Courses Of Consolidation Chemotherapy Research Articles

Clinical Features and Outcomes of Elderly Patients with Acute Promyelocytic Leukemia (APL) - the Japan Adult Leukemia Study Group APL97 Study.

AbstractAbstract 1077 (Background)Studies focused on elderly APL are limited. The European APL study group reported in their APL 93 trial that lower survival rate in elderly APL was mainly due to an increase of early deaths and toxicity of chemotherapy (Ades et al, 2005). On the other hand, PETHEMA group reported in their LPA96 and 99 studies that ATRA combined with anthracycline monochemotherapy resulted in low toxicity and high compliance, and that survival rate is similar to younger patients (Miguel A et al, 2004). We analyzed clinical features and outcomes of elderly APL patients with APL who were treated with ATRA and intensive chemotherapy and compared with those of younger patients in long term follow-up of the JALSG-APL97 Study. (Methods)Patients with newly diagnosed APL were continuously registered from May 1997 to June 2002, and induction therapy was composed of ATRA and chemotherapy including idarubicin and cytarabine. The dose and duration of chemotherapy were based on initial leukocyte count. After completion of 3 courses of consolidation chemotherapy, patients negative for the PML-RARA transcript were randomly allocated either to receive 6 courses of intensified maintenance chemotherapy or to observation. Elderly patients were treated with the same schedule to younger patients (Asou et al, 2007). Clinical features as well as relapse rate (RR), overall survival (OS) and disease-free survival (DFS) were assessed in elderly group with aged 60 or more in comparison with younger group. Clinical outcomes were updated on January, 2009 and the median follow up period is 7.3 years. (Results)Of 302 patients registered in this study, 283 patients were assessable. The median age was 48 years (range, 15–70 years), with 237 patients in younger group (median age, 44 years) and 46 patients in elder group (median age, 63 years). Significantly lower platelet count (less than 10 × 109/L), higher incidence of ECOG performance status 3 to 4, lower albumin level (< 3.5g/dl) were observed in elderly group compared to younger group (P = 0.04, P = 0.02 and P < 0.001, respectively), while clinical characteristics including gender, initial leukocyte count, APL cells in peripheral blood, DIC score, frequency of variant type (M3v), expression of CD-phenotype, past history of chemotherapy and/or radiotherapy and number of infectious complications at diagnosis, did not differ between two groups. The CR rates and early mortality during induction therapy including to hemorrhagic complications were similar between two groups (89% vs. 96%, P = 0.06; 11% vs. 4%, P = 0.08), whereas induction death due to differentiation syndrome in elderly group is higher compared with younger group (4% vs. 0%, P = 0.03). The cumulative incidence of non relapse mortality (NRM) during the third consolidation chemotherapy was significantly higher in elderly group (9% vs. 1%., P = 0.04). All of the mortality occurred during consolidation therapy was associated with infection. Although OS was lower in elderly groups at 10 year compared with younger group (65% vs. 87%, P < 0.001), DFS and RR were similar between two groups (65% vs. 67%, P = 0.70; 13% vs. 26%, P = 0.15, respectively). (Conclusion)The present study demonstrated that efficacy of ATRA combined with chemotherapy in elderly APL was similar to younger APL. Nevertheless, lower OS at 10 year in elderly APL was observed in this study. One of the reasons was an increase of NRM, especially induction death due to differentiation syndrome and infection death during consolidation chemotherapy. Thus, reduction of intensity of post remission chemotherapy should be considered in elderly patients. Non-myelosuppressive agents such as arsenic trioxide and/or tamibarotene should be incorporated into the post remission therapy for elderly patients with APL. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Combination Chemotherapy Leading In Advanced MDS Patients to a Rapid Clearence of Bone Marrow Blasts Prior Stem Cell transplantation (SCT) Is Superior to up-Front SCT Even with Intensified Conditioning for Long-Term Survival

AbstractAbstract 4020A retrospective analysis of influence of different clinical and laboratory parameters on disease outcome was performed in a cohort of 43 patients with advanced myelodysplasia (MDS)(RAEB > 10% blasts + RAEB-T according to the FAB classification) who underwent allogeneic stem cell transplantation (SCT) in our institute within past 20 years; 21 patients were transplanted with < 10% of bone marrow (BM) blasts after 1 or 2 courses of induction followed by 1 or 2 courses of consolidation chemotherapy (Group A), 22 patients were transplanted with > 10% BM blasts either prior treated with combination chemotherapy or transplanted up-front with intensified conditioning (Group B). Median survival of all transplanted patients was 35,5 months (+/− 53,9 months) with a significant difference between Group A and B (57,5+/−62,3 months v.s. 18,0 +/−36,7 months, p=0.017). Estimated 3 year and 10 year survival for all patients were 53,5% and 41,9%, respectively. Estimated 3 and 10 year survival also significantly differed between Group A and B (71,4% and 57,1% for Group A and 36,4% and 27,3% for Group B). Complete remission (CR) rate was 44,2%, 18,6% patients relapsed (14,3% in Group A and 22,7% in Group B). No difference in overall survival was observed between patients with > 10% BM blasts transplanted either after chemotherapy or up-front (median survival: 26,8+/− 41,4 v.s. 18,0+/−33,8 months, respectively, p=0.65). Univariate analysis using Kaplan-Meier curves and log-rank2 test revealed as significant variables affecting overall survival: achievement of CR (p=0.007), achievement of < 10% BM blasts prior SCT (p=0.011), SCT performed < 4 months after diagnosis (p=0.031) and absence of relapse (p=0.046). Independent variables for determining overall survival (identified by Cox regression multivariate analysis) were: SCT performed < 4 months after dg. (p=0.003,χ2= 8,798), achievement of CR (p=0.011,χ2= 6,457), and age < 50 years (p=0.044,χ2= 4,053). None independent variable determining occurrence of relapse was found. Neither the percentage of BM blasts at the time of dg. and initial transfusion dependency, nor the donor origin (related or unrelated) and number of consolidation courses affected survival. Conclusions:combination chemotherapy leading to a rapid clearance of BM blasts below 10% followed by immediate SCT represented the best treatment option for younger patients with MDS with > 10% BM blasts. Patients transplanted with > 10% BM blasts at the time of conditioning had significantly inferior outcome either transplanted after previous chemotherapy or up-front with intensified conditioning. In this subset of patients, a possible benefit of addition of hypomethylating agents to the treatment schedules prior SCT should be studied. The study was supported by scientific programme MZCR 00023736. Disclosures:No relevant conflicts of interest to declare.

Prognostic Impact of DNA Repair and MDR-1 Gene Polymorphisms In De Novo Acute Myeloid Leukemia with t(8;21) or Inv(16)

AbstractAbstract 1714 Background:Single nucleotide polymorphisms (SNPs) within the genes involving DNA repair, drug metabolism, oxidative stress, and drug transport may be associated with tumorigenesis and lead to the interindividual differences in treatment outcome. Reciprocal translocations like t(8;21) or inv(16) in acute myeloid leukemia (AML) usually predict a good response to chemotherapy with a high remission rate and a relatively long median survival. However, some of these patients still experience the recurrent relapse of disease and poor clinical outcome. We assessed the prevalence and the prognostic impact of SNPs of genes involving DNA repair, drug metabolism, oxidative stress, and drug transport in de novo AML patients with t(8;21) or inv(16). Methods:Ninety-four bone marrow (BM) DNA samples obtained at initial diagnosis from the AML patients with t(8;21) or inv(16) were genotyped for 25 polymorphisms on genes encoding proteins involved in drug metabolism (NQO1_rs1800566, CYP1A1_rs1048943, rs4646903), oxidative stress mechanisms (GSTT1, GSTM1, GSTP1_rs1695), drug transport system (multidrug resistance gene-1, MDR-1; ABCB1_rs104568, rs112850, rs203258, rs414873, rs1732274, rs102568, rs698010), and DNA repair (XRCC1_rs25487, rs1799782, XRCC3_rs861539, XRCC4_rs1056503, RAD51_rs1801321, ERCC2_rs13181, XPC_rs2228001, MGMT_rs12917, OGG1_ rs1052133, ERCC1_rs321296, WRN_rs1800392, BRCA1_rs799917). DNA sequencing and GeneScan analysis were performed to confirm the genotyping results. All enrolled patients received intensive remission induction therapy consisting of 3 days of idarubicin at 12 mg/m2/day and 7 days of cytarabine 100 mg/m2/day or N4-behenoyl-1-D-arabinofuranosylcytosine (BH-AC) (300 mg/m2/day for patients younger than 40 years old, 200 mg/m2/day for patients older than 40 years old). If patients failed to achieve complete remission (CR) after the first round of induction chemotherapy, they received reinduction chemotherapy using the same regimen. Patients achieving CR received two or three courses of consolidation chemotherapy. Leukemic-free survival (LFS) and overall survival (OS) before transplantation were assessed in order to eliminate confounding bias and defined as the time without relapse or transplantation from the date of CR and the time from diagnosis to death or transplantation, respectively. Results:Of total 94 patients, 71 were AML with t(8;21) and 23 were AML with inv(16). The median age of patients was 38 years (17-69 years). There was no statistically significant difference in age, gender, leukocyte count, hemoglobin level, platelet count and percentage of peripheral or BM blasts between the patients with or without certain SNPs. There was significant difference in CR rate within XRCC1 polymorphisms (rs25487, GG/GA: 100% vs. AA: 85.7%, P=0.002). Heterozygous (GC) OGG1 gene polymorphism (rs1052133) showed higher rate of relapse (35.6% vs. 13.3%, P=0.014) and shorter LFS [N.A. vs. 7.2 ms. (3.7-10.8 ms.), P=0.026] than those of homozygous (GG/CC). AA/AC genotypes of XPC_rs2228001 also presented higher rate of relapse than that of CC genotype (28.9% vs. 0%, P=0.018). The polymorphisms of ABCB1 gene (rs203258) typed as GG also presented higher rate of relapse (46.7% vs. 20.3 %, P=0.031) and shorter LFS [6.9 ms. (4.4-9.5 ms.) vs. 13.0 ms. (7.3-18.7 ms), P=0.005] than those of GT GA or TT TA AA. Conclusions:This study revealed the association between SNPs within DNA repair/MDR-1 genes and the treatment outcomes for AML with favorable cytogenetics. More stratified treatment plans in induction chemotherapy such as augmentation or addition of other chemotherapeutic agents and in consideration of allogeneic stem cell transplantation may be warranted for the AML patients with t(8;21) or inv(16) harvoring these polymorphisms. Disclosures:No relevant conflicts of interest to declare.

Long-term survey of outcome in acute promyelocytic leukemia: a single center experience in 340 patients

The aims of this study are to investigate the outcome and prognostic factors influencing long-term survival on patients with acute promyelocytic leukemia (APL). A total of 340 APL patients admitted to the Department of Hematology from January 1988 to December 2009 were enrolled in this study. All patients received all-trans retinoic acid (ATRA) and/or arsenic trioxide (ATO) with anthracycline-based induction therapy. After three courses of consolidation chemotherapy, 279 patients received 2 years of maintenance therapy. Survival analyses were carried out using the Kaplan-Meier method and the Cox regression model. In total, 288 achieved CR with the CR rate of 84.7%, and 50 patients died during induction therapy. Univariate analysis identified the following three risk factors for hemorrhagic mortality: fibrinogen level (<1.0 g/l) (P = 0.0007), initial peripheral WBC count(>4 × 10(9)/l) (P = 0.0001), as well as the presence of coagulopathy(P < 0.0001). With a median follow-up of 49 (6-255) months, the estimated 5-year overall survival (OS) and relapse-free survival (RFS) were (89.0 ± 2.4)% and (83.7 ± 2.6)%, respectively. Cox regression analysis of the 290 patients showed initial WBC count, years of diagnosis, and the status of PML-RARα in remission seemed to be independent prognostic indicators for OS and RFS (P = 0.03, P < 0.01 and P = 0.0001, respectively). Cytogenetics in addition to above three variables remained significant for RFS (P = 0.01). Our retrospective observations suggest that the combination of ATRA and/or ATO with anthracycline-based therapy may have useful implications in the perspective of long-term prognosis for adult APL.

Role of autotransplantation in the treatment of acute promyelocytic leukemia patients in remission: Fukuoka BMT Group observations and a literature review

We retrospectively analyzed the outcomes of 26 patients with acute promyelocytic leukemia (APL) in the first CR (CR1) or second CR (CR2), who underwent autologous PBSCT (auto-PBSCT) between 1992 and 2008. All patients received all-trans retinoic acid-based induction therapy. After two courses of consolidation chemotherapy, upfront auto-PBSCT was performed in 20 patients in the CR1. Five patients had a high WBC count of more than 10 × 10(9)/L (high risk), while 15 patients had a count of less than 10 × 10(9)/L (low risk) at initial presentation. In addition, six patients, who were considered as low-risk patients at presentation, had a relapse after three cycles of consolidation and 2 years of maintenance therapy, but gained the molecular remission after re-induction and consolidation, and underwent auto-PBSCT in the CR2. In 26 recipients, engraftment was rapid and no TRM was documented. All 20 patients autotransplanted in CR1 were still in CR at a median of 133 months (73-193 months), and six patients who underwent auto-PBSCT in CR2 were also still in CR at a median of 41 months (2-187 months) without maintenance therapy. PML/RARα chimeric mRNA was undetectable in PBSC or BM samples examined before auto-PBSCT. Despite a small number of cases studied, our retrospective observations suggest that auto-PBSCT may be an effective treatment option to continue durable CR in the treatment of high-risk APL. We review previous reports and discuss the role of autotransplantation in the treatment of APL patients in CR.

Immunotherapy with histamine dihydrochloride for the prevention of relapse in acute myeloid leukemia

Most patients with acute myeloid leukemia (AML) achieve complete remission (CR) after induction chemotherapy. Despite ensuing courses of consolidation chemotherapy, a large fraction of patients will experience relapses with poor prospects of long-term survival. Histamine dihydrochloride (HDC) in combination with the T-cell-derived cytokine IL-2 was recently approved within the EU as a remission maintenance immunotherapy in AML. HDC reduces myeloid cell-derived suppression of anti-leukemic lymphocytes, and aims to unravel a therapeutic benefit of IL-2 in AML by improving natural killer and T-cell activation. A randomized Phase III trial with 320 AML patients in CR demonstrated a significant reduction of relapse risk after immunotherapy with HDC plus low-dose IL-2 in the post-consolidation phase. HDC is the first approved therapeutic to target the state of immunosuppression in AML; further development in this area may comprise supplementary or alternative counter-suppressive agents with the aim to improve the efficacy of cancer immunotherapy.

Increased Plasma FLT3 Ligand Levels Following Chemotherapy May Interfere with the Clinical Efficacy of FLT3 Inhibitors.

Abstract 937FLT3 mutations are relatively common in AML and are associated with a poor prognosis. A large number of different small molecule inhibitors of FLT3 tyrosine kinase activity have been identified and many are being studied in clinical trials. There are currently several trials in the planning stage or actively accruing in which the FLT3 inhibitor is administered along with a chemotherapy regimen. While FLT3 inhibitors have some degree of clinical activity when given as monotherapy, their efficacy in the setting of chemotherapy is not well understood. We examined in vivo FLT3 inhibition in AML patients treated with chemotherapy followed by the FLT3 inhibitor lestaurtinib (CEP-701), comparing newly-diagnosed AML patients (enrolled on the MRC AML15 trial) with relapsed patients enrolled on the Cephalon 204 trial. We noted that in vivo FLT3 inhibition by lestaurtinib (as measured by a plasma inhibitory activity assay) was less effective in the relapsed patients (204 trial) compared with the newly-diagnosed patients (AML15 trial). It has been noted by others that FLT3 ligand (FL) levels increase dramatically following myelosuppressive therapy. We hypothesized that FL could be interfering with the ability of lestaurtinib to inhibit FLT3 autophosphorylation, particularly in the patients enrolled on the 204 trial. Using an ELISA assay, we measured plasma FL levels in the two patient populations at Day 15 following the start of intensive chemotherapy (34 patients from the AML15 trial, 78 patients from the 204 trial). FL levels averaged 2.7 pg/mL in newly-diagnosed AML and 15.6 pg/mL in AML patients at first relapse (prior to therapy). FL levels rose to a mean of 402 pg/mL (range 3-3183 pg/mL) on day 15 of induction therapy for the AML15 trial (newly diagnosed) patients, while they rose to a mean of 1174 pg/mL (range 18.6-3818) in the 204 trial (relapsed) patients. In many patients on the 204 (relapsed) trial, FL levels remained elevated at day 42 of therapy (mean 641 pg/mL, range 4.4-5767) pg/mL). Following successive courses of consolidation chemotherapy, FL levels continued to rise higher with each course of chemotherapy in patients on AML15, with a mean of 3151 pg/mL after the 4th course. On comparing individual samples from both trials, we noted that samples with similar levels of drug but different levels of FL showed different degrees of FLT3 inhibition, with FL levels seeming to exert a negative influence on inhibition. To explore this phenomenon in vitro, we tested the influence of exogenous FL on FLT3 inhibition and cytotoxic effects exerted by lestaurtinib and 4 other FLT3 inhibitors- AC220, KW-2449, PKC-412, and sorafenib. In culture medium using FLT3 mutant cell lines (Molm14, TF/ITD), the IC50 for cytotoxic effect of all inhibitors shifted upwards 2-4-fold in the presence of exogenous FL at concentrations of 1000-3000 pg/mL (the levels we observed in patients following chemotherapy). A similar degree of shift was observed in immunoblot assays of FLT3 autophosphorylation using the same cell lines. In primary samples from AML patients that expressed predominantly the mutant allele (i.e., hemi- or homozygous FLT3/ITD), exogenous FL had similar effect as that seen in the cell lines: a modest effect on FLT3 autophosporylation, and a 2-4-fold shift upward of the cytotoxicity IC50 of FLT3 inhibitors. However, a somewhat different pattern was observed in samples from patients with heterozygous FLT3/ITD mutations (i.e., both mutant and wild type allele present). The addition of exogenous FL increased the degree of FLT3 autophosphorylation, and dramatically increased cell survival in culture medium. The enhanced survival was abrogated by FLT3 inhibition. These findings have important implications regarding trial design for FLT3 mutant AML. It is possible that any FLT3 inhibitor administered concomitantly with chemotherapy could be affected by this phenomenon, with only the most potent inhibitors being able to overcome the effects of FL in vivo. Furthermore, newly diagnosed FLT3/ITD patients (in whom the mutations are commonly heterozygous) might be predicted to respond differently to FLT3 inhibition according to the context in which the inhibitor is given- i.e., in the presence of absence of chemotherapy. Finally, we might speculate that FL is an important driver in FLT3 mutant AML, and may have a strong influence on prognosis. This hypothesis should be tested prospectively by examining FL levels in ingoing clinical trials in which FLT3 mutant AML patients are enrolled. Disclosures:Sato:Kyowa Hakko-Kirin: Employment. Knapper:Cephalon: Served on scientific advisory board. Levis:Cephalon: Member, clinical advisory board.

Factors Affecting Neutrophil Recovery After Autologous Bone Marrow-Derived Stem Cell Transplantation in Patients With Acute Myeloid Leukemia

Bone marrow is currently regarded as the most appropriate source of stem cells for patients with acute myeloid leukemia (AML) undergoing autologous transplants. A total of 55 adult patients with AML in first complete remission receiving autologous bone marrow-derived stem cell (BMSC) transplantation (BMSCT) were analyzed to determine factors affecting the rate of neutrophil recovery. All patients were treated with standard induction and three to four courses of consolidation chemotherapy and, after collection of BMSC, conditioned with BuCy2. The median time to neutrophil reconstitution was 30 (10–62) days and was delayed in 24 patients. Neutrophil recovery was faster in patients who had received granulocyte-macrophage progenitors (CFU-GM) dose >23.5 × 10 4/kg, CD34 + cells >3.2 × 10 6/kg, and mononuclear cells (MNCs) >3 × 10 8/kg. The speed of neutrophil recovery correlated with the number of transplanted CFU-GM progenitors ( P = .0077) and MNCs ( P = .0015). CFU-GM progenitors dose was the only factor close to significance in univariate analysis of neutrophil engraftment. Probability for neutrophil recovery was higher in patients transplanted with a higher dose of MNCs. These data suggested that the content of CFU-GM progenitors and MNCs within the bone marrow graft was the most important factor for the quality of neutrophil recovery after autologous BMSCT in AML patients.

Composite gastrointestinal lymphoma consisting of diffuse large B-cell lymphoma and peripheral T-cell lymphoma

Composite lymphomas are defined as two different types of lymphomas presenting in the same anatomic site [1]. A rare case of a composite gastrointestinal lymphoma consisting of diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell lymphoma (PTCL) is presented. A 65-year-old woman was diagnosed with mucosaassociated lymphoid tissue lymphoma of the duodenum in 2001. Eradication therapy for Helicobacter pylori resulted in complete remission of the lymphoma. After 4 years, she was admitted to our hospital due to hematemesis in December 2005. The levels of hemoglobin and soluble interleukin-2 receptor were 10.4 g/dL and 938.1 U/mL, respectively. Endoscopic examination revealed multiple ulcers in the stomach and ileum. On microscopy, both gastric and ileal ulcers showed diffuse proliferation of large lymphoid cells, which were positive for CD20, CD79a, and Epstein–Barr virus (EBV) encoded RNA-1 (EBER-1) in situ hybridization (ISH) and negative for CD3 and CD45RO (Fig. 1a–d). These findings were compatible with EBV-positive DLBCL of the elderly, according to the new WHO classification [2]. After 3 courses of combination chemotherapy (pirarubicin, vincristine, cyclophosphamide and prednisolone; THP-COP) with rituximab, the ileal ulcers disappeared, but the area of the gastric lymphoma enlarged. A partial gastrectomy was performed with a diagnosis of perforation of the stomach in April 2006. Unexpectedly, pathological examination of the resected specimen demonstrated diffuse proliferation of smallto large-sized lymphocytes with T-cell markers (positive for CD3, CD4, CD45RO, CD56 and TIA-1, and negative for CD8, CD20, CD79a and EBER-ISH, Fig. 1e–h). The diagnosis of PTCL was made, and the distribution of the disease and strong positivity of TIA-1 suggested enteropathyassociated T-cell lymphoma. Since the size of the lymphoma cells was mainly small to medium and they were positive for CD56, we speculated that the lymphoma could be classified into enteropathy-associated T-cell lymphoma type 2 [3, 4]. However, the mucosa of the specimen was almost destroyed and the distribution pattern was not clear. Retrospectively, we performed PCR analysis of T-cell receptor (TCR) gamma chain gene in the gastric specimen at the DLBCL stage in 2005 and PTCL stage in 2006 (Fig. 2). Although scattered T cells were present in the specimen, rearrangement of TCR was not detected. On the other hand, strong rearranged band was detected at the PTCL stage. Since PTCL was diagnosed during the course of chemotherapy against DLBCL and residual B-cell disease could not be denied after gastrectomy, the patient was given 2 courses of consolidation chemotherapy (etoposide, methylpredonisolone, cytarabine and cisplatin; ESHAP) with rituximab. Achievement of complete remission was confirmed by 18[F]fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan in June 2006. However, Y. Tachikawa M. Shiratsuchi E. Sada K. Idutsu J. Kiyasu R. Takayanagi Y. Abe (&) Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan e-mail: abey@intmed3.med.kyushu-u.ac.jp

Randomized, phase III study of mitomycin/vindesine/cisplatin (MVP) versus weekly irinotecan/carboplatin (IC) or weekly paclitaxel/carboplatin (PC) with concurrent thoracic radiotherapy (TRT) for unresectable stage III non-small cell lung cancer (NSCLC): WJTOG0105

7504 Background: Weekly chemotherapy with concurrent TRT displays acceptable toxicities and dependable efficacy. We conducted a randomized phase III trial to assess the efficacy and toxicity of weekly chemotherapy with concurrent TRT against MVP with concurrent TRT via a non-inferiority design. Methods: MVP: mitomycin (8 mg/m2 on days 1, 29), vindesine (3 mg/m2 on days 1, 8, 29, 36), and cisplatin (80 mg/m2 on days 1, 29) with concurrent TRT (60 Gy). Patients (pts) subsequently received 2 courses of consolidation chemotherapy with MVP; IC: weekly irinotecan (20 mg/m2)/carboplatin (AUC 2) for 6 weeks and TRT (60 Gy) followed by 2 courses of irinotecan (50 mg/m2)/carboplatin (AUC 5); PC: weekly paclitaxel (40 mg/m2)/carboplatin (AUC 2) for 6 weeks and TRT (60 Gy) followed by 2 courses of paclitaxel (200 mg/m2)/carboplatin (AUC 5). The primary endpoint was overall survival (OS), with secondary endpoints of progression free survival (PFS), response, and toxicity. Results: From Sep 2001 to Sep 2005, 456 pts were randomized. Pretreatment characteristics were well-balanced among 3 arms. Major toxicity incidences: The incidence of G3–4 neutropenia in the MVP, IC, and PC arms was 95.9, 72.1, and 46.9 % (p&lt;0.001). The G3–4 non-hematologic toxicity incidences in terms of fatigue, febrile neutropenia, and gastrointestinal disorder were 13.0, 6.1, and 4.8 % (p&lt;0.001), 37.0, 8.8, and 10.2 % (p&lt;0.001), and 24.0, 8.2, and 9.5% (p&lt;0.001) in the respective arms. The overall response rates were 66.4, 56.5, and 63.3 %, in the MVP, IC and PC arms, respectively. The median survival times were 20.5, 19.8 and 22.0 months and the median PFS (MPFS), 8.2, 8.0 and 9.5 months in MVP, IC and PC. Non-inferiority of the 2 experimental arms compared with MVP was not achieved, though no significant differences in OS and PFS were apparent among treatments. The PC arm displayed the most favorable MST, MPFS, and hematologic/non-hematologic toxicities. Conclusions: Weekly PC with TRT displays similar efficacy and more favorable toxicity profiles compared to MVP with TRT. Weekly PC with TRT warrants use as the reference regimen in forthcoming studies. [Table: see text]

Successful Prevention of Acute Graft-versus-Host Disease Using Low-Dose Antithymocyte Globulin after Mismatched, Unrelated, Hematopoietic Stem Cell Transplantation for Acute Myelogenous Leukemia

In this study, we investigated the effects of low-dose antithymocyte globulin (ATG, thymoglobulin) in the prevention of acute graft-versus-host disease (aGVHD) in mismatched, unrelated hematopoietic stem cell transplantations (uHSCTs) in patients with the single disease entity of acute myelogenous leukemia (AML). Patients (n = 103) with a variable risk for AML who received uHSCTs from available Asian and Caucasian donors were enrolled. First, we compared HLA-matched (group 1, n = 54) and HLA-mismatched (group 2, n = 49) transplantation patients. Then, we divided the patients in group 2, who had received transplants from allele(s)/antigen-mismatched donors, into 2 subgroups: patients who used ATG (group 3, n = 24) and those who did not (group 4, n = 25). To prevent the development of aGVHD, the patients in group 3 received ATG at a dose of 1.25 mg/kg body weight per day for 2 consecutive days, together with our standard regimen of methotrexate (MTX) and tacrolimus. The median CD34(+) cell infusion was 4.2 x 10(6)/kg (range: 1.2-34.4). The median patient age was 41 years (range: 16-57), and the median follow-up duration of patients who were event-free survivors was 23 months (range: 2-72). The overall incidences of aGVHD and chronic GVHD (cGVHD) were 38% and 56%, respectively. Of 48 evaluable patients in group 2, 10 (21%) developed moderate to severe aGVHD (grades II-IV). In contrast, 2 (8%) of the 24 patients in group 3 and 7 (29%) of the 24 evaluated patients in group 4 required therapy for aGVHD (grades II-IV; P = .038). The incidence of cGVHD was not different between groups 3 and 4. The estimated probabilities of overall survival (OS) and event-free survival (EFS) at 2 years for group 2 were 55% and 44%, respectively. In comparison, the estimated probabilities of OS and EFS at 2 years for groups 3 and 4 were 68% versus 38% (P = .043) and 58% versus 38% (P = .103), respectively. The overall cumulative incidence of nonrelapse mortality (NRM) was 29% in group 2. The cumulative incidence of NRM differed markedly between group 3 (16%; 95% confidence interval [CI], 4%-28%) and group 4 (44%, 95% CI, 34%-54%) (P = .013). We found no difference in cytomegalovirus (CMV) reactivation between groups 3 and 4. These results suggest that in mismatched uHSCT, a low dose of ATG (total 2.5 mg/kg) may prevent moderate to severe aGVHD, with comparable rates of relapse and CMV reactivation and a greatly decreased rate of NRM.

Gemtuzumab Ozogamicin as Induction Therapy Followed by Post-Remission Hematopoietic Stem Cell Transplantation in Elderly Patients with Acute Myeloid Leukemia

Previously, we reported the effectiveness and safety of combining gemtuzumab ozogamicin (GO) with our center's modified standard induction chemotherapy (IC) in elderly patients with untreated acute myelogenous leukemia (eAML)(Eom et al., Eur J Haematol 2007; 79:398–404). However, little is known about the impact of GO IC on hematopoietic stem cell transplantation (HSCT) and no study in this setting has been published. We hypothesized that GO IC could have beneficial effects on HSCT in eAML. On day 1, GO was administered at a dose of 6 mg/m2 as a single 2-h intravenous infusion. Following GO, a modified schedule of our center's standard IC consisting of idarubicin (12 mg/m2/d, days 2–4) and N4-behenoyl-1-β-arabinofuranosyl cytosine (300 mg/m2/d, days 2–6) was given. All patients in complete remission (CR) received 1 or 2 cycles of consolidation chemotherapy depending on whether they were to undergo autologous or allogeneic HSCT. Patients with HLA-matched sibling donors received one course of consolidation chemotherapy, which consisted of 4~5 d of modified FLANG (fludarabine, cytosine arabinoside, mitoxantrone, and G-CSF) or a short repeated schedule of 4d of GO IC, and then proceeded to autologous or reduced intensity conditioning (RIC) HSCT. The preparative regimens for allogeneic transplants consisted of fludarabine (30 mg/m2/d, days–6 to –2) and busulfan (3.2 mg/kg/d, days–5 and –4) intravenously, or total body irradiation (1200 cGY fractionated, days–7 to –5), cytosine arabinoside (1.5 g/m2 bid, days–4 to –2) and melphalan (100 mg/m2/d, day–1) intravenously for autologous HSCT. In an allogeneic setting, cyclosporine and a short course of methotrexate were used to prevent graft-versus-host disease. Subcutaneous granulocyte colony-stimulating factor (G-CSF) was started on day +3 (autologous) or day +7 (allogeneic) and continued until the absolute neutrophil count reached 0.5 × 109/L on three consecutive days. Fifty-six elderly patients diagnosed as de novo AML have received GO IC since June 2005, and CR was achieved in 42 patients (75%). Sixteen of the patients were enrolled in a setting of HSCT: 10 patients were categorized as intermediate-risk and the others as high-risk cytogenetically. There were 6 men and 10 women with a median age of 61 years (range 56–66 years). All were in CR (CR1=15, CR2=1) pretransplant and the median follow-up duration was 21 months (range 13–34). Of these, seven patients underwent autologous HSCT and four patients are alive in CR. The cause of death for all three patients was relapse. Five and four patients received RIC HSCT from HLA-matched sibling and unrelated donors, respectively, and six patients are alive in CR. The causes of death include one case of relapse and two nonrelapse transplant-related deaths, including one case of severe acute GvHD. The estimated 3-year overall survival and event-free survival rates were 60 and 53%, respectively. Despite the limited numbers, GO IC induced CR with good efficacy and enabled HSCT with no critical sequelae for elderly patients. Our results suggest that elderly patients with AML have a better chance when undergoing HSCT and a better outcome using GO IC.

Impact of CRi on the Outcome of Elderly Patients with Untreated Acute Myeloid Leukemia (AML)

New international recommendations of response for treatment of AML include morphologic complete remission with incomplete blood count recovery (CRi). This response criteria was defined following evaluation of new drugs used for the treatment of AML in first relapse (Sievers et al., JCO 2001; 19:3244–3254). The objective of our study was to evaluate this criterion in elderly patients with AML who are in first line of treatment. Between 1995 and 2006, 454 patients aged 55 years or older with previously untreated acute non promyelocytic leukemia received a conventional anthracycline and cytarabine induction chemotherapy in our institution. Ages were between 55 and 85 years (median 65 years). Two hundred and fourty-eight patients achieved a complete response (CR) (55%), 37 patients achieved CRi (8%), 104 patients had persisting leukemia (23%), and 49 died during remission induction therapy (13%). Multilineage dysplasia, secondary AML and blasts expressing CD34 were significantly more frequent in patients achieving CRi than CR (58% versus 29%, p=0.001, 33% versus 15%, p=0.007, and 79% versus 54%, p=0.01, respectively). No favorable prognostic karyotype was found in the CRi group but cytogenetic distribution did not differ statistically between the two groups. All patients who reached CR or CRi were scheduled to receive consolidation. Only 24 patients (65%) in CRi actually received this consolidation chemotherapy course and 11 patients (30%) had intensification (intermediate-dose cytarabine and/or autologous stem cell transplantation) whereas for patients achieving CR, 233 (94%) and 214 patients (86%) received consolidation and intensification, respectively (p<0,001 for both). None of the patients in CRi received an allogenic stem cell transplantation whereas 18 (7%) of CR patients had one (p=0,2). Disease-free survival (DFS) and remission duration were significantly different between patients in CRi and CR, with a median of 4 and 12 months, and 5 and 9 months respectively (p<0,001 and 0,03). The median overall survival (OS) was also significantly lower for patients in CRi versus CR, respectively 8 and 23 months (p<0,001). By landmark analysis, there was no difference in OS between patients in CRi and a group of 98 patients with induction failure surviving at least 60 days (p=0,4). We also noted that OS was better, in the group of patients in CRi, for those who finally achieved CR criteria after 1 or more course of post-remission chemotherapy (median 16 months, against 7 months for patients still in CRi, p=0,03). Our results show that the CRi criterion is not equivalent to CR in elderly patients who received intensive chemotherapy as the first line treatment of AML. This should be kept in mind when the results of new agents used in this setting are compared to historical data.

Anal Cancer: The End of the Road for Neoadjuvant Chemoradiotherapy?

Anal Cancer: The End of the Road for Neoadjuvant Chemoradiotherapy?

Chemoradiotherapy with or without consolidation chemotherapy using cisplatin and 5-fluorouracil in anal squamous cell carcinoma: long-term results in 31 patients

BackgroundThe objectives of this study were to evaluate long-term results of concurrent chemoradiotherapy (CRT) with 5-fluorouracil and cisplatin and the potential benefit of consolidation chemotherapy in patients with anal squamous cell carcinoma (ASCC).MethodsBetween January 1995 and February 2006, 31 patients with ASCC were treated with CRT. Radiotherapy was administered at 45 Gy over 5 weeks, followed by a boost of 9 Gy to complete or partial responders. Chemotherapy consisted of 5-fluorouracil (750 or 1,000 mg/m2) daily on days 1 to 5 and days 29 to 33; and, cisplatin (75 or 100 mg/m2) on day 2 and day 30. Twelve patients had T3–4 disease, whereas 18 patients presented with lymphadenopathy. Twenty-one (67.7%) received consolidation chemotherapy with the same doses of 5-fluorouracil and cisplatin, repeated every 4 weeks for maximum 4 cycles.ResultsNineteen patients (90.5%) completed all four courses of consolidation chemotherapy. After CRT, 28 patients showed complete responses, while 3 showed partial responses. After a median follow-up period of 72 months, the 5-year overall, disease-free, and colostomy-free survival rates were 84.7%, 82.9% and 96.6%, demonstrating that CRT with 5-fluorouracil and cisplatin yields a good outcome in terms of survival and sphincter preservation. No differences in 5-year OS and DFS rates between patients treated with CRT alone and CRT with consolidation chemotherapy was observed.Conclusionour study shows that CRT with 5-FU and cisplatin, with or without consolidation chemotherapy, was well tolerated and proved highly encouraging in terms of long-term survival and the preservation of anal function in ASCC. Further trials with a larger patient population are warranted in order to evaluate the potential role of consolidation chemotherapy.

Randomized Trials in Oncology Stopped Early for Benefit

atedwithimprovedsurvival(hazardratio[HR],0.55;95%CI,0.38 to0.80;P.002).Giventheimplausibilityoftheseresults(because ofthelargerthanexpectedeffectonmortalityanditsinconsistency with the reduction in the risk of relapse, the key postulated mechanism for improved survival), the investigators continued the trial despite the apparent difference in survival. After random assignment of more than 1,000 patients, a significant survival advantage for five courses of consolidation chemotherapy could not be demonstrated, with an HR of 1.09 (95% CI, 0.87 to 1.37; P .4). The apparently significant results observed after few end points (ie, deaths) had occurred may be explained by data analysis at a “random high,” when a disproportionate number of events had occurred in the experimental arm by chance. Had this trial been stopped early and its results used to justify an additional course of consolidation chemotherapy, subsequent patients with acute myeloid leukemia would have been exposed to a costly, potentially toxic and ineffective therapy. The extent to which medical oncology RCTs that are stopped early for benefit manifest problems of inadequate reporting and likely effect overestimations, remains uncertain. Therefore, we examinedindetailthemedicaloncologyRCTspreviouslyreportedin the larger systematic review. 1 We reviewed the study characteristics, features related to the decision to monitor and stop the study early (sample size, interim analyses, monitoring and stopping rules), the number of events, and the estimated treatment effects reportedinthe29RCTsinmedicaloncologythathadbeenstopped early for benefit (Appendix, online only).

Autologous Peripheral Blood Stem Cell Transplantation (PBSCT) Combined with Haploidentical Lymphocytes Infusion Increases the Long Term Survival of Adult Acute Myeloid Leukemia with Standard Risk.

OBJECTIVES: The long term survival of adult patients with acute myeloid leukemia with standard risk factor which treated by autologous peripheral blood stem cell transplantation is about 30–50%. We designed a new therapy to improve the long term survival of adult patients with acute myeloid leukemia with standard risk factor. After completely remission, patients underwent 2–3 courses of consolidation chemotherapy. Autologous peripheral blood stem cell transplantation (PBSCT) was performed. After hematology recovery, haploidentical lymphocytes irradiated with 7.5 Gy were infused into patients. Here we evaluate the outcome of this approach in adult patients with acute myeloid leukemia with standard risk.METHODS: From July 1998 to July 2007, twenty-four patients including 17 males and 7 females, median age 36 year old (range 14–58) with acute myeloid leukemia with morphology M2 subtype and normal karotype received this approach therapy. Autologous peripheral blood stem cells were collected by aphereses and froze in −198° and storied after 2–3 courses of median dose cytarabine consolidation chemotherapy The autologous stem cells were grafted to patients following the conditioning with the BuCy regimen (Bu16mg/kg and CTX 120mg/kg). Haploidentical lymphocytes obtained by leukapheresis from sibling donors or other relatives were irradiated with 7.5 Gy and were infused into patients after hematopoietic reconstitution.RESULTS: A median dose of 2.5×108/kg, nucleated cells/kg (range, 2.97×107/kg-6.0×108/kg)containing 5 × 106 CD34+ cells/kg (range,1.5– 4.8) were autografted. All patients were got hematopoietic reconstitution. The median time for granulocyte recovery >0.5 × 109 /L was 11 days and for platelets >20 × 109/L was 14 days following transplantation. All patients were administrated a median dose of 2.0×108/kg haploidentical lymphocytes irradiated with 7.5 Gy. Severe acute GVHD occurred in two patients. One died with severe acute GVHD. Hematopoietic reconstitution delayed in four patients. No other side effects were observed. For the whole group of 24 patients, the median overall survival rate (OSR) was 83.7%. The median disease-free survival (DFS) time was 28.3 moths (range 2–120 m) and the 5-year DFS rate was 50%. The 2-year OS rate was 71%. After a median follow-up of 5.0 years from transplantation, the median DFS and OS were 28.3 years respectively, and the 3-year rates were 50%. Nineteen patients were still in continuous complete remission, 4 patients had relapsed and 3 had died.CONCLUSIONS: Autologous peripheral blood stem cell transplantation (PBSCT) combined with haploidentical lymphocytes infusion may prolong the long term survival of adult acute myeloid leukemia with standard risk.

Treatment Type Determines Gene Expression Changes from Pretreatment (PTx) to Relapse (Rel) in Acute Promyelocytic Leukemia (APL).

The molecular changes responsible for the recurrence of APL after achieving complete remission are largely unknown. The Phase III trial E2491 provided a venue for investigating whether treatment type had an effect on the changes in gene expression that occur from PTx to Rel, since ¼ of patients were randomized to receive only chemotherapy (C-set patients), while ¾ of patients additionally received all-trans retinoic acid (ATRA) either during the induction and/or maintenance phases of treatment (A-set patients). High-quality, ethanol-stored RNA was available from matched PTx and Rel samples with ≥85% blasts from 3 C-set and 3 A-set patients, who had the following characteristics:Patient-SetPTx WBCFAB ClassP-Rα TypePTx MutationsRel MutationsDays on ATRADays off ATRA1-C68.6M3VNoneFlt3ITD & D8350N/A2-C2.4M3SFlt3ITD & D835Flt3ITD0N/A3-C0.4M3vSFlt3ITD & D835Flt3ITD0N/A4-A77.4M3vVFlt3ITDPML-RARα142 Maintenance05-A3.0M3L--365 Maintenance3446-A10.9M3VPMLPML19 Induction410Gene expression analysis utilized the Affymetrix Human Genome U-133 Plus 2.0 chip. Of 54,613 gene probe sets (gps), 6220 gps for named genes with a mean value >100 for all samples and a ≥100 absolute difference between PTx and Rel values were selected for study. By unsupervised hierarchical cluster analysis, the overall samples segregated into 2 major groups, PTx or Rel with single exceptions. The PTx samples co-segregated into 2 groups according to the co-incident parameters of high WBC count and V-form PML-RARα (Patients 1,4,6 vs 2,3,5). Most notably, the Rel samples segregated by treatment type, C-set and A-set. In order to identify the gps most significantly contributory to differences between the C- and A-set gene expression profiles, we made two linked analyses. First, 575 gps were selected based on the criteria of an ≥1.5-fold difference, p <0.05, between the average expression level of each gps in the 3 relapse samples of the A-set vs the C-set. Second, we identified 92/575 genes with a statistically-significant fold-change (p ≤0.05, paired T-test) from PTx to Rel. After editing out redundant gps, 21 unique gene transcripts (ugt) were upregulated (Up) and 54 ugt were downregulated (Dn) from PTx to Rel. There was a high degree of concordance between the fold-difference values in the Rel samples and the fold-change values from PTx to Rel. Remarkably, for 19/21 Up ugt and 49/54 Dn ugt, the selection was based on greater change in A-set than C-set samples. Prominent among the selected A-set ugt were those affecting DNA repair/replication (Up: NPN; Dn: RAD17, RPA1, PARP1, MCM3) and signal transduction (Up: STAT3, IRAK3, LIMK2, GRB10; Dn, STS-1, CSNK2A1, PAK2, OPN3). These results indicate that the addition of ATRA to chemotherapy-based treatment of APL (all patients received 2 courses of consolidation chemotherapy) had a major impact on the gene expression profile at relapse, which further suggests that ATRA treatment made an important and unique contribution to the molecular progression process leading to relapse.

Impact of CRi on the Outcome of Elderly Patients with Acute Myeloid Leukemia.

New international recommendations of response for treatment of acute myeloid leukemia (AML) include morphologic complete remission with incomplete blood count recovery (CRi). This response criteria was defined following evaluation of new drugs used for the treatment of AML in first relapse (Sievers et al., JCO 2001; 19:3244–3254). The objective of our study was to determine the outcome of elderly patients with newly diagnosed AML achieving CRi. Between 1995 and 2006, 240 patients aged 65 years or older with previously untreated acute non promyelocytic leukemia received a conventional anthracycline and cytarabine induction chemotherapy at a single institution. Median age was 71 years (range, 65–85). One hundred and nineteen patients achieved a complete response (CR) (50%), 15 patients achieved CRi (6%), 69 patients had persisting leukemia (29%), and 37 died during remission induction therapy (15%). Patients who reached a CR or CRi after 1 or 2 cycles of induction chemotherapy proceeded to consolidation. Only 9 patients in CRi received this consolidation chemotherapy course (60%) and none had intensification (intermediate-dose cytarabine and/or autologous stem cell transplantation) whereas for patients achieving CR, 88% (n=104) and 69% (n=82) had consolidation and intensification, respectively (p=0,01 and p=0,03). The median overall survival (OS) was respectively 9 and 18 months for patients in CRi and CR (p=0,08). OS was significantly lower for patients in CRi younger than 70 years (5 versus 17 months for CR, p=0,02). By landmark analysis, there was no difference in OS between patients in CRi and a group of 67 patients with induction failure surviving at less 40 days (p=0,14). Disease-free survival (DFS) and remission duration were not significantly different between patients in CRi and CR overall (5 and 8 months, and 5 and 7 months, respectively), but we found a difference for patients younger than 70 years (p=0,004 and p=0,009 for DFS and remission duration, respectively). There was significantly more multilineage dysplasia in patients achieving CRi (8 versus 33, p=0,009) and platelet count at diagnosis were lower (44 G/L versus 82 G/L). Cytogenetic did not differ between the two groups. Our results show that the outcome of elderly patients who achieved CRi is inferior to patients in CR, especially for patients younger than 70 years. Although this response criteria seems to indicate activity, we were not able to found a difference with patients who did not achieve CR. This result will be revaluated in a larger study. Our data also suggest that patients with CRi have different initial disease characteristics. [Display omitted]

Gemtuzumab ozogamicin in combination with attenuated doses of standard induction chemotherapy can successfully induce complete remission without increasing toxicity in patients with acute myeloid leukemia aged 55 or older

In this study, the effectiveness and safety of combining gemtuzumab ozogamicin (GO) with an abbreviated schedule of standard induction chemotherapy were assessed in 37 patients (aged > or =55) yr with previously untreated acute myeloid leukemia (AML). GO was administered at a dose of 6 mg/m(2) as a single 2-h intravenous infusion on day 1. Following GO, an abbreviated schedule of induction chemotherapy consisting of idarubicin (12 mg/m(2)/d, days 2-4), and N4-behenoyl-1-beta-arabinofuranosyl cytosine (300 mg/m(2)/d, days 2-6) was given. Thirty-seven patients were treated with GO in combination with chemotherapy. Complete remission (CR) and CR with incomplete platelet recovery were achieved in 28 patients (75.7%) and one patient (2.7%) respectively. Two patients (5.4%) died during induction and two patients (5.4%) with grade 4 treatment emergent adverse effects during chemotherapy did not complete induction chemotherapy. The majority of toxicities were mild and manageable. Severe myelosuppression was universal with significantly prolonged thrombocytopenic period. In total, 25 patients who received consolidation treatment, 19 patients remain alive at the time of analysis. Thirteen patients had undergone hematopoietic stem cell transplantation, three are preparing for transplantation and seven are receiving their consolidation chemotherapy course. Although only a relatively small number of cases were included in this preliminary study and the follow-up duration was short, frontline GO in combination with attenuated conventional chemotherapy was found to be effective and feasible in elderly patients with AML.