Clinical Outcome of Therapy-Related Acute Myeloid Leukemia Is Strongly Related to Cytogenetic Analysis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1401-1401
Author(s):  
Croix Fossum ◽  
Rhett P. Ketterling ◽  
Lindsey E. Roeker ◽  
Ajoy L. Dias ◽  
Michelle Elliott ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Hodgkin Lymphoma ◽  
Alkylating Agent ◽  
De Novo ◽  
Disease Course ◽  
Primary Malignancy ◽  
Non Hodgkin Lymphoma ◽  
Cytogenetic Profile ◽  
De Novo Aml

Abstract Background: Treatment-related AML (t-AML) accounts for 10 to 20% of all AML cases and carries an especially poor prognosis (Kayser et al. 2011, Godley et al. 2008). Patients diagnosed with t-AML are likely to have abnormal cytogenetic profiles with chromosome changes that are predictive of an aggressive malignancy, poor response to therapy, and decreased overall survival(Smith et al. 2003). The simultaneous use of multiple chemotherapeutic agents of different classes makes it increasingly difficult to predict risk for developing t-AML and determining disease course. An updated analysis of predictive factors for t-AML is needed so clinicians can more accurately inform patients of their prognosis. The aim of this study was to classify t-AML according to primary malignancy, previous chemotherapy exposure, and cytogenetic profile. Methods: A retrospective chart review of patients that were diagnosed with AML at Mayo Clinic from 7/1/1990 to 5/13/2015 was performed following IRB approval. AML patients found to have a previous malignancy treated with chemotherapy were classified as t-AML. Chemotherapeutics were classified as alkylating agents, antimetabolites, anti-tubulin agents, and topoisomerase II inhibitors. Patients diagnosed with a myelodysplastic or myeloproliferative disorder prior to development of AML were excluded from this study. Previous chemotherapy exposures, duration of chemotherapy exposure, complete blood count, chromosome abnormalities, and survival data were collected for t-AML cases. Cytogenetic changes were classified as favorable, intermediate, and adverse according to the system used by Kayser et al. 2011. JMP 10.0 was used for statistical analysis. Results: Out of 584 patients, 64 patients (11%) had a primary malignancy that was treated with chemotherapy prior to being diagnosed with AML. The most common primary malignancies were breast cancer (31%), non-Hodgkin lymphoma (27%), colorectal cancer (8%), and Hodgkin lymphoma (8%). Laboratory findings showed median hemoglobin 9.6 g/dL (4.7-13.8), median white blood cells 3.2 x109 (0.6-126), median platelets 50x109 (3-320), median peripheral blood blasts of 8% (0-91), and median bone marrow blasts 38% (1-94). 95% of patients diagnosed with t-AML had been previously treated with an alkylating agent. Additional exposure to an anti-metabolite trended towards a more adverse cytogenetic profile (χ2=5.0, p=0.08) but there was not a statistically significant decrease in overall survival (KM analysis, p=0.31). The median overall survival for patients diagnosed with t-AML was 10.2 months compared to 19.2 months for patients with de-novo AML (KM analysis, p=0.04). Adverse cytogenetic profiles were associated with decreased survival (KM analysis, p <0.0001). However, there was no difference in overall survival between patients with t-AML that had intermediate cytogenetics and those with de-novo AML (KM analysis, p=0.36). None of the chemotherapy classes other than antimetabolites were associated with poor cytogenetics or survival when combined with an alkylating agent. Conclusion: Over half of all patients classified as having t-AML in this study received prior chemotherapy for breast cancer or non-Hodgkin lymphoma. Cytogenetic classification of t-AML into favorable, intermediate and adverse groups is useful in predicting disease course. Interestingly, t-AML patients with intermediate risk cytogenetics had similar overall survival to patients with de-novo AML. This suggests that the poor outcomes observed in patients with t-AML is predominantly due to the subset with adverse cytogenetics. Thus, cytogenetic analysis remains the best indicator of overall survival regardless of chemotherapy exposure. Additional work is needed to delineate the risk associated with the aforementioned chemotherapy classes. Disclosures Al-Kali: Celgene: Research Funding.

Treatment-Related AML Is An Independent Adverse Prognostic Factor for Relapse-Free and Overall Survival. An Analysis of 2,868 Adult Patients with Newly Diagnosed AML Enrolled On Seven AMLSG Treatment Trials.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 578-578
Author(s):  
Sabine Kayser ◽  
Konstanze Doehner ◽  
Juergen Krauter ◽  
Heinz A. Horst ◽  
Marie von Lilienfeld-Toal ◽  
...  
Keyword(s):  
Overall Survival ◽  
Prognostic Factor ◽  
De Novo ◽  
Negative Impact ◽  
Adult Patients ◽  
Newly Diagnosed ◽  
Primary Malignancy ◽  
Adverse Prognostic Factor ◽  
De Novo Aml ◽  
Independent Adverse Prognostic Factor

Abstract Abstract 578 Background: Therapy-related AML (t-AML) is a recognized clinical syndrome occurring as a complication following cytotoxic and/or radiation therapy. The etiology and specific factors that predispose to t-AML largely remain unknown. Survival of t-AML patients has been poor compared with that of patients with de novo AML. However, there is a paucity of studies evaluating the impact of t-AML as a risk factor, in particular in the context of other clinical and biological prognostic markers. Aims: To study the clinical impact of t-AML in a large cohort of patients with newly diagnosed AML, in the context of clinical characteristics as well as cytogenetics and mutational status of the NPM1 and FLT3 genes. Methods: The study included 3,139 adult patients (median age, 53.5 years; range, 16-85 years) with newly diagnosed AML entered on 7 protocols of the German-Austrian AML Study Group (AMLSG) between 1993 and 2008. In all protocols intensive induction and consolidation therapy was used. Information on type of AML, karyotype and molecular marker status of NPM1 and FLT3 (internal tandem duplication [ITD] and tyrosine kinase domain mutation [TKD]) was availabel in 2,858 of 3,139 (91%) and 2,126 of 3,139 (68%) patients, respectively. Since this report focuses on the comparison of t-AML versus de novo AML, patients with secondary AML following myelodysplastic syndrome (s-AML) and those lacking information on type of AML were excluded (n=151, n=120, respectively). Results: Two hundred of the 2,868 patients (7%) were classified as t-AML. In more than two thirds of t-AML cases, a solid cancer was the primary malignancy with breast cancer being the most common (55%), followed by gastrointestinal (7.5%), prostate (7%) and testicular cancer (7%). In 27% of the cases, a hematologic neoplasm was the primary malignancy with non-Hodgkin (43%) and Hodgkin lymphoma (35%) being the most common. Three patients received cytotoxic treatment for autoimmune diseases. The median latency period between diagnosis of primary malignancy and occurrence of t-AML was 4 years (range, 4 months to 44 years). Patients with t-AML were significantly older compared to patients with de novo AML (58 versus 53 years; p<0.0001), and they had significantly lower median white blood counts (WBC) (7.4 vs 12.5 ×109/L; p=0.002). The frequencies of cytogenetic risk groups in t-AML versus de novo AML were as follows: favorable [t(8;21), t(15;17), inv(16) or t(16;16)] (16% vs. 16%), intermediate [all cytogenetic abnormalities not classified as favorable or adverse] (46% vs. 66%), and adverse [t(v;11q23), inv(3) or t(3;3), t(9;22), -5 or 5q-, -7 or 7q-, abn(17p), complex karyotype] (38% vs. 18%, respectively). Response to induction therapy was not significantly different between t-AML (64%) and de novo AML (69%) in uni- (p=0.18) and multivariable (p=0.58) analysis. In contrast, for the clinical endpoints relapse-free (RFS) and overall survival (OS), t-AML was an adverse prognostic factor in univariable (p<0.00001, p<0.00001, respectively) and multivariable analyses (HR, 1.69, p=0.001; HR, 1.3, p=0.004, respectively). The negative prognostic impact of t-AML on RFS was due to both a higher cumulative incidence of relapse (p=0.01) and death in complete remission (CR) (p=0.0001). In cytogenetic subgroup analyses, t-AML was an unfavorable factor for OS in particular in patients with inv(16) or t(16;16) (p=0.008), whereas this was not the case in t(8;21) and t(15;17). In cytogentically normal AML, OS was significantly inferior in t-AML patients (p=0.009), and this negative impact was due to a significant inferior OS in the molecularly defined subgroups NPM1mut/FLT3-ITDneg (p=0.05) and the triple negative group (p=0.004), whereas there was no difference in the subgroup FLT3-ITD and CEBPAmut. In as treated analyses in patients younger than 61 years with t-AML, allogeneic hematopoietic stem cell transplantation (HSCT) in first CR had a beneficial effect in cytogenetic intermediate- and adverse-risk (OS, p=0.008), but not favorable-risk patients. Conclusions: In this large cohort of adult patients with newly diagnosed AML, t-AML was an independent adverse prognostic factor for RFS and OS. The negative impact on RFS was not only due to an increased relapse rate but also to a higher rate of deaths in CR, possibly reflecting cumulative toxicity of primary and secondary cancer therapy. Allogeneic HSCT appears to have a beneficial impact in younger adults with t-AML. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Changes in Overall Survival Over Time for Patients With de Novo Metastatic Breast Cancer

2021 ◽  
Author(s):  
Toshiaki Iwase ◽  
Tushaar Vishal Shrimanker ◽  
Ruben Rodriguez-Bautista ◽  
Onur Sahin ◽  
Anjali James ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Metastatic Breast Cancer ◽  
De Novo ◽  
Metastatic Breast ◽  
Locoregional Therapy ◽  
Cancer Center ◽  
Her2 Positive ◽  
Time Periods ◽  
Over Time

The purpose of this study was to determine the change in overall survival (OS) for patients with de novo metastatic breast cancer (dnMBC) over time. We conducted a retrospective cohort study with 1981 patients with dnMBC diagnosed between January 1995 and December 2017 at The University of Texas MD Anderson Cancer Center. OS was measured from the date of diagnosis of dnMBC. OS was compared between patients diagnosed during different time periods: 5-year periods and periods defined according to when key agents were approved for clinical use. The median OS was 3.4 years. The 5- and 10-year OS rates improved over time across both types of time periods. A subgroup analysis showed that OS improved significantly over time for the estrogen-receptor-positive/HER2-positive (ER+/HER2+) subtype, and exhibited a tendency toward improvement over time for the ER-negative (ER-)/HER2+ subtype. Median OS was significantly longer in patients with non-inflammatory breast cancer (P = .02) and in patients with ER+ disease, progesterone-receptor-positive disease, HER2+ disease, lower nuclear grade, locoregional therapy, and metastasis to a single organ (all P &amp;lt;.0001). These findings showed that OS at 5 and 10 years after diagnosis in patients with dnMBC improved over time. The significant improvements in OS over time for the ER+/HER2+ subtype and the tendency toward improvement for ER-/HER2+ subtype suggest the contribution of HER2-targeted therapy to survival.

scholarly journals Radioimmunotherapy with iodine 131I tositumomab for relapsed or refractory B-cell non-Hodgkin lymphoma: updated results and long-term follow-up of the University of Michigan experience

Blood ◽  
2000 ◽  
Vol 96 (4) ◽  
pp. 1259-1266 ◽  
Author(s):  
Mark S. Kaminski ◽  
Judith Estes ◽  
Kenneth R. Zasadny ◽  
Isaac R. Francis ◽  
Charles W. Ross ◽  
...  
Keyword(s):  
B Cell ◽  
Hodgkin Lymphoma ◽  
De Novo ◽  
Hematologic Toxicity ◽  
Low Grade ◽  
Cell Transplant ◽  
Non Hodgkin Lymphoma ◽  
Therapeutic Doses ◽  
131I Tositumomab

Abstract CD20-targeted radioimmunotherapy is a promising new treatment for B-cell non-Hodgkin lymphoma (NHL). We now provide updated and long-term data on 59 chemotherapy-relapsed/refractory patients treated with iodine 131I tositumomab in a phase I/II single-center study. Fifty-three patients received individualized therapeutic doses, delivering a specified total-body radiation dose (TBD) based on the clearance rate of a preceding dosimetric dose. Six patients received dosimetric doses only. Dose-escalations of TBD were conducted separately in patients who had or had not undergone a prior autologous stem cell transplant (ASCT) until a nonmyeloablative maximally tolerated TBD was established (non-ASCT = 75 cGy, post-ASCT = 45 cGy). Fourteen additional non-ASCT patients were treated with 75 cGy. Unlabeled antibody was given prior to labeled dosimetric and therapeutic doses to improve biodistribution. Forty-two (71%) of 59 patients responded; 20 (34%) had complete responses (CR). Thirty-five (83%) of 42 with low-grade or transformed NHL responded versus 7 (41%) of 17 with de novo intermediate-grade NHL (P = .005). For all 42 responders, the median progression-free survival was 12 months, 20.3 for those with CR. Seven patients remain in CR 3 to 5.7 years. Sixteen patients were re-treated after progression; 9 responded and 5 had a CR. Reversible hematologic toxicity was dose limiting. Only 10 patients (17%) had human anti-mouse antibodies detected. Long-term, 5 patients developed elevated thyroid-stimulating hormone levels, 5 were diagnosed with myelodysplasia and 3 with solid tumors. A single, well-tolerated treatment with iodine 131I tositumomab can, therefore, produce frequent and durable responses in NHL, especially low-grade or transformed NHL.

scholarly journals Malignancy Trends in HIV-Infected Patients Over the Past 10 Years in a Single-Center Retrospective Observational Study in the United States

2018 ◽  
Vol 25 (1) ◽  
pp. 107327481879795 ◽  
Author(s):  
Nancy Rihana ◽  
Sowmya Nanjappa ◽  
Cara Sullivan ◽  
Ana Paula Velez ◽  
Narach Tienchai ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Hodgkin Lymphoma ◽  
Anal Cancer ◽  
Invasive Cervical Cancer ◽  
Human Herpesvirus ◽  
Kaposi Sarcoma ◽  
Retrospective Chart Review ◽  
The United States ◽  
Cancer Center ◽  
Non Hodgkin Lymphoma

The introduction of antiretroviral therapy (ART) in 1995 had a dramatic impact on the morbidity and mortality of the HIV population, and subsequently, the natural history of cancer has changed. The purpose of our study was to review the prevalence of AIDS-defining malignancies and non-AIDS defining cancers (NADC), taking into consideration racial and gender variations. After the institutional review board approval, the study was conducted as a retrospective chart review of 279 HIV-infected patients who were treated at the Moffitt Cancer Center between January 1, 2000 and December 31, 2010. The demographic characteristics included gender, ethnicity, race, presence or absence of ART, and the type of malignancy reviewed. Of 233 men, 78 (33.5%) had AIDS-defining malignancies. AIDS-related non-Hodgkin lymphoma (NHL) was detected in 49 (21%) patients and Kaposi sarcoma (KS) in 29 (12%) patients. Two-thirds of male patients had NADC, with anal cancer being the most prevalent (8.5%), followed by Hodgkin lymphoma (6%). AIDS-related NHL was also the predominant malignancy for women with a prevalence of 19.5% followed by invasive cervical cancer (ICC) and breast cancer, both with a similar prevalence of 11%. Kaposi sarcoma and anal cancer were equally detected in 2% of women. The prevalence rates of AIDS-defining malignancies among those of white race were 34%, ranging from 21% for NHL to 13% for KS and 1.5% for ICC. Twenty-one (7.7%) patients had anal cancer. AIDS-defining malignancies were found in 36% of patients of black race and 60% had NHL. Non-AIDS-related NHL was the second most common malignancy, followed by breast cancer and anal cancer with a similar prevalence of 6.5%. Of 279 patients, 53% were taking ART; 39.4% were not taking ART; and in 7.5% of the patients, it was unknown if they were taking ART. In the ART era, our study found NADC to be more prevalent than AIDS-defining malignancies with 60% versus 40%, respectively. Non-Hodgkin lymphoma remained the most common AIDS-related malignancy in both genders. Among the patients with NADC, anal cancer was the predominant malignancy. The increasing incidence of some of the NADC is expected as this population is living longer with chronic exposure of viral replication of virus with oncogenic potential such as Human papillomavirus (HPV), Hepatitis B virus (HBV), Epstein-Barr virus (EBV), and Human herpesvirus 8 (HHV-8). Early ART initiation, aggressive vaccination, and judicious cancer screening are the cornerstone of cancer prevention of this growing population.

scholarly journals BMI-1 and survivin expression with clinicopathological correlation and prognostic impact in B and T/NK- cell non-Hodgkin lymphoma

2019 ◽  
Vol 9 (2) ◽  
pp. 11
Author(s):  
Nahed Ahmed Soliman ◽  
Lamia M Abdalkader ◽  
Doaa Shams
Keyword(s):  
Overall Survival ◽  
Hodgkin Lymphoma ◽  
Nk Cell ◽  
Survivin Expression ◽  
Polycomb Group ◽  
Clinicopathological Parameters ◽  
Prognostic Impact ◽  
Non Hodgkin Lymphoma ◽  
Significant Difference ◽  
Well Correlation

Background: The pathogenesis of non-Hodgkin lymphoma is a complex process that involves several molecular changes. Alterations in polycomb group proteins as well as Survivin have been described but details are still lacking particularly in T/NK-cell lymphomas. Polycomb proteins have a big role in cell cycle and differentiation. Survivin is another recently recognized player in non-Hodgkin lymphoma.Objective: To study the pattern of Bmi-1 and Survivin in different categories of B- and T/NK- cell non-Hodgkin lymphomas, their association with the clinicopathological parameters, and their impact on the prognosis of non-Hodgkin lymphomas.Material& methods: Immunohistochemical staining was used to study paraffin samples of 267 patients’ biopsies. We used tonsils and reactive lymph node as normal control.Results: Both Bmi-1 and Survivin showed significant upregulation in several subtypes B- (P = .000-.02 for Bmi-1 and .00- .03 forSurvivin) and T/NK cell lymphomas (P= .009-.03 for Bmi-1 and 0.008- 0.009 for Survivin) compared to normal tissue. Significantpositive correlation between Bmi-1 and Survivin was detected in both B- (Co= 0.539**, P = .00) and T - cell lymphomas (Co= 0.560**, P = .000). A statistically significant difference between overall survival and expression of both BMI-1 and Survivin was detected (P = .00 for BMI-1and survivin).Conclusion: Bmi-1 and Survivin show significant upregulation as well correlation with clinicopathological parameters and overall survival of non-Hodgkin lymphomas.

The impact of therapy-related acute myeloid leukemia (AML) on outcome in 2853 adult patients with newly diagnosed AML

Blood ◽  
2011 ◽  
Vol 117 (7) ◽  
pp. 2137-2145 ◽  
Author(s):  
Sabine Kayser ◽  
Konstanze Döhner ◽  
Jürgen Krauter ◽  
Claus-Henning Köhne ◽  
Heinz A. Horst ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Topoisomerase Ii ◽  
De Novo ◽  
Negative Impact ◽  
Primary Malignancy ◽  
De Novo Aml ◽  
The Impact ◽  
Acute Myeloid

Abstract To study the characteristics and clinical impact of therapy-related acute myeloid leukemia (t-AML). 200 patients (7.0%) had t-AML and 2653 de novo AML (93%). Patients with t-AML were older (P < .0001) and they had lower white blood counts (P = .003) compared with de novo AML patients; t-AML patients had abnormal cytogenetics more frequently, with overrepresentation of 11q23 translocations as well as adverse cytogenetics, including complex and monosomal karyotypes, and with underrepresentation of intermediate-risk karyotypes (P < .0001); t-AML patients had NPM1 mutations (P < .0001) and FLT3 internal tandem duplications (P = .0005) less frequently. Younger age at diagnosis of primary malignancy and treatment with intercalating agents as well as topoisomerase II inhibitors were associated with shorter latency periods to the occurrence of t-AML. In multivariable analyses, t-AML was an adverse prognostic factor for death in complete remission but not relapse in younger intensively treated patients (P < .0001 and P = .39, respectively), relapse but not death in complete remission in older, less intensively treated patients (P = .02 and P = .22, respectively) and overall survival in younger intensively treated patients (P = .01). In more intensively treated younger adults, treatment-related toxicity had a major negative impact on outcome, possibly reflecting cumulative toxicity of cancer treatment.

Changes in the Hierarchy of Risk Factors with Older Age in De-Novo Acute Myeloid Leukemia (AML).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1977-1977
Author(s):  
Thomas Buchner ◽  
Wolfgang E. Berdel ◽  
Claudia Schoch ◽  
Torsten Haferlach ◽  
Hubert L. Serve ◽  
...  
Keyword(s):  
Risk Factors ◽  
Overall Survival ◽  
Complete Remission ◽  
De Novo ◽  
Older Age ◽  
High Dose ◽  
Age Group ◽  
Risk Profiles ◽  
Age Related ◽  
De Novo Aml

Abstract After recent reports addressed prognostic factors and outcome in older age AML (Burnett et al. Blood106:162a,2005; Wheatley et al. Blood106:199a,2005; Appelbaum et al. Blood107:3481–5,2006; Farag et al. Blood108:63–73,2006) we evaluated 764 patients of 60–85 (median 66) years reduced to those with de-novo AML, known karyotype, and identical consolidation-maintenance chemotherapy, who were part of the 1992 and 1999 multicenter randomized trials by the German AMLCG (Buchner et al. J Clin Oncol21:4496–504,2003;24:2480–9,2006). 521 patients were 60 -< 70 (median 64) and 243 patients were 70–85 (median 73) years of age. 64% and 50% patients respectively went into complete remission, 24% and 29% remained with persistent AML, 12% and 21% succumbed to early and hypoplastic death (p<.001). The overall survival in the younger (60- < 70y) and older (70+) patients was at a median of 13 vs 6 months and 18% vs 8% survived at 5 years (p<.001). Once in complete remission, the remission duration was 14 vs 12 months (median) and equally 18% at 5 years; the relapse-free survival is 13 vs 11 months (median) and 14% vs 13% at 5 years. While all patients were randomized up-front for 2 versions of induction either by TAD-HAM (HAM, high-dose araC 1g/m2x6 and mitox 10mg/m2x3) or by HAM-HAM, response and survival did not differ between the two arms in neither age group. In contrast to response and survival between the younger (60-<70y) and older (70+y) age group corresponding differences in the risk profiles were missing. Thus, favorable/intermediate/unfavorable karyotypes accounted for 8% vs 4% / 67% vs 73% / and 25% vs 24% of patients (p=.073); WBC > 20.000/ccm was found in 40% vs 39% (p=.52); LDH > 700U/L was remarkably 26% vs 18% (p=.014), and the day 16 b.m. blasts ≥ 10% accounted for 41% and 41% of patients. Conclusion: Approximately 50% of patients 70 years of age or older benefit from standard or intensive chemotherapy by complete remission which continues after 1 year in about 50% of responders. The inferior overall survival in the patients of 70+ versus those of 60- < 70 years is mainly explained by more frequent early and hypoplastic death (21% vs 12%) (p=.0016) and death with persistent AML (26% vs 18%) (p=.0145); while death in remission (7% vs 6%), relapse rate (50% vs 53%) and death after relapse (21% vs 26%) did not show this trend. In contrast to the important differences in outcome, established risk factors such as cytogenetic groups, WBC, and early blast clearance show concordance between the two age groups. The even lower LDH may support assumptions of older age AML as a less proliferative disease (Appelbaum et al. Blood 107:3481–5,2006). Thus, the hierarchical risk profiles cannot predict the age related outcome beyond 60 years in patients with de-novo AML.

High Antileukemic Efficacy and Shortened Neutropenia of Dose-Dense Induction (Sequential-HAM Followed by Pegfilgrastim) in Primary Acute Myeloid Leukemia - Results of a Pilot Study of the German AML-CG.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 295-295
Author(s):  
Jan Braess ◽  
Karsten Spiekermann ◽  
Christian Buske ◽  
Peter Staib ◽  
Wolf-Dieter Ludwig ◽  
...  
Keyword(s):  
Overall Survival ◽  
De Novo ◽  
Hospital Costs ◽  
Early Death ◽  
Control Group ◽  
Favourable Safety ◽  
Favourable Safety Profile ◽  
Blast Count ◽  
De Novo Aml ◽  
Dose Dense

Abstract Dose density during early induction has been demonstrated to be one of the prime determinants for antileukemic efficacy. The German AML-CG therefore pilots a dose dense induction regimen S-HAM (sequential HD-AraC [3g/m2/12h d1,2,8,9] and Mitoxantrone 10mg/m2 [d3,4,10,11] followed by pegfilgrastim) in which two induction cycles are applied over 11 – 12 days as compared to conventional double induction, in which two cycles are applied over 25 – 29 days - thereby increasing dose density ca. two-fold in the critical first weeks of treatment. In the past 2,5 years 168 patients with de-novo AML (excluding APL) have been recruited into the trial with a median age of 53 years (range 18 – 78). Of 136 patients evaluable for response the following results were achieved: CR 62%, CRi 22%, PL 7%, ED 9% - resulting in an overall response rate (ORR) of 84%. The early death rate (ED) of 9% and the toxicity profile compared favourably with a historical control group of the AML-CG 1999 study (de-novo AML, < 60 years, HAM-HAM double induction) which demonstrated an ED rate of 14% (ORR 68%, persistent leukemia (PL) 18%). The high antileukemic efficacy of S-HAM was also demonstrated by the fact that 89% of patients had a blast count of < 10% one week after therapy as compared to less than 48% of patients of the HAM-HAM double induction group. Whereas even for patients with unfavourable cytogenetics (including complex aberrations) a median overall survival of 13,5 months was reached (23% at 2 years), for patients with favourable karyotypes overall survival at 2 years was 81%and for patients with intermediate karyotypes 74% after S-HAM treatment. Importantly the compression of the two induction cycles into the first 11 – 12 days of treatment seems actually beneficial for normal hematopoesis as demonstrated by a significantly shortened duration of critical neutropenia of 30 days as compared to 45 days after conventionally timed double induction. This shortening of critical neutropenia by more than 2 weeks was highly relevant for the duration of hospital stay and hospital costs. In conclusion S-HAM with pegfilgrastim support is a highly effective regimen in primary de-novo AML with a very favourable safety profile and significantly shortened duration of neutropenia. This regimen will therefore constitute the (dose-dense) experimental arm for a randomized comparison with standard double induction in the next generation of the German AML-CG studies.

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