Successful Induction Chemotherapy Research Articles

Monosomy 7 and Co-Occurrent Genomic Aberrations Determine Chemotherapy Response in Acute Myeloid Leukemia (AML) Patients Using the Cellworks Omics Biology Model (CBM): Mycare-021-04

Background: Monosomy 7/Del 7 (-7) or its long arm (del(7q)) is one of the most common cytogenetic abnormalities in pediatric and adult myeloid malignancies, particularly in adverse-risk acute myeloid leukemias (AMLs). In general, (-7) is associated with poor response to induction chemotherapy (PMID 12393746). At the same time, not all patients fare poorly so the ability to identify responders and non-responders remains a high priority. Aim: To predict the response for induction chemotherapy in AML patients with (-7) and identify novel genomic signatures of response and resistance. Methods: Genomic data from 13 consecutive patients with (-7) were analyzed using the Cellworks Omics Biology Model (CBM) to generate patient-specific protein network models. All data was anonymized, de-identified and exempt from IRB review. For each model, disease simulations were performed and patients were segregated into HOXA-upregulated and HOXA-downregulated cohorts based on the simulation levels of HOXA5 and HOXA9. Digital drug simulations for induction chemotherapy were accomplished by measuring the impact of drug effect on a cell growth score, a composite of cell proliferation, viability and apoptosis indices. Each patient-specific model was analyzed to identify mechanisms underlying treatment outcomes. Results: 7/13 (54%) of (-7) patients failed to achieve remission after induction chemotherapy (Table 1) which highlighted that (-7) alone does not confer resistance to chemotherapy. CBM identified other genomic alterations that determine chemotherapy response, including DNA repair deficiency genes, mismatch repair (MMR), and homologous recombination repair (HRR) genes. DNA methylation and histone methylation (H3K27me) impacting HOXA gene expression, mainly HOXA5 and HOXA9, were identified as upstream regulators of DNA repair genes. Loss or reduced levels of EZH2 is associated with lower H3K27 methylation and thereby higher expression of HOXA5 and HOXA9 gene targets. High active levels of HOXA correlated with low rates of successful remission induction (22%, n=7) and lower activity levels of HOXA correlated with successful induction chemotherapy (100%, n=4) (Table 1). CBM identified that (-7) results in a decreased expression of EZH2, CARD11, EIF3, PMS2, HUS1, KMT2C (MLL3), CDK5 and IKZF1 genes. Since EZH2 abnormalities alone are not implicated in poor prognosis for AML patients, we sought other aberrations that prevent HOXA upregulation. Using CBM, we identified multiple accompanying aberrations which regulate HOXA genes. Deletions of KAT6A, ASXL1, DNMT3B, DNMT3L genes and high KMT2A-partial tandem duplication correspond to HOXA-upregulation whereas EED amplification, gain of function mutations in DNMT3A, mutations in IDH1/2, MYC and KAT6A amplification and KDM4A deletion result in HOXA-downregulation. Conclusion: Alterations of chromatin regulation have consequences for transcription factors that regulate expression of DNA repair genes. Under conditions where DNA repair is enhanced, induction chemotherapy was 78% less likely to effect remission in (-7) AML patients undergoing induction chemotherapy. Loss of H3K27 methylation associated with loss of PRC2 function by any means resulted in HOXA-upregulation and upregulation of DNA repair genes induced resistance to induction therapy. On the other hand, CBM analysis identified genetic signatures associated with a 100% remission rate from AML induction therapy despite the presence of (-7). Generation of H3K27me caused by PRC2 activation resulting from numerous mechanisms led to HOXA-downregulation and 100% response to induction therapy. Stratification of patients harboring (-7) by HOXA biomarker analysis could inform treatment planning, avoid drug-related adverse events and reduce treatment costs after validation with a larger prospective dataset. Disclosures Castro: Cellworks Group Inc: Consultancy. Watson:Cellworks Group Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellmax Life Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mercy Bioanalytics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; SEER Biosciences, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioAI Health Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kumar:Cellworks Research India Private Limited: Current Employment. Nair:Cellworks Research India Private Limited: Current Employment. Grover:Cellworks Research India Private Limited: Current Employment. Sahu:Cellworks Research India Private Limited: Current Employment. Mohapatra:Cellworks Research India Private Limited: Current Employment. G:Cellworks Research India Private Limited: Current Employment. Agarwal:Cellworks Research India Private Limited: Current Employment. Suseela:Cellworks Research India Private Limited: Current Employment. Ganesh:Cellworks Research India Private Limited: Current Employment. Sauban:Cellworks Research India Private Limited: Current Employment. Kumar:Cellworks Research India Private Limited: Current Employment. Raman:Cellworks Research India Private Limited: Current Employment. Singh:Cellworks Research India Private Limited: Current Employment. Basu:Cellworks Research India Private Limited: Current Employment. Lunkad:Cellworks Research India Private Limited: Current Employment. Mundkur:Cellworks Group Inc.: Current Employment. Macpherson:Cellworks Group Inc.: Current Employment. Kapoor:Cellworks Research India Private Limited: Current Employment. Howard:Servier: Consultancy, Other: Speaker; Boston Scientific: Consultancy; Sanofi: Consultancy, Other: Speaker; EUSA Pharma: Consultancy; Cellworks: Consultancy.

Impact Of The Early Intensification Of Induction Chemotherapy On Complete Remission and Survival Rates For De Novo Adult Acute Myeloid Leukemia

BackgroundThe successful induction chemotherapy of acute myeloid leukemia (AML) depends on the ability to achieve complete remission (CR) and to maintain remission status as long as possible. Approach to improve the rate of CR includes the intensification of induction chemotherapy for AML. The primary goal of this study was to evaluate and compare the long-term outcomes between remission induction therapy with and without early intensification added to the standard 3+7 remission induction regimen. MethodsA retrospective analysis was performed on de novo AML patients diagnosed and treated at Catholic Blood and Marrow Transplantation Center between January 2001 and December 2010. Six hundred forty-one adults of ages between 16 and 60 were included, all of whom received induction chemotherapy starting with 3 days of idarubicin and 7 days of cytarabine or behenoyl cytarabine (BHAC). Cases with t(9;22) and t(15;17) were excluded. Bone marrow (BM) aspiration study was assessed on day 7 of induction in all patients. Factors which were considered for early intensification of induction were the presence of ≥ 5% BM blasts, patient performance, and other high risk clinical characteristics, such as karyotype. Groups according to early intensification on days 8 to 10 of induction were as followings: no intensification (3+7), n=156; cytarabine or BHAC for 3 days (3+10), n=233; addition of idarubicin for 2 days to 3+10 regimen (5+10), n=252. After a median duration of 5.5 months (3.3-19.0) from diagnosis, 479 patients underwent stem cell transplantation (autologous [auto-SCT], n=144; allogeneic [allo-SCT], n=335). Conditioning regimen for auto-SCT consisted of fractionated total body irradiation (TBI), melphalan, and cytarabine, whereas 83% (n=278) of patients with allo-SCT received myeloablative conditioning, of which was mostly TBI-based regimen (92%). Donors were matched sibling (n=213), matched unrelated (n=63), mismatched unrelated (n=39), and haploidentical related (n=20). ResultsThe median age at diagnosis was 39 years (16-60). Mean values of BM blast % on day 7 of induction was 3.5 in 3+7 group, 7.9 in 3+10, and 33.6 in 5+10 (p=<0.0001), while no significant difference in the proportion of adverse karyotype was shown (11.7% vs. 12.8%, p=0.804). After first induction (3+7, n=165; 3+10/5+10, n=465), the CR/CRi rate was significantly higher in 3+10/5+10 versus 3+7 (78.1% vs. 69.2%, p=0.023), while the rate for death in aplasia was lower (4.3% vs. 9.6%, p=0.013). After re-induction with various regimens, the CR/CRi rate was still significantly higher in intensified group (p=0.012). The relapse rates between the groups in 536 patients achieving CR (83.6%), however, was not significantly different (8.9% vs. 9.9%, p=0.737). SCT was performed at CR1 (n=459), CR2 (n=10), or relapsed/refractory status (n=10). Patients with auto-SCT mostly had better/intermediate cytogenetic risk (96%) at diagnosis, while 12% of allo-SCT had poor karyotype. After the median follow-up duration of 60.2 months (2.2-143.5), the median overall survival (OS) in all patients (n=641) was 65.6 months. The 5-year disease-free survival (DFS) of patients with auto- and allo-SCT was 58.4±4.2 and 64.9±2.7, respectively. Of 334 patients receiving allo-SCT, the 5-year DFS was significantly higher in patients achieving CR1 (n=299) after first induction therapy (p<0.0001), in whom 75% of them had early intensification. Other factors with significant impact on DFS after allo-SCT (n=334) were karyotype at diagnosis (p=0.032) and donor type (HLA-matched vs. HLA-mismatched sibling or unrelated, 58.1%±3.8 vs. 45.1±8.0, p=0.016). The significances were confirmed in multivariate analysis, which demonstrated that achieving CR1 after first induction regimen and its maintenance until SCT was the most powerful predictor for DFS after allo-SCT (67.1±2.9 vs. 34.6±7.8, p=<0.0001). When all patients were analyzed, according to induction intensification, a statistically significant benefit in 10-year OS was observed in 5+10 intensified group (44.8% vs. 52.9%, p=0.032). ConclusionOur results suggest possible benefit of examining day 7 BM aspiration for the strategy of early intensification of induction chemotherapy for adult AML patients and our intensification doses can be safely added with high efficacy in the achievement of CR1 compared to 3+7 standard regimen, and may have affected for better DFS after allo-SCT. Disclosures:Kim:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Autologous Stem Cell Transplantation and Addition of Rituximab Independently Prolong Response Duration in Advanced Stage Mantle Cell Lymphoma.

Abstract 880On behalf of the German Low-Grade Lymphoma Study Group (GLSG) and the European MCL Network Background:In younger patients with mantle cell lymphoma (MCL), autologous stem cell transplantation (ASCT) significantly prolonged response duration with a trend towards improved overall survival in a randomized trial of the European MCL Network (Dreyling et al., ASH 2008). A recently updated clinical trial of the German Low-Grade Lymphoma Study Group (GLSG) also reported a significantly prolonged response duration by the addition of Rituximab to first-line CHOP (Hoster et al., ASH 2008). By pooled analysis of these trials we investigated whether Rituximab and ASCT independently prolong response duration. Methods:The analysis included all advanced stage MCL patients of the trials “CHOP vs. MCP” (Nickenig et al., Cancer 2006), “CHOP vs. R-CHOP” (Lenz et al., JCO 2005) and European MCL trial 1 (Dreyling et al., Blood 2005) with complete or partial remission to either CHOP or R-CHOP first-line induction and randomization between ASCT and Interferon-α maintenance. Response duration was defined as time from the end of successful induction chemotherapy to relapse or death from any cause, overall survival from the end of successful induction chemotherapy to death from any cause. Stratified Kaplan-Meier curves for response duration and overall survival were calculated for the four treatment groups (CHOP without ASCT, CHOP with ASCT, R-CHOP without ASCT and R-CHOP with ASCT). By multiple Cox regression we tested whether the impact of Rituximab (R) and ASCT was independent and additive. Results:One-hundred and eighty patients with MCL were evaluable, 80 treated with R-CHOP, 78 with ASCT (CHOP without ASCT: 56, CHOP with ASCT: 46, R-CHOP without ASCT: 44 and R-CHOP with ASCT: 34). Median age was 55 years (range 34-65), the MIPI classified 71% as low risk, 22% as intermediate risk, and 6% as high risk, and baseline characteristics were comparable between treatment groups. With a median follow-up of 63 months, median response duration was 16 months after CHOP without ASCT, 26 months after R-CHOP without ASCT, 39 months after CHOP with ASCT, and 41 months after R-CHOP with ASCT. In multiple Cox regression including R and ASCT, the hazard ratios of R (0.60, 95% CI 0.42-0.86, p = 0.0056) and ASCT (0.50, 95% CI 0.35-0.70, p = 0.0001) were independently significant. There was no interaction between R and ASCT (p=0.43). Median overall survival was 54 months after CHOP without ASCT, 66 months after R-CHOP without ASCT, 90 months after CHOP with ASCT, and not reached after R-CHOP with ASCT. The hazard ratios for OS were 0.70 (95% CI 0.44-1.12, p = 0.14) for R and 0.63 (95% CI 0.41-0.97, p = 0.0379) for ASCT. Conclusions:Our results indicate an additive effect of ASCT and Rituximab in combination with CHOP on response duration in advanced stage MCL patients and support strategies of several study groups to combine Rituximab-containing induction therapies with ASCT in younger MCL patients. However, even after combined treatment approaches, delayed relapses have been observed, supporting the use of maintenance therapy and the introduction of molecular targeted therapeutical strategies. Disclosures:Hoster:Roche: Travel Support. Off Label Use: Rituximab in Mantle Cell Lymphoma. Pfreundschuh:Roche: Membership on an entity's Board of Directors or advisory committees. Dührsen:Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Gisselbrecht:Roche: Research Funding, Speakers Bureau. Unterhalt:Roche: Travel Support. Dreyling:Roche: Honoraria, Research Funding.

Molecular quantitation of minimal residual disease in acute myeloid leukemia with t(8;21) can identify patients in durable remission and predict clinical relapse

One of the most common translocations in acute myeloid leukemia (AML) is the t(8;21), which produces the fusion gene AML1-MTG8. We have developed a sensitive competitive reverse transcriptase-polymerase chain reaction (RT-PCR) assay for AML1-MTG8 transcripts, coupled with a competitive RT-PCR for the ABL transcript as a control to accurately estimate the level of amplifiable RNA. We have shown that AML1-MTG8 and ABL transcripts have equal degradation rates. Thus, this method is useful for multicenter studies. We studied 25 patients with t(8;21) AML by means of serial analysis done on bone marrow (BM) and peripheral blood (PB) samples from 21 patients. Our analysis showed that, in general, a successful induction chemotherapy produces a reduction of 2 to 3 log in the level of AML1-MTG8, followed by a further 2 to 3 log after consolidation/intensification chemotherapy. Levels up to 1 x 10(3) and 1 x 10(2) molecules/microg of RNA in BM and PB, respectively, were compatible with durable remission. On the other hand, 5 patients with levels of 0.71 x 10(5) to 2.27 x 10(5) molecules/microg of RNA in BM and 2.27 x 10(3) to 2.27 x 10(4) molecules/microg of RNA in PB had hematologic relapse within 3 to 6 months. Our data indicate that serial quantitation of AML1-MTG8 transcripts is useful in identifying patients at high risk of relapse and may offer an opportunity for clinical intervention to prevent hematologic relapse. This approach was applied successfully in a patient who had an allogeneic BM transplantation. We also suggest that PB may be used an alternative to BM for quantitating AML1-MTG8 transcripts.

Detection of minimal residual disease in patients with AML1/ETO-associated acute myeloid leukemia using a novel quantitative reverse transcription polymerase chain reaction assay.

The AML1/ETO fusion transcript can be detected by reverse transcription polymerase chain reaction (RT-PCR) in patients with t(8;21)-associated acute myeloid leukemia (AML) in long-term complete remission (CR). Quantitation of the amount of the fusion transcript during CR may therefore be more predictive of cure or relapse than a simple qualitative assessment. Real Time PCR, a fluorometric-based technique, allows simple and rapid quantitation of a target sequence during the extension phase of PCR amplification, in contrast to end-point quantitative methods. Six patients with t(8;21)(q22;q22) AML, who achieved CR were studied by Real Time RT-PCR at different time intervals following diagnosis and high-dose cytarabine and anthracycline-based induction therapy. Five patients had a diagnostic bone marrow (BM) sample available for molecular analysis. Each patient showed > or = 10(3) copies of the AML1/ETO fusion transcript at diagnosis, and each showed a 2- to 4-log decrease in copy number following successful induction chemotherapy. This is comparable to the log-fold reduction in leukemic blasts that is thought to occur in patients successfully cytoreduced into CR by induction chemotherapy. The sixth patient showed a relatively high copy number immediately following successful remission induction chemotherapy, which continued to increase during early CR and was later followed by relapse. Real Time RT-PCR appears to offer advantages over previously used quantitative RT-PCR methods by providing absolute quantitation of the target sequence, expanding the dynamic range of quantitation to over six orders of magnitude, eliminating the post-PCR processing, and reducing labor and carryover contamination. These features make this an attractive method to prospectively evaluate the prognostic value of AML1/ETO fusion transcript quantitation in a larger patient population with t(8;21)(q22;q22) AML in CR.

初診時S状結腸癌によるイレウスを合併し，結腸切除術施行後，寛解導入療法に成功した急性リンパ性白血病の1例

初診時S状結腸癌によるイレウスを合併し，結腸切除術施行後，寛解導入療法に成功した急性リンパ性白血病の1例

Superselective Intra-arterial Chemotherapy of Advanced Paranasal Sinus Tumors

Twenty-four patients with advanced paranasal sinus tumors were treated with combined superselective intra-arterial and systemic chemotherapy, yielding an immediate satisfactory tumor response rate of 91%, significantly better than previously reported. Eight patients had craniofacial surgery circumvented because of complete or near complete response. Repetitive uncomplicated catheterization of the pterygoid segment of the internal maxillary artery using a coaxial system is the cornerstone of successful induction chemotherapy. Strenuous screening of medical status is mandatory for this aggressive introduction chemotherapy.

Successful Induction Chemotherapy for Childhood RAEB-T with VP-16: a Case Report

Successful Induction Chemotherapy for Childhood RAEB-T with VP-16: a Case Report

PRETREATMENT TESTICULAR BIOPSY IN CHILDHOOD ACUTE LYMPHOCYTIC LEUKAEMIA

Between August, 1978, and March, 1981, 24 boys with acute lymphocytic leukaemia (ALL) (14 non-B-cell non-T-cell, 6 pre-B-cell, and 4 T-cell) underwent bilateral wedge testicular biopsy at initial diagnosis. All testes were of normal size. Histological analysis was performed independently by three pathologists, 4 (3 non-B non-T, and 1 pre-B) of 20 patients with non-T-cell ALL demonstrated testicular focal lymphoblastic involvement. Successful induction chemotherapy without concomitant testicular irradiation completely eradicated testicular infiltrates in all 4 patients. Only 1 of the 4 T-cell patients had pre-treatment testicular infiltrates. Unlike boys with non-B non-T leukaemia, attainment of bone-marrow remission in this patient was associated with persistent testicular disease. These preliminary data indicate that in patients with ALL of non-T-cell type, systemic induction chemotherapy eradicates the small testicular infiltrates of lymphoblasts. Prophylactic testicular irradiation in this group of patients does not seem to be warranted.