VP-16 Regimen Research Articles

Combination of Olverembatinib and VP Regimen As First-Line Therapy for Adult Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Backgrand ： Ph+ALL is the largest genetically defined subtype in adult ALL and is considered associated with high relapse risk and inferior clinical outcomes. The combination of tyrosine kinase inhibitors (TKI) with intensive chemotherapy has achieved a major step forward in the therapy of Ph+ALL in deep response and long-term survival. The upfront use of third generation TKI ponatinib has improved the frequency of complete molecular response (CMR) and the overall survival rate to a greater extent. More interesting, the data coming from MDACC showed that combination of ponatinib in the chemotherapy in Ph+ALL maybe challenge the need for stem cell transplantation (SCT) in most patients who achieved CMR (defined BCR-ABL1 transcript < 0·01%) within 3 months after induction therapy. But the cardiovascular adverse event(AE) of ponatinib was more and severely frequently occurred in the former reports. Olverembatinib,a new third generation of TKI, which can also suppress the mutation of T315I and showed promising results in the Ph+CML. Herein we designed the clinical trial to invest the efficiency and safety of Olverembatinib combine with VP regimen (OVP) on Ph+ALL patients as the first-line therapy. Motheds: In this multi-centers, phase 2, single-arm trial, adult patients with previously untreated Ph+ALL were sequentially enrolled. The patients had to be aged 18 years or older, have normal cardiac function (defined by ejection fraction above 50%), and have adequate organ function (serum creatinine≦3*ULN，BUN≦3*ULN，ALT≦3*ULN，AST≦3*ULN，serum bilirubin≦3*ULN). They received three cycles of OVP regimen(for 28 days each cycle :olverembatinib 40mg qod d1-28，Vindesine 4mg d1,8,15,22,Prednisone1mg/Kg/d d1-21,0.5mg/kg/dd22-28). Twelve intrathecal injections of cytarabine alternating with methotrexate were designed as central nervous system prophylaxis in the following therapy after the diagnosis. Findings: 32 patients were screened and 29 were eligible from June 21, 2022 until 21 July,2023. 3 Patients were withdrawn from the clinical trial(1 refused therapy after induction,1 early death due to Covid infection, 1 Protocol deviation ).Among all , Male 12 and Female 17. BCR/ABL1 transcript:M-p210 (11),m-p190（18）.The Median Age was 45(19-74) years old. The Median WBC was 24.8(1.06-308.00) *10E9/L. The treatment has resulted in a 100% overall response, including 96% (24/25) CR and 4% (1/25) CRp. As of data collection,23 finished 3cycles of OVP chemotherapy and 82.6% (19/23) got CMR.AS far the rest 6 patients, 1 got CMR after 1 cycle OVP,1 got CMR after 2cycles of OVP, the other 4 patients were undergoing induction therapy. The total CMR rate was 84% (21/25) at any time. The CMR rate was 36%（9/25） ,76%（19/25）and 82.6%(19/23) at 4weeks,8weeks and 12 weeks respectively. Among all the patients finished the 3 cycles, there were 4 patients not reached the CMR and all of them were M-bcr/abl-p210 protein status. The best response was MMR for 3 patients and CR for 1patient. The CMR rate was 70% (7/10) in M-bcr/abl-p210 transcript and 100% (13/13) in that of m-bcr/abl-p190. During a median follow-up of 241 days, one patient died within one month after transplantation, while all the remaining survived without relapse. During induction therapy, 4 patients had platelets consistently above normal values and 4 patients did not experience a further decrease in hemoglobin compared to baseline. The median time for the occurrence of the lowest values of platelets, hemoglobin, and neutrophils was 6th, 12th, and 11th respectively. The most common non-Hematology AE was liver function damage. AE events greater than or equal to grade 3 included 2 cases of elevated Alanine transaminase ,3 cases γ- GT elevation and 2 cases of triglyceride elevation. Other AEs were mild and less than level 3. Discussion: Ongoing efforts exist to optimize therapeutic options in the frontline for Ph+ALL. The future lies in using less cytotoxic and more targeted agents. The first results of our ongoing trial indicate that the OVP regimen is effective in achieving early high rate of CMR in patients with newly diagnosed Ph+ALL as first-line therapy. All these results were achieved with surprisingly few toxic effects.Until now,16 patients underwent ASCT. Will the excellent outcomes be preserved with longer？ Will there be a difference in long-term outcomes between patients who underwent ASCT and those who do not?The trial is ongoing. we need more time to observe.

Olverembatinib Plus Low-Intensive Regimen in Frontline Therapy for Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia： a Case Series from a Single Center

BCR::ABL1 tyrosine kinase inhibitors (TKI) have shown promising results in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). However, resistance and intolerance to TKIs remains a clinical challenge. Olverembatinib is an oral, novel third-generation TKI developed by Ascentage Pharma. Olverembatinib is effective against most ABL1 kinase domain mutants, including mutant T315I. In November 2021, olverembatinib was approved in China for the treatment of adults with BCR::ABL1T315I-mutant chronic myeloid leukemia (CML). However, data on clinical use of olverembatinib in Ph+ ALL are very limited. Herein, we report a retrospective analysis of patients with newly diagnosed Ph+ ALL who received olverembatinib plus low-intensive regimen (VP: Vindesine + dexamethasone / prednisone ) at our institution. Olverembatinib was administered at a dose of 40 mg orally QOD continuously. Vindesine was given 4 mg intravenously on day 1, 8, 15, 22 and dexamethasone /prednisone was administered from days 1 to 22 during induction. After two courses of olverembatinib plus VP, olverembatinib-based regimens was recommended for consolidation. The choice of sequentially consolidation treatment with allogeneic hematopoietic stem-cell transplantation (allo-HSCT), blinatumomab or intensive chemotherapy, was made by the investigators and patients preference. Prophylactic intrathecal chemotherapy with cytarabine and dexamethasone was administered in each cycle. Maintenance therapy was olverembatinib and low-intensive regimens. The primary endpoint was complete molecular response (CMR) rate. CMR was defined as BCR-ABL1/ABL1 ratio < 0.01% by quantitative real-time polymerase chain reaction(qPCR). Between November 2021 and June 2022, a total of 12 consecutive patients with Ph +ALL treated with the olverembatinib plus VP at our center were enrolled. The median age was 48 years (range, 18-72 years). Ten patients were male and two were female. The median white-cell counts were 77,000 per cubic millimeter (range, 1200 to 356,000). Seven patients had the p190 fusion transcript, five had the p210 transcript. All 12 patients completed induction phase with olverembatinib plus VP regimen. At the end of the 4 weeks of induction , all 12 patients (100%) achieved complete hematologic response. The primary endpoint CMR was reached in 6/12 patients (60%) at 4 weeks; in 12/12 patients (100%) at 8 weeks. For treatment-emergent adverse events, most of which were mild and manageable. No serious nonhematologic toxicities were observed. With a median follow-up of 5 months, all patients were in CMR in the last follow-up, four patients proceeded to allo-HSCT. Conclusions: Olverembatinib was well tolerated and showed high early response in newly diagnosed Ph +ALL. These promising findings warrant further investigation in future trials.

Safety and tolerability of T-SIGn vectors when administered using “flat” versus “low-high-high” (LHH) dosing regimens.

2572 Background: Tumor-selective viruses, particularly those dosed systemically to deliver transgenes, are potentially powerful cancer therapies. However, acute cytokine reactions to viral particle (vp) infusion may affect vector tolerability [Small 2006], thereby limiting the maximum tolerated dose (MTD) and subsequent transgene delivery. T-SIGn vectors (e.g. NG-641 and NG-350A) are transgene-armed variants of the epithelial tumor-selective adenovirus enadenotucirev (EnAd). Acute serum cytokine increases post-dosing have been seen at the MTD of EnAd (“flat” dosing of 3 x 1012 vp on Days [D] 1, 3 and 5) [Machiels 2019]. Following supportive preclinical data [McElwaine-Johnn 2019], we explored if a LHH dosing regimen, in which a lower dose is given on D1 prior to two higher doses on D3 and 5, may improve vector safety/tolerability thereby allowing higher cumulative doses to be given. Methods: Data were pooled from three Phase 1 dose-escalation studies in advanced/metastatic epithelial cancer: SPICE (EnAd + pembrolizumab/nivolumab; NCT02636036), FORTITUDE (NG-350A ± pembrolizumab; NCT03852511) and STAR (NG-641; NCT04053283). Serum cytokines were measured using a 17-analyte Luminex assay. IL-6/MCP-1 data for D1, 3 and 5 (pre- and 6-10 hrs post-dose) were analyzed to examine acute cytokine changes. TNFα/IFNγ were examined due to their association with cytokine release syndrome (CRS). Samples analyzed from SPICE/FORTITUDE were taken before PD-1 inhibitor administration. Results: 84 patients (SPICE n=51; FORTITUDE n=18; STAR n=15) were included in these analyses; 79 had cytokine data. AEs and Gr≥3 AEs within 1 wk of first dose, and DLTs at any time, were less frequent with a LHH vs flat dosing regimen (Tbl). Importantly, a LHH dose of 1-6-6 (1 x 1012 vp on D1; 6 x 1012 vp on D3 and 5; greater than the previous flat MTD) was tolerated. Acute increases in TNFα/IFNγ were limited and no severe CRS was seen. Increases in IL-6/MCP-1 with 1 x 1011 or 1 x 1012 vp flat dosing were negligible, whereas acute increases in IL-6/MCP-1 were seen after the first dose of 3 x 1012 vp when given as a flat dose (negligible increases on D3/5). Notably, cytokine responses with 1-3-3 dosing (1 x 1012 vp on D1; 3 x 1012 vp on D3 and 5), including after the first 3 x 1012 vp dose on D3, were negligible. Cytokine responses after the first dose of 6 x 1012 vp in the 1-6-6 regimen were similar to those seen with the first dose of the flat 3 x 1012 vp regimen. Conclusions: LHH dosing appears to induce a desensitization mechanism allowing higher cumulative doses of T-SIGn vectors to be given without the associated acute reactions to viral infusions. This finding may have implications for optimizing safety-efficacy profiles of viral vectors in cancer. Clinical trial information: NCT02636036, NCT03852511 and NCT04053283. [Table: see text]

Comparison of Cyclophosphamide- Versus Etoposide-Based Chemomobilization for Autologous Stem Cell Transplant in Lymphoma

Background Chemomobilization is a strategy commonly used for hematopoietic progenitor cell collection prior to high dose chemotherapy followed by autologous stem cell transplant (aHCT). Collection protocols and target yields for aHCT are variable and institution specific. At UNC Hospital, etoposide (VP16) was the preferred chemomobilization agent, but was switched to cyclophosphamide (Cy) due to a drug shortage beginning in February 2018. This study compares the efficacy and safety of Cy- and VP16-based chemomobilization strategies. Methods This is a single-center retrospective review comparing all lymphoma patients between January 1, 2017 and April 30, 2019 receiving chemomobilization with either a single dose of Cy 2 g/m2 or VP16 300 mg/m2 daily for two days. All patients received G-CSF at 10 mcg/kg rounded to nearest vial size starting approximately 24 hours after chemotherapy through completion of collection, while select patients used plerixifor per institutional algorithm. The primary endpoint was the rate of successful stem cell collection, defined as 2 × 106 CD34+ cells/kg in two or fewer apheresis sessions. Secondary endpoints included the rate of optimal stem cell collection of at least 4 × 106 CD34+ cells/kg in two or fewer apheresis sessions, time between chemomobilization and final apheresis session, rate of plerixafor use, incidence of febrile neutropenia, hemorrhagic cystitis, emergency department (ED) visits, and hospital admission rates between chemomobilization and final apheresis session as well as time to neutrophil and platelet engraftment. Results There were no differences in sex, race, or diagnoses between patients receiving Cy (n=28) vs. those who received VP16 (n=31). There was a trend towards older age in the Cy group, [median age 60 (range, 20-76) vs 53 (23-75) years; p=0.06]. All patients in both arms collected 2 × 106 CD34+ cells/kg in two or fewer apheresis sessions and there was no difference in stem cell collection of at least 4 × 106 CD34+ cells/kg in two or fewer apheresis sessions between the groups (Cy: 85.7%, VP16: 74.2%; p=0.27). Plerixafor was used in 23 patients (Cy: 39.3%, VP16: 38.7%; p=0.96). Rates of febrile neutropenia (Cy: 10.7%, VP16: 3.2%; p=0.34), hemorrhagic cystitis (Cy: 0%, VP16: 0%; p>0.99), ED visits (Cy: 10.7%, VP16: 12.9%; p>0.99), and hospital admission (Cy: 7.1%, VP16: 6.5%; p>0.99) were similar. The median days between chemomobilization and final apheresis were similar [Cy: 12 days (8-18), VP16: 12 days (8-15); p=0.32]. There were no differences in the median days to neutrophil [Cy: 11 (9-26), VP16: 11 (9-14); p=0.80) or platelet engraftment [Cy: 14 (10-38), VP16: 15 (11-149); p=0.16) between Cy and VP16 regimens. Conclusion There was no difference in the rates of successful stem cell collection or adverse events between Cy and VP16 chemomobilization. Both regimens are reasonable options for chemomobilization in lymphoma patients.

PS964 COMPARISON OF CONDITIONING REGIMEN CONTAINING TOTAL BODY IRRADIATION OR NOT FOR AUTOLOGOUS TRANSPLANTATION IN ADOLESCENTS AND YOUNG ADULTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA

Background:Autologous stem cell transplantation (ASCT) still plays an role in treatment of acute lymphoblastic leukemia (ALL). A myeloablative conditioning therapy should be done before ASCT. Many trials comparing regimens with total body irradiation (TBI) and non‐TBI in allogeneic stem cell tansplantation have been reported. However, very limited analysis focused on patients with ALL undergoing ASCT.Aims:The present study was undertaken to analyse retrospectively the outcome following conditioning with TBI regimens versus non‐TBI regimens in ASCT in adolescents and young adults with Philadelphia chromosome‐negative ALL patient cohorts.Methods:We defined 14–29 years of age as AYAs. Seventy four AYAs of all 95 patients with ALL undergoing consecutive ASCT between January 2007 and December 2016 were included in the study at Lymphoma Center at Blood Disease Hospital of Chinese Academy of Medical Sciences. Patients were chose based on the following criteria: (1) CR1 before ASCT; (2) first ASCT; (3) peripheral blood stem cell; (4) Philadelphia chromosome‐negative; (5) no definite central nervous system disease. According to the conditioning regimens administered, patients were divided into the following two groups: TBI group (consisting of TBI and chemotherapy, n = 38) and non‐TBI group (consisting of only chemotherapy, n = 36). The details of TBI‐based conditioning were TBI plus melphalan ± etoposide(n = 21), TBI plus cyclophosphamide ± cytosine arabinoside or etoposide (n = 14), others (n = 3). The details of non‐TBI conditioning were busulfan plus melphalan (n = 6), busulfan plus cyclophosphamide and etoposide (n = 16), busulfan plus cyclophosphamide and cytosine arabinoside (n = 3), busulfan plus cyclophosphamide and idarubicin (n = 6), others (n = 5). All of patients were received with VDCP ± L induction regimen for 28 days, then patients were administered with four courses of intensive chemotherapy. All of patients received 8–10 intrathecal injections for preventing central nervous system disease. After ASCT, maintenance chemotherapy based on VP regimen was continued for 1–1.5 years.Results:The main features at the time of diagnosis and transplant characteristics (sex, age, number of leukocytes, phenotype, karyotype and molecular biology, interval from treatment to MRD negative, interval between CR1 to patients transplanted) are parallel between the two groups. The median follow‐up for the survivors was 56 months (range, 30 ‐ 130 months) for TBI group and 65 months (range, 27 ‐ 126 months) for non‐TBI group after ASCT, respectively (P = 0.563). The median neutrophil engraftment days were 11days (range, 8–19 days) and 12 days (range, 9–30 days) for TBI group and non‐TBI group (P = 0.432), respectively. The median days to platelet engraftment were 15days (range, 10–95 days) and 14.5 days (range, 9–90 days) (P = 0.656), respectively. Hepatic vein occlusion syndrome occurred in 1 patients administered by busulfan plus melphalan conditioning at the day of 32 from transplantation. Cataract occurred in TBI plus melphalan (n = 1) conditioning group and TBI plus melphalan and etoposide conditioning group (n = 1).Non TRM occurred. The 5‐year disease‐free survival (DFS) was 68.1 ± 7.6% in TBI cohort and 62.3 ± 8.4% in non‐TBI cohort (P = 0.906). The 5‐year overall survival (OS) was 67.5 ± 7.8% and 63.8 ± 8.6% (P = 0.694). The DFS and OS results were no differences between the two regimens in univariate analysis.Summary/Conclusion:These data indicate similar survival with non‐TBI conditioning, compared with TBI‐based conditioning, for ASCT in adolescents and young adults with Philadelphia chromosome‐negative ALL.image

A Retrospective Study on Prephase Therapy Prior to Definitive Multiagent Chemotherapy in Aggressive Lymphomas

Background: Diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL) are aggressive lymphomas that evolve rapidly and are fatal if untreated. Most treatment-related toxicities occur during the initial phase of therapy, particularly in the elderly and in patients with a high disease burden. Prephase therapy is used as a preventive strategy prior to definitive multiagent chemotherapy to ameliorate the development of toxicity, such as febrile neutropenia, tumor lysis syndrome, deterioration in performance status, and death. While this approach is often implemented, there are few data supporting when to initiate a prephase regimen, or whether this approach will be effective. We present data from our experience at the University of North Carolina Cancer Hospital.Methods: We conducted a retrospective analysis of patients (pts) diagnosed with DLBCL and BL between January 2016 and December 2017. Pts were divided into ‘prephase’ (PP) and ‘non-prephase’ (NPP) groups. The PP group received either prednisone (P) alone at 60 mg/kg oral daily from day -6 to day -1, or in combination with vincristine (V) 1 mg intravenously on day -6 (VP regimen), cyclophosphamide 200 mg/m2 on day -6 (CP regimen), or all three drugs (CVP regimen). Multiagent chemotherapy was given at day 0. Both groups were evaluated until day 30. ECOG performance status (PS), grade 3-4 cytopenias, absolute neutrophil count (ANC) and platelet nadirs, time to ANC and platelet recovery, episodes of febrile neutropenia, hospitalization and emergency (ER) visits, and next cycle dose reduction or delay, were compared in both groups.Results: Ninety-two pts (DLBCL n=82, and BL n=10) were identified. Clinical characteristics are shown in Table 1. Twenty-two pts received PP therapy (vs. NPP n=70). Median age at diagnosis was 59 years and 61 years for PP and NPP group, respectively. Female predominance was observed in both groups (PP 59% and NPP 54%). Poor baseline ECOG PS was significantly different between the PP and NPP group (median score 2 vs. 0, p<0.001). Stage III-IV and bulky disease were more common in the PP group, although this was not statistically significant. Oral prednisone was the most common prephase therapy used (P n=17, VP n=1, CP n=1, CVP n=3). All regimens were well tolerated. Definitive chemotherapy regimens and outcomes are summarized in Table 2. The PP group had a significant improvement in PS from a median PS of 2 at baseline to a median PS of 1 (p<0.001) by day 14. The NPP group did not have a significant change in PS. In a subgroup analysis, both pts older than 60 years with any PS (n=10, p=0.027), and pts 60 years or younger with a PS of 2 or more (n=6, p=0.023) had a significant improvement in PS after prephase therapy. PP pts had a shorter time for ANC and platelet count recovery than NPP pts (ANC 4 vs. 8 days, p=0.013; platelet 4 vs. 9 days, p=0.023). The platelet nadir was significantly lower in the PP (80 x 109 plt/L) compared to the NPP group (150 x 109 plt/L) (p=0.025). There was no significant difference in the episodes of febrile neutropenia.Conclusions: Prephase therapy significantly improved PS by day 14 of definitive multiagent chemotherapy at first cycle. The overall improvement in PS was primarily caused by improvements in 2 groups: pts older than 60 years, and pts 60 years or younger with poor PS (ECOG PS 2 or more). This is consistent with who we would expect to benefit the most from prephase therapy. Patients who received prephase therapy had a significant reduction in the length of their ANC nadir, although, interestingly, the rate of febrile neutropenia was low in both arms. The length of the platelet nadir was also significantly reduced in the PP group. Conversely, the depth of platelet nadir was significantly lower in the PP group, which may be a reflection of more aggressive disease in this group. The prephase group trended towards a reduction in the number of hospital admissions, ER visits, and next cycle dose reduction or delays, but these did not reach statistical significance. Based on these results, we will implement a provider reminder to consider prephase therapy when using multiagent chemotherapy in pts with aggressive lymphomas older than 60 years, or pts <60 with PS of 2 or greater. [Display omitted] DisclosuresGrover:Seattle Genetics: Consultancy. Dittus:Seattle Genetics: Consultancy.

Stem Cell Mobilization with High-Dose VP-16 Is Not Associated with an Increased Risk of Secondary MDS/AML after Autologous Transplant Against Malignant Lymphoma

Background: An increased risk of secondary myelodysplastic syndrome and acute myeloid leukemia (sMDS/AML) with a cumulative incidence of 4 to 18% has been described in adult patients with malignant lymphoma who undergo high-dose chemotherapy with autologous stem cell transplantation (ASCT). Although a high-dose VP-16 regimen has been reported to have greater stem cell mobilization potential than a high-dose cyclophosphamide regimen, this regimen was identified as a potential risk factor for sMDS/AML in several studies. Thus, this multi-center retrospective analysis of ASCT recipients with malignant lymphoma was performed to assess the safety of high-dose VP-16 as a stem cell mobilization regimen.Patients and methods: This study analyzed 153 adult patients who underwent ASCT against malignant lymphoma at four institutions in Gunma, Japan between 1997 and 2012. Patients with progressive disease were excluded. There was no restriction on the type of pathological diagnosis and conditioning regimens. The high-dose VP-16 regimen consisted of 350 mg/m2 of VP-16 (days 1 to 4) and 16 mg/body of dexamethasone (days 1 to 4). Overall survival (OS) was defined as the interval from the date of transplant to the date of death. Fisher’s exact test was used to compare binary variables. Cumulative incidences (CIs) of sMDS/AML were compared using the stratified Gray test, considering death without the event as a competing risk. The Fine-Gray proportional hazard model was used for multivariate analysis of risk factors for sMDS/AML. The potential risk factors evaluated in this analysis were age at transplant, sex, pathological diagnosis, prior malignancy, conditioning regimens (LEED or not), number of chemotherapy regimens before ASCT, prior radiation therapy, disease status, and cyclophosphamide equivalent dose (CED). Values of p < 0.05 were considered significant.Results: Of the 153 patients assessed in this study, 93 were male and 60 were female, and the median age was 56 years (range: 18 to 68 years). Underlying diseases were diffuse large B-cell lymphoma (including IVLBCL) in 87 patients, follicular lymphoma in 8, other B-cell lymphoma in 24, Hodgkin lymphoma in 16, and T-NK-cell lymphoma in 18, and 81 patients were conditioned with LEED regimens. Disease status at the time of transplant was first complete remission (CR) in 77, advanced CR in 34, and partial remission in 42. The high-dose VP-16 regimen was used to mobilize stem cells in 85 patients. Of the 68 patients not using the high-dose VP-16 regimen, stem cells were mobilized with (R-)CHOP in 17, CHASE(-R) in 28, and others in 23. There were no significant differences in patient characteristics, disease features, and transplant procedures between patients with and without the high-dose VP-16 regimen. With a median observation time of 55.2 months, eight patients developed sMDS/AML, and the 5-year cumulative incidence of sMDS/AML was 3.5%. Type of sMDS/AML was MDS in six, chronic myelomonocytic leukemia in one, and AML in one, and median duration from ASCT was 52.9 months (range: 31.2 to 104.4 months). On univariate analysis, only age over 50 years was identified as a significant risk factor for sMDS/AML (5-year CIs in age under and over 50 years: 0.0% vs. 5.3%, respectively; p = 0.043), but not stem cell mobilization with the high-dose VP-16 regimen (5-year CIs with and without high-dose VP-16 regimen: 1.5% vs. 6.6%, respectively; p = 0.528). On multivariate analysis, age, using high-dose VP-16, and CED were evaluated. Age over 50 years (hazard ratio [HR] = 44140; p < 0.001) was identified as an independent risk factor for sMDS/AML, but not the high-dose VP-16 regimen (HR = 0.58; p = 0.432). The 5-year OS rates were not significantly different between patients with and without the high-dose VP-16 regimen (56% vs. 54%, respectively; p = 0.845).Conclusion: These results suggest that stem cell mobilization with a high-dose VP-16 regimen was not associated with an increased risk of sMDS/AML and did not affect the long-term survival rate in adult patients who underwent ASCT against malignant lymphoma. Therefore, considering this regimen's greater potential to mobilize stem cells, a high-dose VP-16 regimen is considered a preferable stem cell mobilization regimen in these patients. DisclosuresMatsumoto:Janssen Pharmaceutical: Honoraria; Celgene: Honoraria.

Imatinib Combined with VP Low Dose Regiment for Treating Newly Diagnosed Adult Patients with Ph-positive ALL

To investigate the inductive therapeutic effects of imatinib combined with VP low dose regiment on adult patients with Ph-positive acute lymphoblastic leukemia (Ph(+) ALL). Fourteen newly diagnosed adult patients with Ph(+) ALL were treated with VP regimen, and imatinib (400 mg/d) was added at the 8(th) day. VP regimen would be stopped when neutropenia lasted for 1 week or complicated with infection, fever, etc. Therapeutic effects were assessed by bone marrow morphology and quantitative analysis of BCR/ABL:ABL at the 28(th) - 33(rd) day. Patients could be treated with imatinib combined with chemotherapy for consolidation and maintenance therapy or were treated with allogeneic hematopoietic stem cell transplantation after complete remission. Fourteen cases obtained CR1 after first course of treatment, the median decline of BCR/ABA:ABL was 55.89 (10.25 -180.97) %; during the induction chemotherapy, pulmonary infection occurred in 3 patients, diarrhea in 1 patients, facial edema in 3 patients, however, all these patients were cured after symptomatic treatment, only 1 patient died of relapse after transplantation. In the period of tyrosine kinase inhibitor (TKI), inductive chemotherapy combined with imatinib and low dose VP can obtaine satisfactory CR rate and decrease the toxicity of the traditional drugs. It is suggested that TKI combined with VP regimen chemotherapy can achieve CR1 and make possible for allo-HSCT, from which patients can achieve the long-term survival.

Multiple Unit Umbilical Cord Blood Transplantation with Total Body Irradiation, Etoposide and Antithymocyte Globulin for Adult Hematologic Malignancy Patients.

Abstract 4344Multiple unit umbilical cord blood transplantation (MU-UCBT) has become an acceptable alternative donor transplant approach for adult hematologic malignancy patients without a bone marrow or peripheral blood stem cell donor. Total body irradiation (TBI) and etoposide (VP16) is an effective conditioning regimen for allogeneic hematopoietic stem cell transplantation, but its utility in MU-UCBT has not been well described. From 10/03-2/09 16 adult hematologic malignancy patients were enrolled on a clinical trial at our institution using this regimen prior to MU-UCBT. Patients were eligible if they did not have an HLA matched related or unrelated donor. They also were required to have at least a 4/6 HLA matched UCB unit with at least 0.5 × 107 nucleated cells/kg and a second UCB unit that was at least a 4/6 HLA match with the first UCB unit. The minimum required cryopreserved total nucleated cell (TNC) dose for the combined units was 1 × 107/kg or an infused CD34+ cell dose of 1.5 × 105/kg. Patients received TBI 1,320 cGy (fractionated over days -7 through -4), VP16 60 mg/kg (day -3) and antithymocyte globulin (ATG) 30 mg/kg (days -3 through +1). GVHD prophylaxis consisted of tacrolimus and mycophenolate mofetil. The median age was 47 yrs (range, 18-60) and diagnoses included: 8 AML, 3 CML-accelerated/blast phase, 2 MDS, 1 ALL, 1 CLL 1 NHL. Comorbidity index scores were 9 low, 6 intermediate and 1 high. The median time from diagnosis to UCBT was 8 mos (range, 1-89). HLA match results of the 1st UCB unit infused (UCB1) with the recipient included five 4/6, ten 5/6 and one 6/6 matches, and for the 2nd UCB unit (UCB2) with recipient there were one 3/6, five 4/6, and ten 5/6 matches. The median thawed TNC doses infused for UCB1 and UCB2 were 1.6 × 107/kg (range, 1.0-2.4 × 107/kg) and 1.2 × 107/kg (range, 0.8-2.4 × 107/kg), respectively; the thawed CD34+ cell doses were 0.6 × 105/kg (range, 0.01-2.4 × 105/kg) and 0.6 × 105/kg (range, 0.2-3.1 × 105/kg), respectively. Twelve were evaluable for engraftment analyses; 3 others had early deaths and 1 had graft failure and was rescued with infusion of cryopreserved remission autologous bone marrow. Sustained engraftment in the 12 was observed from a single UCB unit in all cases and the winning unit was UCB1 in 5 (42%). The winning unit had larger median CD8 (p=0.009) and thawed CD34+ cell (p=0.006) doses infused. The median time to achievement of T-cell complete donor chimerism was 30 days (range, 13-139). Median times to neutrophil and platelet engraftment were 20 days (range, 14-48) and 46 days (range, 29-86), respectively. Median time hospitalized was 39 days (range, 20-74). Grade 2-4 and 3-4 acute GVHD developed in 3 pts (19%) and 1 pt (6%), respectively. Chronic GVHD developed in 5 pts (31%) and 4 (25%) were extensive. Graft failure occurred in 2 pts. Six developed CMV infection and 15 developed other infections. There have been 2 (13%) relapses (1 MDS, 1 AML). Eight pts (50%) remain alive at a median follow-up of 15 mos (range, 5-35). Causes of death include 4 infections, 1 graft failure, 1 pulmonary toxicity, 1 CNS bleed, 1 relapse (AML). Incidence of death at 1 and 2 years are 45% (6% relapse, 39% non-relapse) and 59% (6% relapse, 53% non-relapse), respectively. We conclude that the TBI, VP16 and ATG conditioning regimen for MU-UCBT is effective in adult hematologic malignancy patients. Further strategies to enhance immune reconstitution and prevent infections post-transplant are clearly warranted. Disclosures:Off Label Use: Etoposide (VP16) may be considered off-label. Total body irradiation (TBI) and etoposide (VP16) is an effective conditioning regimen for allogeneic hematopoietic stem cell transplantation, but its utility in multiple unit umbilical cord blood transplantation has not been well described. This abstract shares results of a novel trial with TBI/VP/ATG for multiple unit umbilical cord blood transplantation.

Combination chemotherapy with 5-fluorouracil, methotrexate and etoposide for patients with high-risk gestational trophoblastic tumors: A report based on our 11-year clinical experiences

To evaluate the efficacy, toxicity, and survival of patients with high-risk gestational trophoblastic tumors (GTTs) treated with the 5-fluorouracil (5-FU), methotrexate (MTX) and etoposide (VP-16) regimen. Between 1992 and 2003, 26 consecutive patients with FIGO-defined high-risk GTTs were treated with 5-FU, MTX and VP-16 regimen. Among them, 9 patients had received prior chemotherapy. Remission rate, causes of treatment failure, and toxicity were analyzed retrospectively. After treatment with 5-FU, MTX and VP-16 regimen, 21 of 26 gained complete respond (80.8%). Two patients were performed adjuvant hysterectomy and both cured ultimately. Five developed resistance (19.2%), and 1 died of widespread metastases (3.8%). All 5 patients who developed resistance were treated with multidrug regimen of etoposide, methotrexate, and actionmycin D alternating with cyclophosphamide and vincristine (the EMA/CO); 4 were salvaged and 1 died of refractory disease. No ones relapsed. WHO grade 4 leukocytopenia and thrombocytopenia with the 5-FU, MTX and VP-16 regimen occurred in 9.0% and 2.4%, respectively, of the total 167 cycles; other toxic effects were acceptable and manageable. With mean follow up of 37 months, neither relapse nor secondary tumor was observed. According to our 11 years of clinical observation, 5-FU, MTX and VP-16 chemotherapy is one of effective multiagent regimen for patients with high-risk GTTs. Its toxicity is mild and manageable. For patients with high-risk and refractory GTTs, this new triple salvage chemotherapy regimen may be an effective alternative.

Comparison of peripheral blood progenitor cell yield from standard chemotherapy used in the treatment of lymphoid malignancies and high‐dose cyclophosphamide: a retrospective review of 141 patients

Peripheral blood progenitor cells (PBPCs) are often collected after mobilization with high-dose cyclophosphamide (HDC) combined with growth factors. HDC may not be needed for PBPC mobilization, and patients with lymphoid malignancies can be harvested with treatment regimens of chemotherapy. A retrospective analysis was performed on 141 patients with lymphoma or multiple myeloma whose PBPCs were harvested after chemotherapy. The PBPC yield and time to mobilization was compared between patients who received HDC (n = 51) and other chemotherapy regimens (n = 90) including high-dose cyclophosphamide and etoposide (HDC plus VP-16; n = 41), CHOP, ESHAP, ABVD, VAD, and others (n = 49). A multiple linear regression model and proportional hazards model determined factors influencing yield and time to mobilization, respectively. The difference in mean yield between HDC and all non-HDC regimens was significant, with HDC plus VP-16 resulting in the highest yields. The proportion of patients achieving a CD34 count in excess of 5 x 10(6) per kg did not differ significantly between the regimens. In a multiple linear regression model, HDC plus VP-16 resulted in a higher PBPC yield than HDC but all other regimens did not. In addition, patients exposed to more than one prior chemotherapy regimen had lower yield regardless of the mobilization regimen. The mean number of days to mobilization with HDC was 10.2 days, 17.1 days for HDC plus VP-16, and 14.2 days for all other regimens. The timing of mobilization was influenced by the chemotherapy used and the number of prior regimens in a proportional hazards model. These results demonstrate a higher mean yield of PBPCs with HDC plus VP-16 but no difference in yield between non-HDC plus VP-16 regimens used for first-line or relapse therapy and HDC, suggesting that HDC may be an unnecessary additional therapy.

A randomized trial between two neoadjuvant chemotherapy protocols: CDDP + 5-FU versus CDDP + VP16 in advanced cancer of the head and neck

We investigated a phase III randomized trial to compare efficacy and tolerance of CDDP + 5-FU to CDDP + VP16, both given intravenously in patients with unresectable advanced head and neck cancer. The 197 eligible patients were paired off successively on the basis of tumor sites and UICC stage. Comparisons were made through sequential closed plans. In 179 patients, tumor beds and cervical lymph nodes were irradiated, and 20 patients underwent salvage surgical procedures. Cisplatin plus 5-fluorouracil showed a response (CR + PR) rate of 15% greater than that observed with cisplatin plus etoposide (alpha=0.05, power 70%). Complete responses played a major role in the CDDP + 5-FU regimen. Furthermore, we noted a higher cervical node regression with this chemotherapy combination. Because radiotherapy was administered after chemotherapy, we could not analyze the mean duration response for each protocol. No significant difference in survival existed between the two groups. Myelosuppression was the most frequent sign of toxicity observed, especially with the CDDP + VP16 regimen. Mucositis was rare with allopurinol protection. In the CDDP + 5-FU group, one patient had grade 4 cardiac dysfunction, and 3 patients exhibited unconsciousness that may be related to cerebral vascular damage. Thirteen patients died, with 8 cases related to septic shock (5 CPPP + VP16 and 3 CDDP + 5-FU). Cisplatin plus 5-FU chemotherapy showed a satisfactory efficacy and acceptable toxicity profile compared with CDDP + VP16, with caution to patients with a cardiac or vascular history. Although we could not show a benefit in survival with the CDDP + 5-FU protocol, this trial supports literature data and confirms that this regimen may be proposed as a first-line therapy in advanced cancer of the head and neck.

A phase III randomized trial comparing vindesine and cisplatin with or without ifosfamide in patients with advanced non-small-cell lung cancer: long-term follow-up results and analysis of prognostic factors

In order to evaluate the activity and toxicity of a three-drug combination of vindesine, ifosfamide and cisplatin (VIP) for inoperable non-small-cell lung cancer (NSCLC), we conducted a randomized trial comparing VIP with a two-drug combination of cisplatin and vindesine (VP). Between September 1987 and March 1992, a total of 132 patients with stage III or IV NSCLC were randomly allocated to either VIP or VP. The VIP regimen consisted of vindesine (VDS 3 mg/m 2 on days 1 and 8), ifosfamide (IFX 1300 mg/m 2 on days 1–5), and cisplatin (CDDP 20 mg/m 2 on days 1–5). The VP regimen consisted of VDS and CDDP with the same dose and schedule as the VIP regimen. Both regimens were repeated every 4 weeks. Objective response rates were 49.3% (95% confidence interval: 95%CI, 43.1–55.4%) in the VIP arm and 44.6% (95%CI, 38.4–50.2%) in the VP arm; the difference was not significant ( P=0.5390). Median response duration, median survival time, and two-year survival rates were 26.5 weeks, 49.6 weeks, and 14.9% in the VIP arm and 28.7 weeks, 37.1 weeks, and 12.3% in the VP arm, respectively. There were also no significant differences between these two treatment arms. In comparison with the VP regimen, however, a survival advantage of the VIP regimen could be confirmed when the data were evaluated with Cox's multivariate analysis ( P=0.0131). In both arms, the principal toxicity was myelosuppression, which was significantly more frequent in the VIP arm, although generally well tolerated. Conclusion: This study suggested the survival advantage of the VIP regimen over the VP regimen for treatment of patients with advanced NSCLC.

Efficacy of high-dose therapy and autologous hematopoietic stem cell transplantation for non-Hodgkin's lymphoma in adults 60 years of age and older.

High-dose therapy (HDT) with autologous stem cell transplantation (ASCT) is the optimal treatment for patients with relapsed aggressive non-Hodgkin's lymphoma (NHL). HDT, however, is often reserved for relatively younger patients due to limited data in older adults. We treated 53 patients aged 60 years and older (median age 62 years, range 60.3-67.7 years) with HDT and ASCT for NHL at our centers. Forty-four patients (83%) had aggressive histology, 75% had chemosensitive disease and all had failed anthracycline therapy. Conditioning regimens included busulfan, melphalan, and thiotepa (45%); cyclophosphamide (CY), etoposide (VP-16), and total body irradiation (TBI) (30%); CY and TBI (15%); and other regimens (10%). Estimated 4-year overall survival (OS), progression-free survival, and treatment-related mortality (TRM) were 33%, 24% and 22%, respectively. A multivariable analysis demonstrated that patients with chemosensitive disease (P = 0.03) and < or =3 prior regimens (P = 0.03) had superior survival. Four-year OS in patients with chemosensitive disease was 39% vs 15% in patients with chemoresistant disease. Reduced TRM was associated with the CY, VP-16 and TBI regimen (P = 0.02). HDT therapy with ASCT may result in prolonged survival and potential cure for about a quarter of elderly patients, and for almost 40% with chemosensitive disease. Optimal conditioning regimen selection may further improve outcome by reducing TRM. Age alone should not be used to exclude patients from receiving myeloablative therapy with ASCT.

Pregnancy outcome after treatment with etoposide (VP-16) for low-risk gestational trophoblastic tumor.

The aim of this study was to evaluate subsequent fertility and pregnancy in patients treated for persistent trophoblastic tumors with single-agent VP-16. Records of all patients treated for persistent trophoblastic tumors at the Chiba University Hospital between January 1, 1986 and December 31, 1997 were reviewed. Of these, 85 patients were initially treated with single-agent VP-16. Subsequent pregnancy outcome of these patients was investigated. After remission with VP-16, 36 patients (92.3%) of those who wished for a pregnancy (45.9% of all patients studied) conceived, and 91.7% had at least one live birth. A total of 56 conceptions resulted in 42 (75.0%) term live births, seven (12.5%) first-trimester spontaneous abortions, one (1.8%) second-trimester spontaneous abortion, four (7.1%) therapeutic abortions, and two (3.6%) repeated moles. There were no congenital anomalies, no stillbirths, and the neonates' physical growth was comparable to that of the standard population in Japan. Single VP-16 regimen for patients with low-risk gestational trophoblastic tumor appears to have no adverse effects on fertility potential and pregnancy outcome.

Comparison of Chemotherapies with Methotrexate, VP-16 and Actinomycin-D in Low-Risk Gestational Trophoblastic Disease

Objective: To compare the efficiency and toxicity of four chemotherapeutic regimens in low-risk gestational trophoblastic disease. Methods: Since 1974, 247 patients with low-risk gestational trophoblastic disease have been treated with 5-day intramuscular methotrexate (MTX) (conventional MTX), 5-day intravenous drip infusion of VP-16, 5-day intravenous actinomycin-D (Act-D) or 8-day alternating intramuscular MTX-folic acid (MTX-CF) at Chiba University School of Medicine. We compared the primary remission rate, the response of human chorionic gonadotropin and the prevalence of drug toxicities in these 4 regimens. Results: The primary remission rate was 73.6% in the conventional MTX regimen, 90.1% in VP-16, 84.0% in Act-D, and 60.0% in MTX-CF. The primary remission rate was significantly higher in the VP-16 and Act-D regimens than in the conventional MTX and MTX-CF regimens. The response rate was significantly higher in the VP-16 regimen than in the other 3 regimens. The drug toxicity with VP-16 and Act-D was less than that with conventional MTX and MTX-CF regimens. Conclusions: The VP-16 regimen was highly effective and less toxic for gestational trophoblastic disease compared with other chemotherapeutic regimens.

CISPLATIN PLUS VP16 AS SALVAGE TREATMENT FOR ADVANCED BREAST-CARCINOMA RESISTANT OR RECURRENT AFTER 1ST LINE CHEMOTHERAPY FOR METASTATIC DISEASE

Forty patients with chemotherapy refractory metastatic breast carcinoma were enrolled in a phase II study of cisplatin 80 mg/m2 on day 1 plus VP16 100 mg/m2 on days 1-3 every 28 days. The overall response rate was 32% (95% CL 17-47%), with 2 patients (5%) showing a CR with a mean duration of 11.3 months, and 11 patients (27%) a PR with a mean duration of 7.8+ months. Seven patients (17%) had stable disease, and 20 patients (50%) progressed despite chemotherapy. One complete response and 4 partial responses were obtained in patients previously untreated with antracyclines. The overall survival was 10.2+ months. The mean survival of responding patients (CR+PR) was 15.5+ months, while that of non responders (NC+PD) was 8.6+ months. A total of 188 cycles were administered (4.7 cycles/patient) and the most frequent toxicities were gastrointestinal and hematological side-effects. The most severe toxicities were intense vomiting and anemia. Grade 3 vomiting was seen in 11 patients (27%), and grade 1-2 anemia in 30% of cases. Severe grade 3 leukopenia was seen in only 12% of cases. Mild renal toxicity was recorded only in 2 cases, while alopecia was observed in almost all patients. In conclusion, although CDDP plus VP16 regimen, may be safely given on an outpatient basis, its routine use as salvage treatment for chemotherapy refractory metastatic breast carcinoma is not recommended. This regimen may, however, be employed as second line chemotherapy in selected cases.

RESULTS OF A CLINICAL MULTICENTRIC RANDOMIZED PHASE-II STUDY OF NONSMALL CELL LUNG-CANCER TREATED WITH VINORELBINE CISPLATIN VERSUS VINORELBINE ALONE

From July 1992 to December 1993, 62 patients with non-small cell lung cancer (NSCLC) were admitted to a multicentric randomized study. The patients were treated with vinorelbine (V) alone at a dose of 25 mg/m(2)/i.v. weekly or with V at a dose of 25 mg/m(2)/i.v. on day 1 and 8 plus cisplatin at a dose of 80 mg/m(2)/i.v. on day 1 every 3-4 weeks (VP). An objective response was observed in 42% of patients treated with VP versus 12.5% of those treated with vinorelbine alone (p=0.038). There was no significant difference in the median survival duration between the two groups (38 versus 30 weeks for VP and V, respectively). Toxicity was tolerable but more severe in the VP regimen. These data suggest that V is an active agent in NSCLC and that the VP regimen may yield results comparable to other cisplatin combinations for treatment of these tumors.

Liver function studies in children with acute lymphocytic leukemia after cessation of therapy

We investigated liver function in 27 children with acute lymphocytic leukemia (ALL) after cessation of therapy. Induction therapy consisted of prednisolone+vincristine (VP regimen) alone (16 patients) or with addition of daunorubicin (4 patients) or L-asparaginase (7 patients). Patients treated with VP regimen received short courses of VP regimen every 12 weeks for the first year of maintenance. Twenty-five patients remained in first complete remission and had completed 3-year maintenance therapy with methotrexate (MTX) and 6-mercaptopurine (6-MP) 1-7 years prior to this study. Twenty-three patients had received transfusions of packed red blood cells or fresh whole blood (1-11 units; median: 2 units) but none had evidence of either hepatitis B or hepatitis C. Alanine aminotransferase (ALT), which was measured every 3 months during maintenance therapy, had values more than three times the upper limit of the normal range in 25% of the measurements in more than half of the patients. However, by 3 months after the completion of maintenance therapy, ALT had normalized in all patients and remained normal in all but two patients until the time of this study. Serum bilirubin, serum albumin, and prothrombin time were all within normal limits. Fasting and 2-hour postprandial total serum bile acids were high in 5 of 13 patients and in 6 of 13 patients, respectively. The ratio of cholic acids+deoxycholic acids to chenodeoxycholic acids+lithocholic acids was below 1 in all but two patients, whereas this ratio was above 1 in all controls. Our bile acid profile results indicate the necessity of careful long-term follow-up of survivors of ALL treated with hepatotoxic chemotherapy during childhood.

Bone marrow transplantation for peripheral T-cell lymphoma in children and adolescents

We report nine children with relapsed (n = 8) or high-risk (n = 1) peripheral T-cell lymphoma (PTCL) who underwent autologous (n = 6) or allogeneic (n = 3) bone marrow transplantation (BMT). These children received transplants as part of a prospective phase I/II study of thioTEPA (TT) and total body irradiation (TBI) with escalating doses of VP-16. The median age of these patients at time of BMT was 6.5 years (range 2.5 years to 14 years). Three were transplanted with active disease after failing salvage chemotherapy. Of the other six, one was transplanted in first complete remission (CR) and five in second or subsequent CR. Of these nine patients, eight are free of disease a median of 25 months after BMT (range, 6 to 48 months), with an estimated 2-year relapse-free survival (RFS) of 89%. Six of these eight patients have been followed for 12 or more months after BMT, and in each their current remission exceeds their longest previous remission duration. The toxicity of the TT/TBI +/- VP-16 regimens was significant but manageable, predominantly consisting of severe mucositis. For a comparison, we reviewed retrospective data on the six additional children and adolescents with PTCL who underwent BMT during the 3-year period preceding this phase I/II study. The median age at BMT of these six patients was 19 years (range 15.5 years to 20 years). These patients were prepared for BMT with a variety of other regimens. One had no response to BMT and the other five relapsed at 1.5 to 5 months after BMT (median, 3 months) with an RFS of 0%. Our data suggest that thioTEPA plus TBI, with or without VP-16, is an effective preparative regimen for BMT for young patients with relapsed or high-stage PTCL and leads to prolonged RFS.