High-Risk AML, Including Flt3ITD+, Exhibits Resistance To Conventional Cytarabine Induction Associated With Diminished ENT1 and p16INK Expression: Evidence For Epigenetic Repression and HDAC Inhibitor Modulated De-Repression

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2525-2525 ◽  
Author(s):  
H. Scott Boswell ◽  
Sushil Gupta ◽  
Rui Gao ◽  
Katie J Sargent ◽  
Larry D. Cripe ◽  
...  
Keyword(s):  
Hdac Inhibitor ◽  
Conflicts Of Interest ◽  
Normal Karyotype ◽  
Trisomy 13 ◽  
Epigenetic Mechanism ◽  
Remission Induction ◽  
High Dose ◽  
Event Free Survival ◽  
Free Survival ◽  
Poor Risk

Abstract Resistance to conventional induction chemotherapy involving continuous infusion cytarabine, 100mg/m2 X 7 days, has been observed in several poor-risk AML phenotypes including normal karyotype with Flt3ITD or DNMT3A mutations (JP Patel, NEJM; 2012). However, escalated anthracycline dosing along with conventional cytarabine was determined to confer superior survival among certain subgroups, including mDNMT3A, in the randomized E1900 trial. We asked whether optimal therapy among other AML molecular subgroups, where the former combination may be inferior, might preferentially require intermediate/high-dose cytarabine within induction regimens containing conventional anthracycline. This hypothesis was generated in recognition of diminished cytosine analog (cytarabine, azacytidine) transport by the rate-limiting equilibrative nucleoside transporter (ENT1) in poor-risk groups (J Hummel-Eisenbeiss, Mol Pharm, 2013) and observation of disparate cytarabine LC50’s among known AML subgroups: normal karyotype (NK), =/> 10 micromolar; CBF+ve, 1-4 micromolar. In an attempt to identify an impact of diminished ENT1 expression on successful remission induction at day+14 of conventional “7+3” therapy and/or associated severe limitation of event-free survival, an unselected group of 20 AML patients’ blasts were comparatively studied for ENT1 by immunoblot and/or quantitative RT-PCR, and as well were subjected to parallel analysis of p16INK4a transcripts, whose diminution, accompanying an epigenetic mechanism, is also implicated in poor treatment outcomes (HJ DeJonge, Blood; 2009). Median follow-up of the 20 patients exceeded 12 months. Among patients with high ENT1 expression by immunoblot (50kd species) were included CBF+ve and NK AMLs, of whom 7/8 pts. overall (2 CBF+ve, 1 NK-mNPM1, 1 NK-absent Flt3ITD, 2 NK Flt3ITD+, 1 complex/trisomy 13) had no evidence of leukemia on a day +14 marrow, and the event-free survival exceeded the 12 month mark. By contrast, among patients with 2-5-fold lower blast cell ENT1 expression were included a higher fraction of poor-risk (complex) karyotype or normal karyotype with Flt3ITD mutation (62%). These patients either had persistent disease at day +14, or had less than 3-month event-free survival. There was correspondence for differing ENT1 protein expressions with transcript quantity, and coupling between low/nondetection or high/detection of both ENT1/p16INK4, respectively, predicted divergent outcome of therapy from usual prognostic groups. Because the mechanism of repressed ENT1 transcriptional expression resulting from transduction of Flt3ITD gene in model AML systems is linked to transfactor c-jun interaction on the ENT1/SLC29A1 promoter, we tested the activity of tyrosine kinase/FLT3 inhibitor or HDAC inhibitor (SAHA), or their combination, on upmodulation of ENT1 in cultured primary blasts. In patient blasts in which phospho-c-jun expression was associated with diminished ENT1 expression, application of inhibitor(s) yielded downregulation of p-jun and upregulation of ENT1. This result supports an initiative to introduce both epigenetic agent(s) along with intermediate-dose cytarabine into induction therapy of certain poor-risk AML subgroups, including Flt3ITD+. Disclosures: No relevant conflicts of interest to declare.

Sorafenib Is Contributing to Salvage Chemotherapy and Is Effective Given Alone for Maintenance in AML FLT3 ITD Patients Relapsing Post Allo Hematopoietic Stem Cell Transplantation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5265-5265 ◽  
Author(s):  
Emilia Jaskula ◽  
Janusz Lange ◽  
Mariola Sedzimirska ◽  
Andrzej Lange
Keyword(s):  
Maintenance Therapy ◽  
Low Dose ◽  
Liver Toxicity ◽  
Conflicts Of Interest ◽  
Normal Karyotype ◽  
Salvage Chemotherapy ◽  
Remission Induction ◽  
Comparative Genomic ◽  
High Dose ◽  
Hematopoietic Stem

Abstract Normal karyotype AML patients with FLT3 ITD have a higher risk of relapse than those lacking this mutation (Estey EH, Am J Hematol. 2013). Our comparative genomic hybridization study (77 patients) showed that AML cases with as compared to those without FLT3 ITD had significantly lower number of amplifications or deletions (number of total CNV aberrations: 18±4 vs 51±8, p=0.003). The latter observation in concert with that of others (Thiede, Blood 2002) suggest that FLT3 ITD mutation if present in normal karyotype patients is a key player in the pathogenesis of leukaemia and targeting this mutation may be used successfully in FLT3 ITD positive patients relapsing post HSCT. This was also the case in the two patients presented in this study. Patient UPN 952, male, 53 years old, AML M4 (FAB), normal karyotype, received alloHSCT in 2 CR after completion of two lines of remission induction therapies (first: DA3+7 (Daunorubicin, Ara-C), HAM, high dose Ara-C; second: ICE (IDA, Ara-C, VP-16)) and then promptly transplanted. He relapsed 56 days after transplantation. Patient UPN 938, female, 50 years old, AML, normal karyotype, received as an induction DA 3+7, and for consolidation HAM and high dose Ara-C and completed only one course of the maintenance therapy and transplanted in CR. Both cases were transplanted from unrelated donors (10/10 HLA A, B, C, DR and DQ alleles matched), they received myeloablative conditioning (i.v. Busulfan and Cyclophosphamide) and Cyclosporin A as GvHD prophylaxis. At relapse they received salvage chemotherapy tailored to their biological performance (UPN 938 having Age Adjusted Charlson Comorbidity Index 3 received FLAG and UPN 952 with the index 9, ECOG 3, DA2+5). Both cases received in addition Sorafenib (two times 400 mg per day). The response was prompt and the marrow was free from blasts beginning from 11 day post chemotherapy. UPN 952 received as a maintenance only one course of 6-TG with low dose of Ara-C. Due to the substantial comorbidity and liver toxicity WHO3 further chemotherapy treatment was terminated. The patient was left only on Sorafenib (2 times 200 mg per day). UPN 938 was receiving the maintenance therapy (AML protocol) in 6 – 8 weeks intervals based on low dose Ara-C with 6TG or DNR and also Sorafenib (2 times 200 mg per day). In both cases FLT3 signalling pathway (FLT3 Pathway Mutation PCR Array, SABiosciences, Qiagen) revealed a lack of any additional mutation at the check points in FLT3, KRAS, HRAS, NRAS, MEK1, PIK3CA, BRAF and PTEN genes. UPN 938 had in addition to FLT3 ITD mutation c.1807_1808insATGAATATGATCTCAAAT (p.K602_W603insYEYDLK) insertion which relevance was not so far describe. Sorafenib resistance mutations were not found. The patients were on Sorafenib for 8 (UPN 938) and 9 months (UPN 952). The course of UPN938 was uncomplicated. The second case showed mild aGvHD symptoms evolving into cGvHD (skin lesions and dry eye) slowed down with rapamicine. Up to now the patients are in CR and free from FLT3 ITD. The main observation points: - Sorafenib with chemotherapy tailored to the biologic performance of patients contributes to the efficient salvage in patients with relapsing FLT3 ITD positive AML post HSCT and is also effective given alone as a maintenance. - Side effects were seen in one out of two patients likely associated with the blocking of VEGFR signalling transmission (hand foot skin rash, von Willebrandt factor activity – 388%). Conclusion: The use of multikinase inhibitor (Sorafenib) contributes effectively to salvage therapy in FLT3+ AML patients relapsing post alloHSCTSorafenib given alone is able to maintain long-lasting remissionSide effects are individually dependent Supported by NBiR CellsTherpy grant and Byer Health Care Disclosures No relevant conflicts of interest to declare.

scholarly journals Phase II Trial Daily Pulse Interleukin-2 Therapy with Famotidine during Marrow and Lymphocyte Recovery in Acute Myeloid Leukemia: LJCC 0605

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3783-3783
Author(s):  
Reed Friend ◽  
Ridas Juskevicius ◽  
Lauren Salmon ◽  
Hemant S. Murthy ◽  
James Xenakis ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Interleukin 2 ◽  
Hemodynamic Instability ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Event Free Survival ◽  
Eligibility Criteria ◽  
Free Survival ◽  
Acute Myelogenous ◽  
Wbc Count

Abstract Background: Therapeutic advances in treating Acute Myelogenous Leukemia (AML) have been limited in the past two decades. The outcome in patients over the age of 60 and those with high risk cytogenetics remains particularly poor with less than 10% of patients in this age group being cured. High dose Interleukin-2 (IL2) alone in relapsed AML has been shown to induce complete remissions. In this study we report the overall survival (OS), event free survival (EFS), responses and tolerability with IL2 therapy administered during marrow/lymphocyte recovery during induction, re-induction or consolidation. Methods: Eligibility criteria included confirmed hematopathology diagnosis of AML according to WHO classification (not including acute promyelocytic leukemia) receiving marrow suppressive treatment, a total WBC count above 500 mm3, supported platelet count above 20,000, serum creatinine ≤ 2.0 mg/dl, total bilirubin and AST < 3x upper limit of normal and hemodynamic stability. Famotidine 20 mg IV push daily was administered just prior to the IL2. IL2 therapy was infused at 18 million IU/m2 in 50ml 5% D5 or NS IVPB over 15-30 minutes daily for 5 days. Pre-medication prior to each pulse IL2 dose included acetaminophen 650 mg PO, odansetron 8mg IV, and meperidine 25 mg IV. Results: 18 pts enrolled with 12 receiving IL2 infusion. The median age was 57.5 (range 32-72). 67% women, 33% men. 8 of 12 patients had AML with myelodysplasia-related changes (including complex cytogenetics), 2 AML with inv(16), 1 AML with 11q23 translocation and 1 therapy-related AML. Median bone marrow blast percentage at diagnosis was 62% (range 32-96). 3 pts received IL2 during induction recovery, 1 during re-induction recovery, 8 during consolidation recovery. 2 pts subsequently underwent allogeneic stem cell transplantation in remission. Median follow up was 328 days (range 99-3207). Estimated 18 month overall and event free survival was 42% (CI 0.15-0.67). Of the 4 pts alive past 4 years, 3 had complex cytogenetics, 2 were greater than age 60. IL2 infusion was well tolerated without any grade 4 toxicities or hemodynamic instability requiring ventilator or hemodynamic support. Conclusion: IL-2 therapy administered during marrow/lymphocyte recovery after standard induction/consolidation chemotherapy in AML treatment achieved a 33% 4 year overall and event free survival. Disclosures No relevant conflicts of interest to declare.

Rituximab-Supplemented High-Dose Sequential Chemotherapy (HDS) Has Superior Response Rate and Event-Free Survival (EFS) Compared to R-CHOP in Poor Risk Follicular Lymphoma (FL) at Diagnosis: Results from a Multicenter Randomized GITMO Trial.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 675-675 ◽  
Author(s):  
Marco Ladetto ◽  
Irene Ricca ◽  
Fabio Benedetti ◽  
Umberto Vitolo ◽  
Caterina Patti ◽  
...  
Keyword(s):  
High Risk ◽  
Residual Disease ◽  
High Dose ◽  
Event Free Survival ◽  
Bulky Disease ◽  
Free Survival ◽  
Poor Risk ◽  
Sequential Administration

Abstract Introduction. HDS with autografting has proved to be effective (Corradini et al, J Clin Oncol 2004) and feasible at the multicenter level in FL (Ladetto et al, Blood 2002); in addition, it can be successfully combined with Rituximab (R-HDS) (Magni et al, Blood 2000). Aim of this trial was to compare R-HDS with Rituximab-supplemented CHOP (R-CHOP) in poor risk FL patients (pts) younger than 60 years. Patients and methods. Between January 2000 and March 2005, 136 patients have been randomized (68 in each arm). Patients were stratified according to histology (grade I or II 101, grade III 35). Patients were eligible if they had an age-adjusted IPI ≥2 (125 pts) or, in the absence of this criterion if they had three or more adverse parameters according to the Italian Lymphoma Intergroup score (11 pts). Clinical features were: median age 50 yrs. (22–60), stage III-IV 98%, elevated LDH 78%, bulky disease 66%, B symptoms 47%, extranodal disease (other than BM) 45%, leukemic disease 11%, ECOG PS &gt;1 47%. R-HDS consisted of: i. 2 APO and 2 DHAP courses; ii. sequential administration of Etoposide (2 g/sqm), 2 Rituximab, Cyclophosphamide (Cy) (7g/sqm) with PBPC collection (in vivo-purged with two Rituximab on day 1 and 11 post Cy); iii. Mitoxantrone (60mg/sqm) + L-Pam (180mg/sqm) with autografting (5–8x106 CD34+ cells/kg). R-CHOP consisted of 6 CHOP courses followed by 4–6 doses of Rituximab as originally reported (Rambaldi et al, Blood 2002). Cross-over was allowed for patients failing R-CHOP. Minimal residual disease analysis with the bcl-2/IgH was planned on BM cells. Patients were assessed on an “intention to treat” basis. Results. The two treatments arms were well balanced for all the previously described clinical parameters. 68% patients were able to conclude R-CHOP (failure due to progression 29% and toxicity 3%) and 78% R-HDS (failure due to progression 9%, toxicity 5%, poor mobilization 4 %, refusal 4%). Toxic deaths were 4 (2 in each arms); in addition 1 gastric cancer and 1 AML occurred in the R-HDS group. Progressions and non-responders were 35% in the R-CHOP arm and 13% in the R-HDS (p&lt;0.05) with 53% and 82% CR rates, respectively. Current median follow-up is 24 months. Event-free survival (EFS) at 24 months is 41% for the R-CHOP arm and 66% for the R-HDS arm (p&lt; .001). At present there is no difference in terms of OS. We currently have data on salvage treatment in 22 patients failing R-CHOP: 16 of them were treated with R-HDS, with 10 achieving CR. A molecular marker was available in 72% of patients. PCR results at follow-up are available in 27 patients. Molecular remission, defined as two PCR-negative BM samples taken at six months intervals, was observed in 54% of R-CHOP and 77% of R-HDS patients. Conclusions. R-HDS induces a greater number of CR and ensures a better EFS compared to R-CHOP in this rare and extremely aggressive population of high-risk FL patients. It is unknown if these results reflect a peculiar behaviour of high-risk patients or can be relevant for all younger FCL patients with advanced disease requiring cytoreductive treatments.

Primary Clinical Research of FA Regimen as Consolidation Therapy for Patients with Acute Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4380-4380
Author(s):  
Huina Lu ◽  
Wei Qin ◽  
Aibin Liang
Keyword(s):  
Complete Remission ◽  
Myeloid Leukemia ◽  
Recovery Time ◽  
Conflicts Of Interest ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Event Free Survival ◽  
Free Survival ◽  
Nonhematologic Toxicity ◽  
Wbc Count

Abstract Abstract 4380 In our study, 28 patients with AML treated in our department between 2004 and 2009 under complete remission, median age of 54 years (range 23–77) were consolidated with FA regimen which included fludarabine 30mg/m2 (days 1–3) and Ara-C 2g/m2 (days 1–3). Ara-C were administered as a continuous sequential infusion 4 hours later when the application of fludarabine had been over. Another 14 AML patients with matched conditions treated with high dose Ara-C (HDAra-C, 3g/m2, q12h×3d) were designated as controls. Event-free survival of both 2 groups of these patients were analysed. Overall, 14 patients (50%) achieved continuous complete remission for more than 2 years. There is no statistically significant differences between FA group and HDAra-C group (P=0.214>0.05) in CCR. Patients aged >60 years also had no statistically significant differences compared to the patients aged <60 years in CCR. Seven patients relapsed after this treatment in a median survival of 11 months. Two of the relapsed patients had karyotype abnormalities and all of them had a markedly elevated WBC count at diagnosis. The main toxicity was myelosuppression. WBC count and platelet count reached the lowest (about 0.8×10^9/L and 2.0×10^9/L) 6–13 days after the begining of the regimen. Median recovery time for granulocyte (≥1.0×10^9/L) and platelet (≥20×10^9/L) was 12 and 13 days, respectively. Fever(>38°C) caused by granulopenia occurred in 21 patients, recovered to normal for a median time of 5 days (range, 2–23). Heart, liver and enteric toxicity were negligible. There were no significant differences in hematologic toxicity or nonhematologic toxicity between the FA and HDAra-C group. The average hospitalization was about 20 days. The FA is effective and safe as consolidation regimen in AML with acceptable toxicity and is not associated with an increased incidence of infections compared to conventional HDAra-C regimen. Disclosures: No relevant conflicts of interest to declare.

scholarly journals MBCL-37. CHEMOTHERAPY STRATEGIES FOR YOUNG CHILDREN NEWLY DIAGNOSED WITH CLASSIC (CLMB) OR ANAPLASTIC/LARGE CELL (A/LCMB) MEDULLOBLASTOMA UP TO THE ERA OF MOLECULAR PROFILING – A COMPARATIVE OUTCOMES ANALYSIS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii396-iii397
Author(s):  
Jonathan Finlay ◽  
Martin Mynarek ◽  
Girish Dhall ◽  
Claire Mazewski ◽  
Richard Grundy ◽  
...  
Keyword(s):  
Head Start ◽  
Young Children ◽  
Induction Chemotherapy ◽  
Treatment Strategies ◽  
Large Cell ◽  
High Dose ◽  
Event Free Survival ◽  
Standard Chemotherapy ◽  
Outcomes Analysis ◽  
Free Survival

Abstract BACKGROUND/OBJECTIVE The introduction of German regimens, supplementing “standard” chemotherapy with both intravenous high-dose (HD-MTX) and intraventricular (IVENT-MTX) methotrexate, and North American regimens incorporating marrow-ablative chemotherapy with autologous hematopoietic cell rescue (HDCx+AuHCR), report encouraging outcomes for young children with medulloblastoma. We performed a comparative outcomes analysis of treatment strategies for young children with ClMB or A/LCMB. DESIGN/ METHODS Data from 12 prospective multi-center trials published between 2005 and 2019 for children &lt;six-years-old with ClMB or A/LCMB were reviewed; survivals were compared. RESULTS COG-9921, UKCCSG-CNS9204, COG-P9934 and SJYCO7 employing standard chemotherapy with either no or risk-based irradiation, reported 3-5-year event-free survival (EFS) of 17+/-5%, 33+/-28% (ClMB), 14+/-7% and 13.8+/-9% (ClMB) respectively, with reported EFS of 0% for A/LCMB in UKCCSG-CNS9204 and SJYCO7. HIT-SKK’87, HIT-SKK’92 and HIT-SKK’00 incorporating HD-MTX and IVENT-MTX reported 2-10-year EFS of 30–34+/-10–11% for ClMB and 33+/-27% (HIT-SSK’00) for A/LCMB. Head Start HS-I-II combined, CCG-99703 and HS-III employing induction chemotherapy, with or without HD-MTX, followed by single or tandem HDCx+AuHCR reported 3-5-year EFS of 42+/-14%, 50+/-11% and 27+/-6% for ClMB, with EFS for A/LCMB of 38+/-13% (HS-III). Finally, 5-year overall survivals for ACNS0334, without or with induction HD-MTX, are 39% and 69% respectively for ClMB and A/LCMB combined. CONCLUSIONS A trend towards better outcomes for young children with ClMB and A/LCMB is observed in trials including either HD-MTX and IVENT-MTX or including HD-MTX-containing induction chemotherapy and HDCx+AuHCR. Trials excluding HD-MTX, IVENT-MTX and HDCx+AuHCR have poorer outcomes.

Impact of Three Courses of Intensified CHOP Prior to High-Dose Sequential Therapy Followed by Autologous Stem-Cell Transplantation As First-Line Treatment in Poor-Risk, Aggressive Non-Hodgkin's Lymphoma: Comparative Analysis of Dutch-Belgian Hemato-Oncology Cooperative Group Studies 27 and 40

2005 ◽  
Vol 23 (16) ◽  
pp. 3793-3801 ◽  
Author(s):  
Gustaaf W. van Imhoff ◽  
Bronno van der Holt ◽  
Marius A. MacKenzie ◽  
Mars B. van′t Veer ◽  
Pierre W. Wijermans ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Sequential Therapy ◽  
Hodgkin's Lymphoma ◽  
High Dose ◽  
Cooperative Group ◽  
Free Survival ◽  
Poor Risk

Purpose Timing, appropriate amount, and composition of treatment before high-dose therapy and autologous stem-cell transplantation (ASCT) in patients with poor-risk, aggressive non-Hodgkin's lymphoma (NHL) are still unknown. We conducted two consecutive multicenter phase II trials with up-front, high-dose, sequential chemotherapy and ASCT in poor-risk, aggressive NHL. Both trials had identical inclusion criteria and only differed in amount and duration of induction treatment before ASCT. Patients and Methods Between 1994 and 2001, 147 newly diagnosed, poor-risk, aggressive NHL patients, age ≤ 65 years with stage III to IV and lactate dehydrogenase (LDH) more than 1.5× upper limit of normal (ULN), entered the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON) -27 and HOVON-40 trials. Treatment in HOVON-27 consisted of two up-front, high-dose induction courses followed by carmustine, etoposide, cytarabine, and melphalan plus ASCT in responding patients. In HOVON-40, the same treatment was preceded by three intensified courses of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Results Patient characteristics in both trials were comparable: 80% had diffuse large B-cell lymphoma, 77% had stage IV disease, and median LDH levels were 3.1× ULN. Complete remission (CR) in both trials was 45% to 51%. Before ASCT, CR was 14% in HOVON-27 versus 28% in HOVON-40 (P = .03). Treatment failure was similar (27%). Four-year survival estimates in HOVON-27 compared with HOVON-40 were overall survival, 21% v 50% (P = .007); event-free survival, 15% v 49% (P = .0001); and disease-free survival, 34% v 74% (P = .008). This different outcome favoring HOVON-40 remained highly significant when correcting for competing risk factors in multivariate analysis. Conclusion In patients with poor-risk, aggressive NHL, addition of intensified CHOP before up-front, high-dose, sequential therapy and ASCT significantly improved the duration of response and survival.

scholarly journals The Molecular Basis of Long First Remissions in Normal Karyotype AML Patients

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3827-3827
Author(s):  
Francesca Ferraro ◽  
Christopher A Miller ◽  
Amy Abdalla ◽  
Nichole Helton ◽  
Nathan Salomonis ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Somatic Mutations ◽  
Conflicts Of Interest ◽  
Normal Karyotype ◽  
High Dose ◽  
Intermediate Risk ◽  
The Mean ◽  
Cebpa Mutations

Currently, it is not clear why some patients with acute myeloid leukemia (AML) can be "cured" with chemotherapy alone; are they living with small amounts of disease that is held in check by immunologic (or other) mechanisms, or is their disease really eradicated? The percentage of cytogenetically normal AML patients who have long (>5 years) first remissions (LFRs) after chemotherapy alone is low (about 9.1% in patients <60 years and 1.6% in >60 years1). For this reason, most intermediate risk patients are offered allogeneic transplantation to decrease their risk for relapse. To better understand mechanisms of chemotherapy sensitivity in AML, we performed an analysis of the mutation landscape and persistence, using samples from 8 normal karyotype LFR patients (without CEBPA mutations) who received standard "7+3" induction and high dose cytarabine consolidation as their only therapy. The mean age at diagnosis was 43.5 years, and the mean follow up in first remission is 7.6 years; none of these patients has relapsed to date. For each case, we performed enhanced exome sequencing at diagnosis (235x coverage of the entire exome, and ~1008x coverage of recurrently mutated AML genes). Each case had at least one documented AML driver mutation, with a median of 29 somatic mutations in the exome space. We created probes for 225 mutations (mean 28 per case), and performed error-corrected sequencing (Haloplex) for all available remission samples. The mean depth of Haloplex coverage was 1607x, and each sample had at least one AML-specific mutation assayed, with a sensitivity of 1 cell in 1,750 (0.06%). 7/8 patients demonstrated complete clearance of all mutations in all remission samples tested, which was confirmed with digital droplet PCR for 5 cases, with a sensitivity of detection of 1 cell in 100,000. In one case, we detected a persistent ancestral clone harboring DNMT3AR882H, which can be associated with long first remissions for some patients2. Strikingly, the founding clone in all 8 cases had one or more somatic mutations in genes known to drive cell proliferation (e.g. MYC, FLT3, NRAS, PTPN11, Figure 1 top panel). These are usually subclonal mutations that occur late during leukemic progression, suggesting that the presence of a "proliferative hit" in the founding clone might be important for chemotherapy clearance of all the AML cells in a given patient. To support this hypothesis, we analyzed the mutational clearance of 82 AML cases with paired diagnosis and day 30 post-chemotherapy bone marrow samples. We observed that, whether present in the founding clone or in subclones, mutations in MYC, CEBPA, FLT3, NRAS, and PTPN11 cleared after induction chemotherapy in all samples, while other mutations were often persistent at day 30 (e.g. DNMT3A, IDH1, IDH2, NPM1, TET2; Figure 1 bottom panel). Compared to other published sequencing studies of AML, MYC and NRAS mutations were significantly enriched in this small cohort (MYC p= 0.002, and NRAS p= 0.034), with MYC enrichment being particularly striking (37.5% versus 1.8%). All MYC mutations were canonical single base substitutions occurring in the highly conserved MYC Box 2 domain at the N-terminus of MYC (p.P74Q or p.T73N). Overexpression of MYCP74Q in murine hematopoietic progenitors prolonged MYC half life (89 min vs. 44 min for wild type), and enhanced cytarabine sensitivity at all concentrations tested (range 10-1000 nM, p=0.0003), both in vitro and in a MYC-driven leukemia model in vivo. MYC expression measured with flow cytometry in the blasts of the LFR samples was significantly higher (p=0.045) compared to unfavorable risk (complex karyotype) or other intermediate risk categories, but similar to good risk AML (biallelic CEBPA mutations, core binding factor fusion-associated AML, and AML with isolated NPMc), suggesting that activation of the MYC pathway may represent a shared feature of chemosensitive patients. Taken together, these data suggest that some intermediate patients who are effectively "cured" with chemotherapy alone may not have persistent subclinical disease, nor retained ancestral clones that could potentially contribute to relapse. Importantly, these patients often have mutations driving cell proliferation in the founding clone, indicating that the presence of specific mutations in all malignant cells may be critical for complete AML cell clearance with chemotherapy. 1. Blood Adv. 2018 Jul 10; 2(13): 1645-1650 2. N Engl J Med 2018; 378:1189-1199 Disclosures No relevant conflicts of interest to declare.

Intensification of preoperative chemotherapy for osteogenic sarcoma: results of the Memorial Sloan-Kettering (T12) protocol.

1998 ◽  
Vol 16 (7) ◽  
pp. 2452-2458 ◽  
Author(s):  
P A Meyers ◽  
R Gorlick ◽  
G Heller ◽  
E Casper ◽  
J Lane ◽  
...  
Keyword(s):  
Preoperative Chemotherapy ◽  
Osteogenic Sarcoma ◽  
Cancer Center ◽  
High Dose ◽  
Event Free Survival ◽  
Histologic Response ◽  
Free Survival ◽  
Subsequent Event ◽  
Localized Disease ◽  
Resected Primary Tumor

PURPOSE It has been observed previously in osteosarcoma (OS) that the degree of necrosis of the resected primary tumor following a period of preoperative chemotherapy is predictive of subsequent event-free survival (EFS). The aim of this study was to determine if more intensive preoperative chemotherapy would increase the proportion of patients with a good histologic response and improve EFS. PATIENTS AND METHODS Seventy-three patients with OS were treated at Memorial-Sloan Kettering Cancer Center (MSKCC) on the T12 protocol between 1986 and 1993. Patients were randomized between therapy based on the T10 protocol and therapy with more intensive preoperative chemotherapy. The more intensive preoperative regimen consisted of two courses of cisplatin (CDDP) and doxorubicin (DOX) in addition to the usual preoperative regimen of high-dose methotrexate (HD MTX) and bleomycin, cyclophosphamide, and dactinomycin (BCD). RESULTS The regimen with more intensive preoperative chemotherapy achieved a modest increase in the proportion of patients with a good histologic response (44% with a grade III or IV histologic response v 37% in the control arm, 33% with grade IV histologic response v 13% in the control arm). EFS continued to correlate with histologic response. The actuarial 5-year EFS in patients with localized disease was 78% for the regimen with more intensive preoperative chemotherapy and 73% for the control arm. CONCLUSION Despite modest increases in the proportion of patients with good histologic response with intensified preoperative chemotherapy, no improvement in EFS was observed.

Experience With 2-Chlorodeoxyadenosine in Previously Untreated Children With Newly Diagnosed Acute Myeloid Leukemia and Myelodysplastic Diseases

2001 ◽  
Vol 19 (11) ◽  
pp. 2804-2811 ◽  
Author(s):  
R. A. Krance ◽  
C. A. Hurwitz ◽  
D. R. Head ◽  
S. C. Raimondi ◽  
F. G. Behm ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Allogeneic Bone Marrow Transplantation ◽  
Myelogenous Leukemia ◽  
Remission Induction ◽  
Allogeneic Bone ◽  
Event Free Survival ◽  
Free Survival ◽  
Secondary Aml ◽  
Acute Myelogenous ◽  
French American British

PURPOSE: To develop more effective chemotherapy regimens for childhood acute myelogenous leukemia (AML). PATIENTS AND METHODS: Between June 1991 and December 1996, we administered the nucleoside analog 2-chlorodeoxyadenosine (2-CDA) to 73 children with primary AML and 20 children with secondary AML or myelodysplastic syndrome (MDS). Patients received one or two 5-day courses of 2-CDA (8.9 mg/m2/d) given by continuous infusion. All patients then received one to three courses of daunomycin, cytarabine, and etoposide (DAV) remission induction therapy. RESULTS: Seventy-two patients with primary AML were assessable for response. Their rate of complete remission (CR) was 24% after one course of 2-CDA, 40% after two courses of 2-CDA, and 78% after DAV therapy. Of the 57 patients who entered CR, 11 subsequently underwent allogeneic bone marrow transplantation (BMT), and 40 underwent autologous BMT. Twenty-nine patients remain in continuous CR after BMT. Two patients remain in CR after chemotherapy only. The 5-year event-free survival (EFS) estimate was 40% (SE = 0.080%). Patients with French-American-British (FAB) M5 AML had a higher rate of CR after treatment with 2-CDA (45% after one course and 70.6% after two courses) than did others (P = .002). In contrast, no patient with FAB M7 AML (n = 10) entered CR after treatment with 2-CDA. Similarly, no patient with primary MDS (n = 6) responded to 2-CDA. Seven patients with secondary AML or MDS (n = 14) had a partial response to one course of 2-CDA. CONCLUSION: This agent was well tolerated, and its toxicity was acceptable. Future trials should examine the effectiveness of 2-CDA given in combination with other agents effective against AML.

Sign in / Sign up

Export Citation Format

Share Document