Second Course Of Induction Chemotherapy Research Articles

MIDOSTAURIN ADDED TO CYTOSINE ARABINOSIDE PLUS IDARUBICIN (“7+3”) IN NEWLY DIAGNOSED FLT3-MUTATED ACUTE MYELOID LEUKEMIA

The combination of an anthracycline and cytosine arabinoside has been the standard induction therapy for acute myeloid leukemia (AML) for more than four decades. Fetal liver tyrosine kinase 3 (FLT3) mutations are among the most frequently found mutations in newly diagnosed AML. According to the results of RATIFY trial, midostaurin was approved for use together with intensive chemotherapy (cytarabine plus daunorubicin). Recently, idarubicin has been more frequently favored over daunorubicin. Report the outcome of patients with AML and FLT3 mutated treated with a combination of cytosine arabinoside plus anthracycline (“7+3”regimen) and midostaurin. Herein, we retrospectively analyzed the treatment outcome of three patients with newly diagnosed AML and confirmed FLT3-ITD were eligible. The treatment consisted induction with “7+3”regimen and midostaurin (administered at a dose of 50 mg orally twice daily on days 8 through 21). All were male with age between 21 and 38 years old. A normal karyotype was found in all cases. Patients received cytarabine, idarubicin and midostaurin for induction and all experienced febrile neutropenia and two necessitated preemptive liposomal amphotericin B. One patient developed neutropenic enterocolitis. A second course of induction chemotherapy was administered to 2 patients. Relapse was observed in 1 patient (after Allo-HCT). One patient died after allo-HCT due to severe acute GVHD and one patient is alive in CR1. We showed that young patients, who had AML and a FLT3-ITD mutation, can be treated with the combination of cytarabine, idarubicin and midostaurin. The RATIFY study (Stone et al., 2017) and the German-Austrian AML Study Group (Schlenk et al., 2019) used daunorubicin 60 mg/m2 for induction, in combination with cytarabine and midostaurin. The complete remission rates in these trials were 59.8% (CR – Ratify) and 77.9% (CR+Cri - German-Austrian trial). In contrast with these two studies, idarubicin was used for induction in 53.5% of cases and was favored over daunorubicin in a more recent trial (Sierra et al. 2020). Of note, the results of FLT3 are necessary before the day 8 of induction. Hence, some patients may have already received the all three planned doses of anthracycline (idarubicin) before the information on results of FLT3 mutation. The recent approvals of new drugs for treating AML will modify the treatment algorithm and our data indicate that the use of idarubicin in combination with cytarabine and midostaurin is feasible in young patients with FLT3-mutated AML.

The Impact of Induction Treatment Response on the Prognosis of Pediatric Core Binding Factor-Acute Myeloid Leukemia Patients

To explore the impact of induction treatment response on the prognosis of pediatric core binding factor-acute myeloid leukemia (CBF-AML). The result of induce reaction and survival data of 157 pediatric CBF-AML patients in our hospital from September 2008 to December 2018 were retrospectively analyzed．The survival rate of the patients with different degrees of morphological remission after induction chemotherapy was comparative analyzed. Among the 157 children with CBF-AML, 113 (72.4%) patients achieved morphologic leukemia-free state (MLFS) after the first course of induction chemotherapy, 153 (98.1%) patients achieved MLFS after the second course of induction chemotherapy. The 5-year event-free survival (EFS) rate and 5-year overall survival (OS) rate of patients with non-remission (NR) status after the first course of induction of chemotherapy was significantly lower than the patients achieved MLFS and the patients achieved partial remission (PR). The 5-year EFS rate and 5-year OS rate of the patients with PR status after the second course of induction chemotherapy were lower than the patients achieved MLFS, but the difference was not statistically significant. Multivariable analyze showed that NR after the first course of induction chemotherapy and myeloid sarcoma were the independent risk factors affecting EFS of the patients. There were six patients with NR status after the first course of induction chemotherapy, in which all of them harbored t(8;21), three of them with sex chromosome deletion, two of them with myeloid sarcoma. NR status after the first course of induction chemotherapy was the independent risk factor affecting EFS and OS of CBF-AML patients, it can be taken as an indicator for higher risk stratification. PR status after the first course of induction chemotherapy may not be used as a diagnostic criterion for primary drug resistance.

Clinical Prognostic Factors Analysis of Initially Treated AML Children with t(8;21)/RUNX1-RUNX1T1

To investigate the clinical prognostic factors of initially-treated AML children with t(8;21)/RUNX1-RUNX1T1+. Clinical data of 41 initially-treated AML children with t(8;21)/RUNX1-RUNX1T1+ in our hospital in period from January 2009 to January 2017 were retrospectively analyzed. The baseline clinical characteristics, cumulative recurrence, event-free survival (EFS) and overall survival (OS) were recorded, and the influencing factors of prognosis were evaluated by χ2 test and Cox regression model. The complete remission (CR) rates in the first course and the second course of induction chemotherapy were respectively 82.93% (34/41) and 97.56% (40/41). The median EFS time and OS time were 30 months and 31 months respectively. The EFS rate and OS rate of children with CR after the first treatment course were significantly higher than those of children without CR (P＜0.05). The EFS rate of male children was significantly higher than that of female children (P＜0.05). The OS rate of children < 10 years old was significantly higher than that of children≥10 years old (P＜0.05). The expression level of RUNX1-RUNX1T1 gene after the second induction remission was the influencing factor of cumulative recurrence rate, EFS rate and OS rate in children (P＜0.05). Multivariate analysis by Cox regression model showed that the decreased levels of RUNX1-RUNX1T1 gene expression < 3 log after the second induction remission was the independent risk factor for EFS rate and OS rate in children (P＜0.05). The cumulative recurrence rate of children with RUNX1-RUNX1T1 gene expression increase for＞1 log after decreased 3 log was significantly higher than that of children with≤1 log (P＜0.05). Iuithally-treated AML children with t(8;21)/RUNX1-RUNX1T1+ show the fine clinical prognosis after standard chemotherapy. The expression level of RUNX1-RUNX1T1 gene should be closely relates with the recurrence and long-term survival of AML children.

Ultrasound diagnosis of oropharyngeal squamous cell carcinoma and ultrasound evaluation of treatment efficacy (changes in tumor volume)

The study objectiveis to assess the capabilities of ultrasonography in the diagnosis of oropharyngeal squamous cell carcinomas and in the evaluation of treatment efficacy (changes in tumor volume).Materials and methods.This study included 98 patients (27 (27.5 %) females and 71 (72.5 %) males aged between 20 and 78 years with oropharyngeal tumors; of them, 12 (12.2 %) patients had recurrent tumors. Sixty-seven (68.4 %) participants had their tumors located in the tonsils; 31 (31.6 %) patients had tumors of the root of the tongue; 47 (48.0 %) patients presented with tumors invading adjacent tissues; 57 (58.2 %) patients had their lymph nodes involved. Thirty-two patients were operated at the first stage of treatment, whereas 66 (67.3 %) individuals received induction chemotherapy followed by sequential chemoradiotherapy. Treatment efficacy was evaluated 2 weeks following the completion of the second course of induction chemotherapy. We assessed tumor volume, its structure, type and intensity of vascularization, and the number and size of lymph nodes affected by metastasis. Ultrasonography findings were compared with the results of fibroscopy, X-ray computed tomography (CT) and magnetic resonance imaging (MRI) performed 2 weeks following the completion of the second course of induction chemotherapy (no later than 7–10 days).Results.The disagreement between histology and ultrasonography findings reflecting tumor volume (of either newly diagnosed or recurrent tumor) was statistically insignificant. The results of X-ray CT were more likely to be in agreement with histology than the ultrasonography results (85.0 % vs 70.0 %); however, this difference was not statistically significant. Data of X-ray CT and ultrasonography on the tumor volume demonstrated no significant difference between them. MRI and ultrasonography findings on the tumor volume were consistent in 50 % of cases. We identified the most common changes in the structure of the oropharyngeal tumors typical of positive and negative dynamics after 2 courses of induction chemotherapy. Patients with positive dynamics demonstrated a significant decrease in tumor volume detected by all diagnostic methods used (ultrasonography, X-ray CT, and MRI). There was a significant negative correlation between the efficacy of treatment assessed by ultrasonography and the grade of therapeutic pathomorphosis assessed by histology (r = –0.69; р = 0.0014).Conclusion.The accuracy of ultrasonography for the estimation of oropharyngeal tumor volume and its spread is comparable with that of X-ray CT and MRI. The disagreement between these methods was statistically insignificant. Ultrasonography is a more sensitive method for the evaluation of patient response to treatment than clinical data.

Comparison of anthracyclines used for induction chemotherapy in patients with FLT3-ITD-mutated acute myeloid leukemia

This retrospective analysis compared anthracyclines (as part of an induction regimen) in 128 newly diagnosed FLT3-ITD-mutated AML patients. Induction regimens comprised high-dose daunorubicin (HD-DN; 90 mg/m2/d × 3d; n = 44), standard-dose daunorubicin (SD-DN; 45 mg/m2/d × 3d; n = 51), or idarubicin (IDA; 12 mg/m2/d × 3d; n = 33) in combination with cytarabine (100–200 mg/m2/d × 7d). Fifty-three patients showing persistent leukemia on interim bone marrow examination received a second course of induction chemotherapy comprising 2 days of daunorubicin (45 mg/m2/d) or IDA (8 or 12 mg/m2/d) in addition to 5 days of cytarabine. Complete remission (CR) rates were 77.3%, 56.9%, and 69.7% for HD-DN, SD-DN, and IDA, respectively (P = 0.101; HD-DN vs. SD-DN, P = 0.036; HD-DN vs. IDA, P = 0.453; IDA vs. SD-DN, P = 0.237). The HD-DN showed higher overall survival (OS) and event-free survival (EFS) than SD-DN and IDA: the differences between HD-DN and SD-DN (P = 0.009 for OS and P = 0.010 for EFS) were statistically significant.Results of in vitro studies using FLT3-ITD-mutated cell lines supported these findings. In conclusion, HD-DN improved the CR rate, OS, and EFS of FLT3-ITD-mutated AML patients. HD-DN also tended to yield better outcomes than IDA, though the difference was not significant. The superiority of HD-DN over IDA should be confirmed in future studies.

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

BackgroundInduction 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. Patients and MethodsIn 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. ResultsThe 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%. ConclusionThe 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.

BAALC Expression Is a Feasible Marker for Risk Stratification and Detection of Minimal Residual Disease in Cytogenetically Normal Acute Myeloid Leukemia

IntroductionDuring the last years it has been shown that PCR-based assessment of minimal residual disease (MRD) is of great importance for risk stratification and early detection of relapse in acute myeloid leukemia (AML). Most frequently, monitoring of MRD was restricted to patients carrying specific genetic markers such as fusion genes and gene mutations. However, many patients lack such markers amenable to sensitive detection by PCR. For this reason, it is still crucial to identify molecular targets that are applicable for MRD assessment in patients with AML. High brain and acute leukemia, cytoplasmic (BAALC) expression defines an important risk factor in cytogenetically normal AML (CN-AML) and has been proposed to represent a clinically useful biomarker to monitor response to therapy. A significant correlation of BAALC expression levels with the mutation ratio of internal tandem duplications in FLT3 (FLT3-ITD), partial tandem duplications in MLL (MLL-PTD) and NPM1 mutations has been shown previously (Weber et al., BCJ 2014). The objective of this study was to further validate the applicability of BAALC expression as a marker for detection of MRD.Patients and MethodsWe investigated BAALC mRNA expression levels in 550 diagnostic and follow-up samples from 116 de novo CN-AML patients showing high BAALC expression at initial diagnosis. BAALC mRNA expression was assessed by quantitative real-time PCR and normalized against the expression of the control gene ABL1. To identify high BAALC expressers the previously defined cutoff ratio of 33.1% BAALC/ABL1 (Weber et al., BCJ 2014) was used. The cohort was composed of 55 females (47%) and 61 males (53%). Age ranged from 18 to 85 years (median: 55). The median number of follow-up samples per patient was 3 (range: 1-21) with a median follow-up time of 32 months (range: 16-48 months). All patients included in this study were treated according to standard AML protocols in curative intent. In addition to BAALC expression, a full molecular characterization for the presence of FLT3 -ITD (42/116, 36%), MLL -PTD (10/116, 9%) and mutations in NPM1 (38/116, 33%) was performed.ResultsAt diagnosis, BAALC expression ranged from 33.2 to 5655.7% BAALC/ABL1 with a median of 163.9%. Of the 116 patients, 62 patients (53%) harbored at least one of the previously established MRD markers (FLT3-ITD, MLL-PTD and NPM1), while 54 patients (47%) lacked these MRD targets. To validate stability of BAALC expression we analyzed 25 patients with paired diagnostic and relapsed samples available. The respective BAALC expression levels at both time points showed good correlation (Mean % BAALC/ABL1 of diagnosis vs. relapse: 343.1 vs. 297.4, r=0.642, p=0.001). Three of the 25 patients relapsed after allogeneic stem cell transplantation. Also in these patients BAALC expression levels were similar between diagnosis and relapse (Mean %BAALC/ABL1: 686 vs. 684), supporting the use of BAALC expression for follow-up evaluation. Moreover, in 5 cases with cytomorphologic complete remission during follow-up a molecular relapse based on elevated BAALC expression levels (32.4-315.2% BAALC/ABL1) could be detected 21-42 days before cytomorphologic relapse. To investigate the predictive value of BAALC expression levels during follow-up, BAALC expression was analyzed in 58 patients after the second course of induction chemotherapy, but before start of consolidation chemotherapy. To separate low from high BAALC expression in this follow-up analysis, the cutoff established for diagnostic samples (33.1% BAALC/ABL1) was used. According to this cutoff, 29% (17/58) of the patients had high BAALC expression levels, while 71% (41/58) exhibited low BAALC expression levels. High BAALC expression was associated with a shorter EFS (median: 5 month vs. not reached, 1-year-EFS: 61% vs. 21%, p<0.001)ConclusionThis data validates the applicability of BAALC expression as a target for MRD monitoring in CN-AML. A significant number of CN-AML would benefit from molecular monitoring using a quantitative BAALC expression assay aimed at following disease course and early detection of relapse. DisclosuresWeber:MLL Munich Leukemia Laboratory: Employment. Alpermann:MLL Munich Leukemia Laboratory: Employment. Perglerová:MLL2 s.r.o.: Employment. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

The Use of Day 14 Bone Marrow Characteristics in the Decision to Pursue a Second Course of Induction Chemotherapy in the Treatment of Acute Myeloid Leukemia.

Abstract 2596 Background:Patients with acute myeloid leukemia (AML) receiving induction or salvage chemotherapy often undergo bone marrow evaluation around day 14 to determine early treatment response and guide decision-making regarding need for immediate re-induction therapy. However, the parameters that define whether or not to initiate such therapy are seemingly not always objective. Thus we sought to define what factors influence physicians' decisions to pursue a second course of induction chemotherapy in AML. Methods:We retrospectively reviewed 211 patients with newly diagnosed, relapsed, or refractory AML who received induction chemotherapy at the University of Washington /Fred Hutchinson Cancer Research Center from January 2008 to May 2012. 178 had a marrow aspirate and/or biopsy between days 13 to 17 after start of chemotherapy and were included in our “day 14” analysis. Bone marrows were assessed both morphologically and by multi-parameter flow cytometry (MFC). We used the Wilcoxon signed rank test and Fisher exact test to compare patient age, pre-treatment cytogenetics (SWOG criteria), newly diagnosed vs. relapsed or refractory AML, day 14 marrow cellularity, day 14 blast count by morphology or MFC, and induction regimen given on the first course (ara-C-containing vs. not) among patients who did and did not receive a second course of induction chemotherapy within 1 week of the “day 14” marrow. The second course could either be the same or different than the first course. Results:81% of the 178 patients had fewer than 10% blasts by morphology and MFC on day 14. None of these patients received course 2 within 1 week. 34 patients (19%) had greater than 10% blasts on the day 14 marrow by morphology or flow cytometry, of whom 18 (53%; 95% confidence interval 36–70%) received course 2 prior to day 21 and 16 (47%; 95% CI 30–64%) patients did not. As the decision of whether or not to begin course 2 within 1 week varied once blasts counts were >10%, we analyzed the 34 patients with >10% blasts between day 13–17 to assess what factors influenced the decision to begin a second course of treatment. The median age in those who received and did not receive course 2 within 1 week was 60 and 50.5, respectively (p=0.269). The fraction of newly diagnosed AML (as opposed to relapsed or refractory disease) in the two groups was 83% and 69%, respectively (p=0.429). The blast count by morphology was 69.5% in those who did vs. 24.4% in those who did not receive a second course within 1 week of the day 14 marrow (p=0.001) and by flow cytometry were 63% and 10%, respectively (p<0.001). 12 out of 27 (44%; 95% confidence interval 26–63%) patients who received ara-C on course 1 (“higher intensity”) received course 2 within 1 week of the first vs. 6 of 7 who received a lower intensity regimen on course 1 (p=0.09). 56% of the 9 patients with unfavorable cytogenetics received a second course within 1 week, as did the only patient with favorable cytogenetics, and 50% of those with intermediate risk cytogenetics. 1 of the 4 patients with hypocellular marrows on day 14 received a second course within 1 week as did 4 of the 5 with normocellular and 10 of the 21 with hypercellular marrows. Conclusions:Although day 14 blast percentages were significantly higher among patients who received a second course of induction chemotherapy within 1 week of the day 14 marrow, 47% of patients with >10% blasts in a day 14 marrow and 56% who received a higher intensity regimen on course 1 did not begin a second course during the next week despite National Comprehensive Cancer Network (NCCN) guidelines that they do. We are studying whether this reflects objective patient and marrow characteristics, such as change in blast count from pre-treatment to day 14 marrow, or other more subjective factors in clinical practice. Disclosures:Becker:Sanofi: Research Funding.

Lethal Pulmonary Hemorrhage Caused by &lt;i&gt;Stenotrophomonas maltophilia&lt;/i&gt; Pneumonia in a Patient with Acute Myeloid Leukemia

A 63-year-old man had been treated with intensive chemotherapy for acute myeloid leukemia. On the 49th hospital day, he had febrile neutropenia after the second course of induction chemotherapy. On the 53 rd hospital day, he presented with hemoptysis and developed acute respiratory failure requiring ventilator support within several hours. On the 54th hospital day, the patient died with hemorrhagic respiratory infection. Stenotrophomonas maltophilia was detected in bacterial cultures of his blood, bronchoalveolar lavage, and sputum. To our knowledge, nine cases of fatal hemorrhagic pneumonia caused by S. maltophilia have been reported in the literature. All the patients had hematological neoplasms and were severely neutropenic after one or two intensive chemotherapy regimens. They died shortly (within 3 days) after the onset of the hemorrhagic pneumonia. Management of the infection caused by S. maltophilia is hampered by high-level intrinsic resistance to multiple antibiotics and the increasing occurrence of acquired resistance to co-trimoxazole and fluoroquinolones. It would be important to keep in mind that hemorrhagic respiratory infection caused by S. maltophilia may lead to a fulminant and lethal course in severely neutropenic patients with hematological neoplasms and to recognize which antibiotic agents are more sensitive to S. maltophilia in each institution.

RAD001: A Clinico-Biological Phase I GOELAMS trial of Everolimus Association with High Dose Chemotherapy in Late Relapsing AML Patients Under 65 Years of Age

Abstract 945 Background:The mTORC1 signaling pathway is activated in nearly 100% of AML and is one of the key pathway of blast proliferation. RAD001 (Everolimus) is a specific mTORC1 inhibitor with demonstrated clinical activity in solid tumor. We present here a clinico-biological phase I trial combining RAD001 and chemotherapy in younger AML patients (NCT 01074086). Methods:Patients (pts) less than 65 years old with relapsing AML at least one year after CR following prior chemotherapy +/− auto or alloSCT were recruited from the GOELAMS centers from March 2008 to July 2011. The treatment regimen consisted of escalating doses of oral RAD001 at D1 and D7 + daunorubicin 60mg/m2 D1-3 and cytarabine CIV 200 mg/m2/d D1-7. In the absence of dose-limiting toxicity (DLT) after the inclusion of 3 patients, the RAD001 doses were escalated by 10mg over 7 dose levels (DL) from 10mg to 70mg. If there were more than 5% of bone marrow blasts on D15, a second course of induction chemotherapy was administered with daunorubicin 35mg/m2 on D17-D18 and cytarabine 1000mg/m2 BID on D17-D20. A plasma inhibitory activity (PIA) test reflecting the % of inhibition of p70S6K phosphorylation (a direct substrate of mTORC1) in MOLM-14 cells by the serum of the patients was performed. H0, H4, H24 and D7 serum samples were obtained for the DL 10 mg to 40mg and supplementary D3 and D5 samples were collected for the DL 50 and 60mg. Results:Twenty one pts have been included in this trial. Their median age was 50.3y (range 20–65); AML FAB subtypes were as follows: AML0=1, AML1=4, AML2=4, AML4=4, AML5=5, secondary AML=3. Cytogenetics evidenced 1 inv(16), 2 pts with abnormal intermediate risk, 14 normal, 3 poor risk cytogenetics while 1 patient had no available karyotypic information. Documented infections occurred in 16 subjects with grade 3 or more infections in 3 cases. Liver and lung mucormycosis along with appendicitis mass and a septic shock was observed in one patient at 10mg of RAD001. A Fournier gangrene occurred in another one at D40 at DL 50mg. Finally, for another pt, a Candida parapsilosis sepsis occurred on D20 of treatment on a central catheter at DL 50. Two grade 3 oral stomatites at the DL of 20mg and 30mg were observed, as well as 1 grade 3 digestive toxicity at DL 10mg, 2 grade 3 hemorragic events at DL 20mg and 30mg, 2 grade 3 total body erythema at DL 10 and 20mg, 2 grade 3 hepatic cytotoxicity at DL 20mg and 50mg, resolving in less than 14 days and 2 grade 2 renal toxicity at DL 20 and 60mg. None of these effects were considered to be directly related with RAD001. For each DL from 10mg to 40mg and 60mg, 3 pts were included according to the classical 3+3 inclusion schema. For DL 50mg, 6 pts were included as 2 grade>3 SAE have been observed at this level (hepatic dysfunction and fungal sepsis which resolved within 28 days of induction). Hematological toxicities duration were reported as usual (mean neutropenia duration 38 days (range 20–45), mean thrombocytopenia duration 40 days (range 30–65d)). The MTD was not attained at 60mg and accrual is ongoing at 70mg. Four deaths occurred in the study after D40 of induction but none in relation to RAD001 administration.Overall, 15/21 pts achieved CR (71%), among which 9 pts required a second induction course at D15. Four pts were allo-transplanted in CR. Clinical responses occurred across all dose levels but 8/9 pts obtained CR for DL 50mg and 60mg.As shown in Figure 1, the global exposure to RAD001 (as expressed by the area under the curve, AUC) increased with the dose. Using a PIA test in MOLM-14 cells (Figure 2), we observed that there was an excellent inhibition of p70S6K phosphorylation in almost all samples 4 hours after administration of RAD001 whatever the DL (mean decrease of 93%). However, this strong inhibition seems to be maintained until D1 only with 50mg and 60mg of RAD001 (mean decrease of 63% with 10 to 40mg of RAD001 vs 93% with 50 and 60mg). As expected, an increase of RAD001 DL induces an extended inhibition of the mTORC1 signaling pathway until D3 (decrease of 94% with 60mg vs 57% with 50mg). In contrast, at D5 and D7, phosphorylation of p70S6K is only barely affected. Conclusion:In this trial testing the association of RAD001 + chemotherapy, the MTD for RAD001 was not attained at DL 60mg. The CR rate was 71% and the PIA with 60mg of RAD001 seems to be promising. We conclude that these results could be improved with an increased DL of RAD001. The trial is therefore still ongoing with a DL of 70mg and updated results will be presented at the meeting. [Display omitted] [Display omitted] Disclosures:Park:Amgen: Honoraria; Janssen-Cilag: Honoraria; Celgene: Honoraria; Novartis: Research Funding. Off Label Use: RAD001. Merlat:Novartis: Employment.

Flow Cytometric Assessment of Post Induction Response In Patients with Sub-Optimal Morphologic Response to Induction Chemotherapy- A Report From the Children's Oncology Group AML Protocol AAML0531

AbstractAbstract 2740Initial response to induction chemotherapy is a significant predictor of outcome in leukemias. Data from MRC10 AML trial demonstrated that patients (pts) with ≤15% blasts at the end of induction I (EOI1), as determined by morphologic analysis, had a similar outcome as those in morphologic complete remission (mCR, <5% blasts), whereas those with >15% blasts have a significantly diminished survival. The COG Phase III AML protocol AAML0531 has enrolled 968 eligible pts with de novo AML as of March 31, 2010. Those with >15% blasts by morphologic assessment (persistent disease, mPD) at EOI1 are considered a high-risk cohort; those with 5% to 15% blasts (partial remission, mPR) were included in the standard-risk group. As part of AAML0531, pts choose to enroll on a biology study to evaluate treatment response by multidimensional flow cytometry (MDF) after 2 courses of therapy (EOI1 and EOI2). Here we directly compared the morphologic bone marrow (BM) response at EOI1 in pts with mPR or mPD with that assessed by MDF and correlated the remission status at EOI1 to the mCR rate at EOI2. Of the 900 pts with evaluable response data at EOI1, 628 (70%) entered mCR; 104 (12%) had mPR; 126 (14%) had mPD; and 42 (5%) either died (n=19) or had refractory CNS AML (n=23). All pts, regardless of their blast %, were eligible to receive the second course of induction chemotherapy per protocol. Of those with mPD at EOI1 and evaluable data by EOI2, 65 (59%) entered mCR; 1 died; and 44 (40%) had mPD. At EOI1, 180 pts did not enter mCR (80 had mPR, and 100 had mPD). MDF evaluation of those 180 BM specimens showed that 74 (41%) had no evidence of disease by MDF at EOI1. Of those 74 pts, 69 (93%) entered mCR at EOI2. In contrast, mCR at EOI2 for those with any level of disease by MDF at EOI1 was 49% (p<0.001). When a blast threshold of 5% by MDF at EOI1 was used to correlate with EOI2 response, those with 0.5% to 4.9% blasts at EOI1 had an EOI2 mCR rate of 68% compared to 41% in those with >5% blasts by MDF (p=0.013). Because they are in different risk groups, pts with mPR and those with mPD were evaluated separately for the presence of disease by MDF. Median blast % in pts with mPR was 7% (range 5%-15%). Of the 76 pts with mPR at EOI1 with an evaluable EOI2 response, 19 (25%) did not enter mCR at EOI2. At EOI1, morphologic BM response was compared to that by MDF. Of the 80 pts in mPR at EOI1, 43 (54%) had no evidence of AML by MDF; 17 (21%) had <5% blasts; and 7 (9%) in mPR had >15%. In pts in mPR who did not have AML by MDF (n=43), 39 had remission status available by EOI2: 34 (87%) entered mCR, and 5 (13%) had refractory disease (>5% blasts). Of the latter 5 patients, 4 had no evidence of disease by MDF. We subsequently evaluated BM status of the pts with PD by MDF at EOI1 and EOI2. Of those with mPD at EOI1, 62% entered mCR at EOI2. Of the 100 pts with mPD at EOI1 and MDF data for response evaluation, 31 had no evidence of disease by MDF, and all 25 with evaluable response by EOI2 entered mCR. In the remaining 69 pts, the presence of AML by MDF ranged from 0.05% to 95% (median 22%). Patients with mPD at EOI1 with any level of disease by MDF had a mCR rate of 41% at EOI2. Of the 16 pts with mPD and 0.5% to 4.9% blasts by MDF at EOI1, 14 had an evaluable EOI2 response: 11 (79%) entered mCR; 2 (18%) experienced treatment failure at EOI1; and 1 suffered extramedullary relapse. When the EOI1 evaluation was limited to the 53 patients with '5% blasts by MDF, the mCR rate at EOI2 was 30%. This study demonstrates a substantial discrepancy between morphologic and MDF assessments of induction BM specimens and highlights the need to implement MDF for accurate evaluation of remission status. We further demonstrate that a blast threshold of 5% by MDF at EOI1 may be an accurate predictor of response to the second course of therapy. Disclosures:No relevant conflicts of interest to declare.

An Unusual Radiologic Pattern of Cryptogenic Organizing Pneumonia: Diffuse Pulmonary Nodules in a Leukemia Patient

The radiological appearance of diffuse discrete pulmonary nodules associated with cryptogenic organizing pneumonia (COP) has been rarely described. We describe a case of COP in 49-year-old woman with acute myeloid leukemia who developed diffuse pulmonary nodules during the second course of induction chemotherapy. The clinical status of the patient and imaging findings suggested the presence of a pulmonary metastasis or infectious disease. A video-assisted thoracoscopic lung biopsy resulted in the unexpected diagnosis of COP as an isolated entity. Steroid therapy led to dramatic improvement of the clinical symptoms and the pulmonary lesions.

TBI and Allogeneic BMT Do Not Appear To Hinder Growth in Pediatirc Patients with AML Treated on POG 9421 (Now Children's Oncology Group).

The role of allogeneic bone marrow transplantation (BMT) in the treatment of pediatric patients (PT) with de novo AML continues to be discussed: Who should receive BMT? Should BMT be done during the first complete remission (CR)? In the POG 9421 trial 654 PTs with AML were genetically randomized between allogeneic BMT or a chemotherapy regimen; this protocol has been previously published. If a matched sibling was identified during induction, and CR was achieved, the PT received BMT after the second course of induction chemotherapy. The BMT preparative regimen consisted of Total Body Irradiation (TBI; 1200 cGy given as 150 cGy bid for 4 days) and high dose etoposide (60 mg/Kg IV over 4 hrs on day -3). Methotrexate and cyclosporine comprised the GVHD prophylaxis. The use of TBI in prepubertal children is a concern of many clinicians. We are analyzing growth and development data from the PTs who completed the induction and BMT regimen of POG9421 and present here the body mass index (BMI) findings from those PTs whose height and weight data were supplied to the COG Data Center. Of the 654 PTs registered on POG 9421, 32 were ineligible due to wrong diagnosis or major protocol violation. 501 non-Down Syndrome PTs were eligible for BMT if a matched sibling donor was located. 89 (17.8%) of the patients had a donor, proceeded to BMT, and were eligible for evaluation. Of those, 53 (60%) had data supplied for height (ht) and weight (wt) after BMT. Time from BMT ranged from 6 months to 5 yrs and PTs age at diagnosis ranged from 1–20 years. The height data were divided into 2 age groups, <= 10 yrs at diagnosis and > 10 yrs at diagnosis. The younger group consisted of 19 males and 12 females. Of these, 2 males and 2 females had heights that were below the 3rd percentile at last follow-up. The BMI data were then sorted into 2 age groups: <= 14 yrs and > 14 yrs at the time most recent ht and wt data were supplied. The mean age of the younger group was 7.6 yrs and and that of the older group was 17 yrs. The average BMI of the younger group was 18.19, and that of the older group was 22.85. The average time off therapy when the BMI was calculated was 2.3 yrs for both groups. In the young group, 3 males and 1 female were obese; in the older group, 2 males were overweight and 1 male and 1 female were obese. The median BMIs in the young group were 17 at the 84th percentile for females and 17.8 at the 65th percentile for males; those values in the older group were 19.6 for females and 21.3 for males. Percentile is not given for older patients. In conclusion, the BMT preparative regimen did not cause a severe acute change in BMI in this population. Overweight or obesity was not a common problem in this group, and after 4 yrs follow-up, short stature was not evident. Further data regarding stature will need to be evaluated to determine other long term growth effects of TBI and allogeneic BMT in the younger population with AML.

Early restaging whole-body 18F-FDG PET during induction chemotherapy predicts clinical outcome in patients with locoregionally advanced nasopharyngeal carcinoma

This study was undertaken to evaluate the utility of whole-body (18)F-FDG PET in monitoring therapeutic effect during induction chemotherapy (IC) and in predicting prognosis in patients with locoregionally advanced nasopharyngeal carcinoma (NPC). Fifty patients who had histologically proven, locoregionally advanced NPC without distant metastasis and had received IC were recruited in this study. The study cohort consisted of 19 females and 31 males (age 17-72 years, mean 45.9+/-11.9). Whole-body (18)F-FDG PET was performed in each patient after completion of one (33 patients) or two (17 patients) courses of IC. Each patient was restaged on the basis of the (18)F-FDG PET results. Patients who were downstaged to stage I or II were classified as major responders; the rest were classified as non-major responders. Only 1 of the 23 major responders subsequently developed local recurrence. At the time of data analysis, all major responders were alive; by contrast, of the 27 non-major responders, 15 had locoregional recurrence or distant metastasis and nine had died (seven of NPC and two of treatment-related complications). Kaplan-Meier survival analysis showed significantly longer recurrence-free survival and overall survival in major responders (56.4+/-9.2 and 58.1+/-2.2 months) as compared with non-major responders (33.7+/-23.2 and 44.7+/-20.0 months), with p<0.0001 and p=0.0024, respectively. The results of this study suggest that early restaging by a single whole-body (18)F-FDG PET scan after the first or second course of IC is useful for predicting therapeutic response and outcome in patients with locoregionally advanced NPC.

Induction chemotherapy and concomitant chemoradiotherapy (CRT) in patients with unresectable, locally advanced pancreatic carcinoma

4164 Background: The aim of our study was to evaluate the efficacy of chemoradiotherapy (CRT) in patients with unresectable locally advanced pancreatic cancer.Methods: Patients with unresectable, locally advanced pancreatic carcinoma were administered with induction chemotherapy consisted of 5-FU (500 mg/m2, iv bolus, days 1+8+15) and gemcitabine (1000 mg/m2, iv, days 1+8+15). A second course of the regimen was started on the 28th day. The patients who did not have any metastasis after the second course of induction chemotherapy were entered in the CRT phase which was consisted of gemcitabine (350 mg/m2, weekly, during radiotherapy) plus radiotherapy (5400 cGy, 30 fractions, 5 days a week). Patients who achieved response or stabilization with induction chemotherapy were administered 2 additional cycles of the same combined chemotherapy regimen after CRT. Response was evaluated by radiological examinations.Results: Fourteen patients were enrolled in the study. After the completion of the treatments, response was observed in 2 patients (1 CR, 1 PR; ORR %14.28) and stabile disease was observed in 3 patients (%21.42). Grade 3 myelosupression was observed in 3 patients (%21.42). No other Grade ¾ toxicities were observed. The median survival of the patients was 17 (4–40) months.Conclusions: Induction chemotherapy and concomitant CRT according to the current schedule is well tolerated and active treatment of unresectable, locally advanced pancreatic cancer. No significant financial relationships to disclose.

Mega-dose chemotherapy with peripheral blood stem cell transplantation (PBSCT) for small cell lung cancer (SCLC)

Feasibility and the efficacy of mega-dose chemotherapy with peripheral blood stem cell transplantation (PBSCT) for small cell lung cancer (SCLC) were evaluated. Autologous peripheral blood stem cell (APBSC) was collected after induction chemotherapy (Extensive disease: CDDP+etoposide+ADM, Limited disease: CDDP+etoposide) followed by the administration of granulocyte colony stimulating factor (G-CSF). Five cases of ED and 2 cases of LD have been entered in the protocol so far. PBSC was harvested after the second course of induction chemotherapy, and a sufficient number of PBSC (CFU-GM > or = 1 x 10(5)/kg) could be harvested and cryopreserved in all 7 cases. After completion of 4 courses of induction chemotherapy, three patients who achieved CR or good PR were treated by the combination of CBDCA (1,600 mg/m2) plus etoposide (1,600 mg/m2) followed by APBSCT and G-CSF. Hematologic recovery after APBSCT was rapid (absolute granulocyte count > 500/microliters: 9-11 day, Plt > 3 x 10(4)/microliters:10-14 day) and no infectious episode nor bleeding tendency occurred throughout the treatment period. Although grade 3 gastrointestinal toxicity was seen in one patient, the mega-dose chemotherapy with APBSCT in SCLC was considered safe and feasible. Further clinical trials are needed to establish the role of mega-dose chemotherapy for the treatment of SCLC.