compared to 21.00% in those who did not achieve remission. Majority (90.9%) of the patients with ≤15% BM blast on D14 was in remission. Comparing D14 BM blast% with CR, blast >15% cut off (across all the cut offs, i.e., 5%, 10%, 15%, or 20%) was the best to find those who entered remission; but the negative predictive value (NPV) was poor across all groups. Conclusions: There is a trend toward early relapse in patients with higher blast on D14. However, D14 BM marrow blast >15% has a poor NPV for predicting relapse.

Early induction intensification with cladribine, cytarabine, and mitoxantrone (CLAM) in AML patients treated with the DAC induction regimen: a prospective, non-randomized, phase II study of the Polish Adult Leukemia Group (PALG)

We present the results of a prospective, non-randomized phase 2 trial in which 253 AML patients (pts) under 60 years old received DAC (Daunorubicin + AraC + Cladribine) as first induction followed by CLAM (Cladribine + AraC + Mitoxantrone) as early second induction on day 16 based on bone marrow (BM) blasts on day 14 (D14). The CR/CRi rate after a single course of DAC was 83% for pts with D14 BM blasts less than 10%. Forty-six pts had >10% BM blasts on D14, of whom 35 received CLAM with rates of CR/CRi 60% and early death (ED) 23%. The remaining 11 pts were not fit to receive CLAM, with rates of CR/CRi 28%, PR 18%, and ED 18%. Median OS was 7.2 versus 7.5 months, respectively. The overall CR/CRi rate was 77% after the first induction, with final CR/CRi rate 80% after DAC reinduction for pts who achieved PR with initial DAC course. CLAM used as early second induction might improve CR/CRi rates for younger AML pts with poor early response to DAC induction, but may be associated with higher mortality.

Evaluation of prognostic factors after induction therapy in AML.

e18528 Background: Acute myeloid leukemia (AML) is a hematologic myeloid malignancy that carries a poor prognosis. Standard of care is induction chemotherapy with daunorubicin and cytarabine also known as 7 + 3. Bone marrow aspirates are assessed on day 14 (D14) and day 28 (D28). Achievement of CR (complete remission) is predicative of overall survival (OS ).Morphological review of BM (bone marrow) on D14 remains the standard evaluation for any indication for CR. Methods: Our primary objective was to determine if blast % on the D14 bone marrow aspirate is a prognostic indicator for remission in acute leukemia patients who underwent induction chemotherapy. Institutional review board was approved. A retrospective chart review was conducted at North Shore University Hospital. Adult patients with AML who received standard induction chemotherapy from 2010 to 2015 were included. 150 patients were reviewed and their D14 blast %, initial marrow blast %, gender, age, cytogenetics and initial WBC were assessed. The patients’ D14 blast % biopsies were divided into blast percentiles: &lt; 1%, 1-10%, 10-30%, 30-60% and &gt; 60%. CR was defined as patients having &lt; 5% blasts on their D28 bone marrow or day 63 and corresponding neutrophil count &gt; 1,000 and platelet count &gt; 100,000. Results: Fisher’s exact test was used to compare the proportion of patients who reached CR among the D14 blast % categories. The Wilcoxon test was utilized to compare CR on continuous variables. Results were considered statistically significant if p &lt; 0.05. D14 hemoglobin and D14 platelets were not significantly associated with CR status (p = 0.67, p = 0.33, and p = 0.13, respectively). D14 WBC was significantly associated with CR (p = 0.02), but when both D14 WBC and initial blasts % were included in a multiple logistic model, WBC was no longer a significant predictor of outcome. Only initial blast percent at time of diagnosis was deemed predictive of CR response at day D63 (p = 0.0142). Conclusions: Initial blast &gt; 60% was found to be significantly associated with the greatest CR rate. This study provides evidence of initial blast % being a prognostic factor for CR.

Evaluation of Prognostic Factors after Induction Chemotherapy for Acute Myeloid Leukemia

Abstract Purpose: Recent studies have shown that dose escalation of daunorubicin from 45mg/m2 to 90mg/m2 during acute myeloid leukemia (AML) induction showed response benefit and overall survival in patients &lt;=65 years. Yet, the further management of patients with persistent disease based on the evaluation of D14 bone marrow has often been questioned due to lack of data. The primary purpose of this study is to evaluate the overall remission rates of patients with a positive D14 bone marrow compared with those who had a negative D14 results, and to determine if blast % on the D14 bone marrow aspirate is a prognostic indicator for remission and survival in acute leukemia patients who underwent induction chemotherapy. We aim to investigate the relevance of the D14 bone marrow result by dividing the result into blast percent categories and investigate if the there is a correlation between D14 blast % and CR. Patients/Methods: This was an IRB approved retrospective chart review conducted at North Shore University Hospital. Adult patients with AML who received standard induction 7 + 3 Daunorubicin and Cytarabine from 2010 to 2015 were included. 150 patients were reviewed and those that were eligible were evaluated for various factors (D14 blast %, initial marrow blast %, gender, age, cytogenetic risk profile, initial WBC, initial hemoglobin, initial platelets and initial LDH levels, along with those lab values at D14) for tests of association with CR. These patients' D14 blast % biopsies were divided into blast percent categories as followed: (Chemotherapeutic/&lt;1%, 1-10%, 10-30%, 30-60% and &gt; 60%). Complete remission (CR) was defined as patients having &lt;5% blasts on their day 28 bone marrow or day 63 and corresponding neutrophil count &gt;1,000 and platelet count &gt;100 k. Fisher's exact test was used to compare the proportion of patients who reached CR among the D14 blast % categories, and on other categorical data. The Wilcoxon test was utilized to compare CR on continuous variables. Results were considered statistically significant if p &lt; 0.05. Results: 115 patients were analyzed and we found no significant association between D14 blast % and CR status. However, initial blast % was found to be significantly associated with CR status (p=0.009), specifically, those with &gt;60% initially had the greatest CR rate. D14 hemoglobin, D14 platelets or D14 LDH levels were not significantly associated with CR status (p=0.67, p=0.33, and p=0.13, respectively). Similarly, initial WBC, hemoglobin, platelets and LDH levels were each not significantly associated with CR (p=0.99, p=0.51, p=0.47 and p=0.36, respectively). Results did provide evidence to suggest that D14 WBC was significantly associated with CR (p=0.02), but when both D14 WBC and initial blasts % were included in a multiple logistic model, WBC was no longer a significant predictor of outcome. As such, only initial blast percent (at time of diagnosis or initial visit) was deemed predictive of CR response day at D63 (p=0.0142); patients with initial blast &gt;60% had the greatest rate of CR compared with &lt;20% blasts initially. Conclusion: The data suggests that there is no statistical difference between the blast % on the D14 bone marrow and the achievement of CR during induction chemotherapy for AML. Secondary outcomes showed that the initial blast % was associated with CR especially in patients with an initial blast % &gt;60%. Also, D14 WBC might be associated with remission. Prospective studies are required to confirm these findings. Disclosures No relevant conflicts of interest to declare.

Pilot Prospective Phase II Study of Nilotinib Combined with Chemotherapy for Myeloid Blastic Phase of Chronic Myeloid Leukemia or Acute Myeloid Leukemia with BCR/ABL1

Abstract Various chemotherapy regimens attempted however have been evaluated these treatment e not effective in chronic myeloid leukemia myeloid blastic phase (CML-MBP). Imatinib treatment in this subset of patients were also not very promising due to low response rates, short response duration, and transformation to BC. Some studies showed that nilotinib or dasatinib were superior to imatinib in terms of rapid time to response?? and higher molecular response in newly diagnosed CML patients . It can be translated to CML-MBP. We evaluated 2nd generation TKI, nilotinib and high-dose daunorubicin induction chemotherapy combination if to attempt an improvement in the response rate and survival in patients with CML-MBP or acute myeloid leukemia with BCR/ABL1 (AML-BCR/ABL1). The primary end point of the study was complete remission (CR) rate after induction chemotherapy (IC). Patients received cytarabine 200 mg/m2/day by continuous IV infusion over 24 hours daily for 7 days (D 1-7) along with daunorubicin 90 mg/m2/day IV daily for 3 days (D 1-3). Nilotinib 400mg bid PO was added without interruption from D8 of induction chemotherapy until allogeneic hematopoietic cell transplantation (alloHCT) or during 2 years. Re-induction chemotherapy was given as cytarabine 200 mg/m2/day by continuous iv infusion over 24 hours daily for 5 days (D 1-5) plus daunorubicin 45 mg/m2/day iv daily for 2 days (D 1-2) when D14 bone marrow blasts exceeded 5%. Four courses of high-dose cytarabine (Cytarabine 3 g/m2) were administered in 3-hour IV infusion every 12 hours on days 1, 3, and 5 (a total of six doses per course). This prospective phase II study was early terminated due to slow enrollment. A total of 10 (6 male &amp; 4 female) patients were enrolled. Six patients were diagnosed as CML-MBP and 4 patients as AML-BCR/ABL1 (all these patients will be presented as CML-MBP). Median age CML-MBP patients was 50.9 (22.5-63.0) years. Five patients had received prior therapies (low-dose cytarabine in 1, imatinib in 2 and dasatinib in 2 patients). Median time from CML-MBP diagnosis to induction chemotherapy was 3.12 (0-3.12) months. All patients received IC. Nilotinib was interrupted temporarily during IC in 5 patients (hyperbilirubin emia in 2 pts?, cytopenia in 1, rash in 1 and poor general condition in 1 patient). Nine patients showed bone marrow (BM) blast&lt;5% in early evaluation. CR was achieved in all (CR in 9 patients and CRi in 1) patients. One patient who had achieved CRi died of pneumonia without full hematological recovery during IC. Molecular response (MRIS) at the time of CR was not-evaluable in 1, MR1.0 in 3, MR2.0 in 2, MR3.0 in 2 and MR4.5 in 2 patients. Eight patients received 1 or 2 cycles of consolidation and 1 patients died during consolidation therapy. Five patients proceeded to alloHCT after consolidation. Two more (1 by relapse after alloHCT and 1 by graft-versus-host disease) patients died after alloHCT. Two patients died after alloHCT (1 by relapse and 1 after stopping nilotinib by toxicities). Median overall survival was 5.0 (95% CI, 1.5-8.4) months. Four patients are still alive (3 patients after alloHCT and 1 patient without alloHCT; 6.4+, 12.2+, 29.4+ and 43.6 months). In conclusion, nilotinib combined with IC is feasible and can be a good bridging therapy for these extremely rare CML-MBP or AML-BCR/ABL1 if they are IC-eligible although this conclusion is very limited and should be confirmed by large scale studies because of the small sample size of this study. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

Marrow Hypocellularity, But Not Residual Blast Count or Receipt of Reinduction Chemotherapy, Is Prognostic on Day-14 Assessment in Acute Myeloid Leukemia Patients With Morphologic Residual Disease

Induction chemotherapy for acute myeloid leukemia (AML) is based on the "7+3" cytarabine/anthracycline regimen. A nonhypocellular day 14 (D14) bone marrow sample with a blast count > 5% to 10% is suggestive of residual leukemia, for which a second course of induction chemotherapy has been recommended. Although the prognostic value of D14 bone marrow findings has been established, its use as a decision point is controversial because the benefit of repeat induction has been questioned. In the present single-center retrospective study of 113 patients with newly diagnosed AML, we evaluated the role of cellularity on the clinical outcomes of patients with residual morphologic leukemia (blasts≥ 5%). Among 64 patients with D14 bone marrow samples, 31 had residual morphologic leukemia. The complete remission (CR) rates were greater for the hypocellular (11 of 16) than for the nonhypocellular (4 of 15) patients (P= .03). The median overall survival (OS) for the hypocellular D14 patients was longer than that for the nonhypocellular patients (17 vs. 8 months; P= .02). No significant difference between the receipt of reinduction therapy and CR or OS was found on logistic or survival model analysis. The specificity for residual leukemia on D14 bone marrow samples was better for cellularity≥ 20% and blasts≥ 20% than for blasts≥ 5%. The results of our study have shown that patients with< 20% cellularity and< 20% blasts on the D14 bone marrow assessment should continue observation until recovery rather than receive additional immediate therapy.

Cladribine, Cytarabine and Mitoxantrone As Treatment Intensification for Patients with Acute Myeloid Leukemia with the Excess of Bone Marrow Blasts on Day 14 of the First Induction. Prospective, Multicenter Study By the Polish Adult Leukemia Group (PALG)

Abstract Objectives The treatment results of acute myeloid leukemia (AML) patients (pts) younger than 60yo are still unsatisfactory. The strategy of double induction in AMLis based on two courses of chemotherapy depends on percentage of bone marrow (BM) blast at 7-14 days of treatment. This therapy intensification may induce higher response rate but toxicity appeared as early death (ED) rates still a medical dilemma. The advantage from addition of cladribine (2CdA) to standard induction and reinduction treatment was previously confirmed in PALG's trials. Aim The aim of this study was an estimation of efficacy and toxicity of treatment intensification based on BM blast at 14 day (D14) by second early induction, CLAM (2CdA + cytarabine + mitoxantron) Methods We performed multicenter, prospective, non-randomized trial where pts received DAC induction treatment with subsequent second early induction according as D14 BM biopsy results. When BM examination revealed &gt;10% of blast without hypocellular marrowand pts met all criteria to intensive chemotherapy, second intensive induction with CLAM protocol (2CdA 5mg/m2 iv days 1-5, Cytarabine 2g/m2 iv days 1-5, Mitoxantron 10mg/m2 iv days 1-3) from day 16 was applied. The pts were allocated to risk-adjusted postremission treatment with high-dose cytarabine (HD-AraC) for low-risk group according to European Leukemia Net (ELN) classification and allogeneic stem cell transplantation (allo-SCT) recommended for intermediate and high-risk group. Results One hundred seventy one newly diagnosed AML pts from 8 PALG's centers were enrolled to the study. The median age was 47 yo (range19-60). According to WHO 2008 classification, our group consisted of 9% AML with recurrent genetic abnormalities, 19% AML related to myelodysplasia, 3% therapy-related AML and 69% AML not otherwise classified. Analysis of cytogenetic-molecular risk factors based on ELN classification revealed favorable, intermediate-1, intermediate-2, poor-risk groups in 17%, 44%, 18% and 21% AML pts, respectively. Twenty-six (15%) out of 171 pts had elevated BM infiltration of blasts at D14, with the median 44% (range 11-100%). Overall, 22 of 26 pts were judged as eligible to receive second induction, reasons for exclusion being in all cases active infection. Response evaluation was available in 150 pts, 21 pts were still ongoing in the protocol. Complete remission (CR) rate after single DAC induction course was 71% (n=106), partial remission (PR), non-remission (NR) and ED was 8% (n=12), 18% (n=28) and 3% (n=4), respectively. Response after double induction was evaluated in 21 out of 22 cases; one patient still has not reached time of measurement. CR was observed in 14/21 pts (67%), NR in 5% (n=1), ED 28% (n=6). The CR rate after inductiontreatment applied to first hospitalization (DAC or DAC+ CLAM) was 81% (n=120). Twelve pts who had &lt;10% of blasts at day 14 and achieved PR after first induction were allocated to second DAC induction. Six out of them achieved CR leading to the overall CR rate 85%.In 27 pts who achieved CR allo-SCT was performed till June 2016, however there are pts who are still awaiting allo-SCT. The median duration of hospital stay was 31 (11-73) and 66 (52-76) days respectively for the DAC and the DAC + CLAM induction. During the single DAC induction the median number of days with neutropenia &lt;0.5 G/l was 24 (12-101), and with thrombocytopenia &lt;20 G/l was 12 (0-51). The median number of transfused packed red blood cell (PRBC) was 9 (0-32) and the number of platelet concentrate units was 15 (2-124). During DAC+CLAM double induction the median number of days of the neutropenia &lt;0.5 G/l was 53 (17-73) and thrombocytopenia &lt;20 G/l was 19 (4-57). The median number of PRBC was 18 (10-44) and the number of platelet concentrate units was 30 (5-153). With the median time of follow-up 16 months the median overall survival (OS) was not reached. The probability of 1-year OS was 59% and the probability of 1-year disease free survival was 83% (Figure 1, Panel A and B). Conclusion The preliminary results of our study suggest that early second induction CLAM is a feasible and effective treatment option in younger AML patients which further improves the CR rate and do not compromise the feasibility of allo-SCT. Disclosures Grzybowska-Izydorczyk: BMS: Honoraria; Novartis: Honoraria. Warzocha:BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Robak:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Wierzbowska:Novartis: Consultancy, Honoraria; Janssen Cilag: Consultancy.

Prognostic significance of day 14 bone marrow evaluation in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia.

The role of day 14 (D14) bone marrow (BM) assessment in detecting increased blasts in patients undergoing induction for acute lymphoblastic leukemia (ALL) is not well defined. This study evaluated 389 adolescent and adult patients with previously untreated Philadelphia chromosome-negative ALL who received frontline induction chemotherapy and for whom a D14 BM assessment was performed. A D14 BM blast proportion < 10% (including blast-free aplastic BM) was observed in 319 patients (82%), 10% to 29% was observed in 31 patients (8%), and ≥30% was observed in 39 patients (10%). The composite complete remission (CR)/complete remission with inadequate platelet recovery (CRp) rates for these groups were 99.7%, 87%, and 79%, respectively. The median event-free survival (EFS) was 49, 33, and 9 months, respectively (P < .001). The median overall survival (OS) was 88, 37, and 21 months, respectively (P < .001). The D14 BM blast group was the only factor predictive for the achievement of CR/CRp (P < .001). According to a multivariate analysis, the D14 BM blast group was independently prognostic for both EFS (hazard ratio [HR], 1.44; 95% confidence interval [CI], 1.12-1.85; P = .004) and OS (HR, 1.45; 95% CI, 1.14-1.85; P = .003). However, when minimal residual disease (MRD) assessment at the time of CR was added to the model, the D14 BM blast group was no longer prognostic for EFS or OS. An assessment of residual D14 BM blasts in patients with ALL is highly predictive of the achievement of CR with induction chemotherapy and of EFS and OS. However, the D14 BM blast assessment is less prognostic of long-term outcomes when an MRD assessment is also available. Cancer 2016;122:3812-3820. © 2016 American Cancer Society.

Prognostic significance of day 14 (D14) bone marrow (BM) assessment in adult patients receiving induction for Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL).

7035Background: The prognostic impact of D14 BM blast percentage in the context of minimal residual disease (MRD) status at complete response (CR) in pts with ALL undergoing induction chemotherapy ...

Is the D14 bone marrow in acute myeloid leukemia still the gold standard?

Early bone marrow evaluation on day 14 of induction is common practice assisting in decision making regarding reinduction need in acute myeloid leukemia (AML). Studies exploring day 14 bone marrow false positive and negative rates yielded diverse data, and a highly specific method for early bone marrow evaluation is warranted. Given the improved induction-associated death rate, the risk of redundant reinduction administered to patients anticipating remission with one induction cycle may be outweighed by the benefit from the potential reduction in the falsely interpreted nadir bone marrow. The purpose of this review is to analyze current evidence on ways to optimize early bone marrow evaluation during induction in AML. Day 14 bone marrow blast count is affected by patient's age, leukemic risk, and induction regimen, and its remission prediction power is enhanced if more stringent cutoffs are used to define significant residual blast numbers or if morphologic bone marrow evaluation is performed on day 5 of induction. Early bone marrow evaluation has a potential to personalize the induction regimen, but because of limitations of day 14 bone marrow results, earlier bone marrow evaluation or the use of flow cytometry to detect minor blast populations may improve remission prediction in AML.

Routine interim disease assessment in patients undergoing induction chemotherapy for acute myeloid leukemia: Can we do better?

The presence of >5% blasts at "day 14" (D14), in patients undergoing induction chemotherapy for acute myeloid leukemia (AML) is problematic. It is unclear if a second course of chemotherapy for early persistent disease will alter outcome in these patients. We conducted a retrospective study of AML patients undergoing induction chemotherapy where diagnostic, interim (around day 14), and recovery (days 21-42) bone marrow (BM) evaluations were available for review. Of the 113 patients included in the final analysis, 99 (87.6%) achieved CR at hematologic recovery. At D14, 90 patients (79.6%) had <5% blasts and of these, 87 (96.7%) ultimately achieved CR. At D14, Twenty-three (20.4%) patients had residual leukemia (>5% blasts). Of these, 11 (47.8%) received a second course of chemotherapy (double induction [DI]) and 12 (52.2%) were observed until count recovery (single induction [SI]). No significant difference in CR rates was observed between these two groups (58.3% DI group vs. 45.5% SI group, P value = 0.684). In our analysis, D14 BM evaluation did not uniformly identify patients with primary induction failure. To unequivocally determine the value of a D14 marrow assessment in AML, prospective studies in the context of large cooperative group trials are required. Considering our findings and similar reports from others, we propose that D14 marrow assessment should be individualized, and that other factors, such as cytogenetics and early peripheral blood blast clearance should be considered, to identify patients most likely to benefit from interim disease assessment during AML induction therapy.

Clinical Utility of Morphological Evaluation of Day 14 Bone Marrow Biopsies in Acute Myeloid Leukemia Patients Undergoing Standard Induction Chemotherapy: Time to Change Practice?

Abstract Introduction Early bone marrow (BM) evaluation (during aplasia or at “day 14” (D14)) in patients with AML undergoing conventional induction therapy has been adopted from clinical practice in pediatric acute lymphoblastic leukemia (ALL). While it has been shown that early persistence of AML correlates with decreased complete remission (CR) rates and overall survival (OS), unlike in ALL, there are no data to indicate that early initiation of re-induction therapy based on these findings will positively influence outcome. In fact, early re-induction, especially in older patients, may increase morbidity and mortality from prolonged cytopenias, infectious complications, and longer hospital stays. Moreover, it can be challenging to determine the nature of scattered blasts identified in a hypocellular BM at D14, as they may represent normal recovering marrow elements or malignant blasts. Even if malignant, the chemosensitivityof these cells will only be fully determined by later assessment of the BM at the time of expected count recovery (“day 28”). For these reasons, early re-induction therapy may not be advisable. In this retrospective study, we sought to evaluate the validity of D14 BM assessments as post-therapy prognostication to guide treatment decisions in AML. Methods We conducted a retrospective institutional study (2006-2014) of AML patients undergoing routine induction chemotherapy where diagnostic, interim (around D14) and recovery (D21-42) BM evaluations were available for review. Clinical information and pathology data were retrieved from our institutional database. Responses at D14 were categorized morphologically into three categories: optimal response (OR, blasts ≤5%), indeterminate response (IR, blasts 6-19%), and residual leukemia (RL, blasts ≥20% or a relative decrease in blast count from baseline of &lt;20%). Published response criteria were used to define responses at marrow recovery. Suboptimal response (SOR) at D14 was defined as either IR or RL during the assessment period. Mann-Whitney's U test was used to compare non-normally distributed variables. The Fisher's exact test was employed to assess for associations between response to treatment at D14 and likelihood of recovering in CR. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of a D14 BM to predict CR were calculated for patients that were observed without re-induction. Results Evaluable patients (n=98) had a mean age of 51 years (20-73), and 45% were male. The median BM blast percentages at diagnosis, D14 and recovery were respectively 54.5%, 0% and 2.5% (Figure 1). There was a significantly greater absolute decrease in blast percentage from diagnosis to D14 in patients who recovered in CR compared to those who did not achieve CR (median: 53.5% vs 23.0%, P = 0.001). In patients that got early re-induction therapy for SOR at D14, the relative differential in baseline and D14 BM blasts was significantly lower compared to patients with D14 SOR who did not get re-induction therapy (median: 21.8% vs 77.8%, P=0.004) Ninety patients did not receive early re-induction therapy. Of these, 86 (95.6%) achieved CR and 4 patients (4.4%) recovered counts with residual leukemia. Fourteen (14.3%) patients were classified as SOR at D14. Of these, 6 (6.7%) did not receive re-induction therapy and 4 of these 6 patients (67%) achieved a CR. Eight patients received early re-induction therapy based on SOR at D14 (IR = 2, RL = 6); of these, 4 patients (50%) achieved CR at count recovery. Achieving an OR at D14 was predictive of achieving CR at recovery (sensitivity = 95.3%, PPV = 97.6%). However, not achieving an OR at D14 had low specificity (50%) and NPV (33.3%) for achieving CR (P = 0.021). Conclusions Our results indicate that a SOR at the D14 BM evaluation does not uniformly identify patients with primary induction failure (low NPV) and should not be used to dictate the timing of re-induction therapy. We confirmed the PPV of achieving an OR at D14 as previously reported, but we argue that no additional prognostic data is provided by an OR at D14, beyond what can already be predicted by pre-treatment variables (e.g., age and chromosomal abnormalities). We suggest that the D14 BM should be omitted from the routine evaluation of AML patients during induction therapy outside the context of a clinical trial. Figure 1 Figure 1. Progression and percentage of blasts at diagnosis, day 14 and recovery assessments (n = 98). Disclosures No relevant conflicts of interest to declare.

Early Blast Clearance Evaluation after Induction Chemotherapy for Acute Myeloid Leukemia By Multiparameter Flow Cytometry and WT1-RNA Quantification: A Single Center Experience

Abstract Introduction: in acute myeloid leukemia (AML) the response to treatment is evaluated upon full recovery of peripheral blood counts by bone marrow (BM) assessment using morphology and cytogenetics, if appropriate number of metaphases is obtained. Real time quantitative PCR (RQ-PCR) and multiparametric flow citometry (MFC) are sensitive techniques to assess minimal residual disease (MRD) mostly used to refine risk stratification and to guide therapy. Evaluation of response to induction chemotherapy (CT) during aplasia (around day 14 from start of induction) has shown a significant prognostic impact, the presence of residual disease predicting a worse prognosis. All reported studies on early BM blast clearance evaluation rely on morphology as a single technique. Unfortunately, at day 14 BM is often not evaluable for cytology and morphologyc blast count. Unpredictability and intra-observer variability must also be considered when assessing blast count by morphology alone. No studies analysing early BM blast clearance by means of MFC and/or PCR have been published and the correlation between the two assays is unknown in this setting. Moreover, it is to be established if early intensification (around day 15 from start of induction) with a second cycle of CT could increase the CR rate in pts with disease persistence in the BM evaluated at day 14. Matherial and methods: we retrospectively evaluated data of 23 newly diagnosed AML pts who received induction CT at our center between 02/2009 and 05/2014, and for whom analysis of BM both at day 14 and after hematologic recovery (around day 28) was performed. The aim of our study was to define the prognostic value of early MRD quantification by MFC (d14-LAIP) and WT1 quantification by PCR (d14-WT1) in predicting the response to induction. Firstly we compared d14-LAIP and d14-WT1 to identify the more sensitive and specific assay in predicting the response to induction, in particular for cases not evaluable for morphologic blast count. Then we compared the outcome of pts who received or did not receive an early intensification for persistence of disease at d14 BM evaluation. Results: 20 pts received the 3+7 induction regimen, 3 pts the ICE induction regimen. After BM evaluation at day 14, 7 pts received early reinduction CT (FLAG-IDA regimen) starting at day 16 (median), 16 pts did not receive further therapy before BM evaluation at day 28. Overall CR rate was 70% (16 pts), PR/NR 30% (7 pts), TRM 4% (1 pt). At day 14, leukemic blast percentage was not evaluable by morphology in 8 (35%) cases due to marrow aplasia, in 1 (4%) case blasts were &lt;5%, in 14 (61%) cases blasts were ≥5%; by MFC (23 cases), in 9 (39%) cases blasts were ≤2%, in 14 (61%) were &gt;2%; by PCR (17 cases), in 4 (24%) cases WT1 was &lt;250 cp/10e4 ABL, in 13 (76%) WT1 was ≥250 cp/10e4 ABL. At day 28 BM evaluation, of the 8 pts with aplastic marrow at day 14, 6 (75%) were in CR and 2 (25%) in PR/NR, of the 14 pts with blasts ≥5% at day 14, 9 (64%) were in CR and 5 (36%) in PR/NR. Analysis of the paired results from nadir to recovery revealed that d14-LAIP 2% had a positive predictive value (PPV) of CR at day 28 of 71% and negative predictive value (NPV) of 89%, with a sensitivity of 83% and a specificity of 80%, d14-WT1 250 had a PPV of 50% and NPV of 25%, with a sensitivity of 57% and a specificity of 20%. The d14-LAIP analysis was strongly associated with CR after induction (p 0.034). Considering the 14 pts with blasts ≥5% at day 14, 6/7 (86%) who received early reinduction CT and 3/7 (43%) who did not, obtained the CR at day 28 (p ns). Discussion: in our series d14-LAIP proved to be more predictive of response after induction CT than d14-WT1. Although one-third of pts had an early morphologic response not evaluable due to marrow aplasia MFC proved to be a useful assessment tool with a 100% applicability. Moreover, correlation between D14-LAIP and d14-WT1 was &gt; 90%. Our data confirm the prognostic value of day 14 BM evaluation and suggest that MRD detection, also in aplasia, could drive early reinduction CT which probably could increase the CR rate, without significantly clinical complications. Anyway, this last point must be confirmed with a larger study. Disclosures Bordignon: MolMed S.p.A: Chairman and CEO Other.

Clinical and Laboratory Factors Influencing The Probability Of Complete Remission In AML Patients With Positive Day 14 Bone Marrows

Abstract Background Early response to induction therapy for AML assessed by bone marrow (BM) evaluation on day 14 (D14) post chemotherapy is considered an important predictor of achieving complete remission (CR). Our aim was to identify clinical and laboratory factors influencing the probability of CR in AML patients (pts) with positive D14 BM without receiving further chemotherapy. Methods Records of pts with AML treated between 1998 and 2011 were retrospectively reviewed to identify subjects with positive D14 BM who did not receive re-induction chemotherapy. The distribution of following variables such as age, white blood cell count (WBC) at the time of induction therapy, BM cellularity, percentage of blasts, disease status, and risk was compared by the univariate analysis. Recovery BM status (positive vs. negative for disease) as the response variable and age, WBC at the time of induction therapy, BM cellularity, percentage of blasts, disease status, and risk as explanatory variables were assessed by the logistic regression analysis. Poor risk AML was defined as the presence of adverse karyotype, treatment related disease or presence of antecedent hematologic disorder. Positive BM was defined as either cellularity ≥20% or ≥5% myeloblasts by IHC staining. CR was defined according to IWG 2003 criteria. Results 169/378 (44%) had a positive D14 BM after induction therapy and 92/169 (54%) did not receive re-induction chemotherapy. 68/92 (74%) underwent repeated BM evaluation at WBC recovery, which occurred 4-5 weeks after induction chemotherapy. Recovery BM showed refractory AML in 38/68 (56%) of cases. However, in 30/68 (44%) cases CR was achieved despite previously positive D14 BM. As demonstrated in Table 1, clinical and laboratory characteristics of the CR and refractory groups showed significant differences in the absolute percentage of D14 myeloblasts, abnormal vs. normal myeloblast phenotype, de novo vs. relapse disease status, and risk stratification. Higher blast percentage (P=.0016) was associated with significantly higher probability of having refractory AML and each 1% increase blasts on D14 BM increased the odds of refractory AML on recovery BM by 6% (OR=1.06 95% CI 1.022-1.099) (Figure 1) In contrast, no clear association between D14 BM cellularity and the recovery BM status was found. The results from the multivariate analysis were comparable with that from the univariate analysis. Blast percentage, disease status, and AML risk were strongly and jointly associated with the status of BM recovery. By using a logistic model including myeloblast percentage, myeloblast phenotype, disease status, and AML risk category we correctly predicted 31 refractory AML cases out of 38 (sensitivity = 82%) and we correctly predicted 23 CR cases out of 30 (specificity = 77%). For example, based on our formula, which incorporated blast percentage, disease status, and AML risk we estimated that in a patient with de novo, not a poor risk AML with 5% blasts on D14 BM the probability of positive recovery BM status was 6%, whereas in a patient with relapsed poor risk AML and 50% blasts on D14 BM the probability of positive recovery BM status was 98%. Conclusions Significant proportion of pts with positive D14 BM may achieve CR without subsequent chemotherapy administration. Low blast percentage, absence of phenotypically abnormal myeloblasts, de novo diagnosed AML, and absence of poor risk AML are associated with a significantly higher probability of CR. We developed a useful formula for predicting remission status in the setting of positive D14 BM that would be valuable in clinical trial protocols involving decision trees for re-induction chemotherapy. Disclosures: No relevant conflicts of interest to declare.