Dose-Dense Induction Followed by Autologous Stem Cell Transplant (ASCT) as 1st Line Treatment in Peripheral T-Cell Lymphomas (PTCL) - A Phase II Study of the Nordic Lymphoma Group (NLG).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 401-401 ◽  
Author(s):  
Francesco d’Amore ◽  
Thomas Relander ◽  
Grete Lauritzsen ◽  
Esa Jantunen ◽  
Hans Hagberg ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Large Cell ◽  
High Dose ◽  
Cell Transplant ◽  
Post Transplant ◽  
Patient Cohort ◽  
Alk Positive ◽  
The Impact

Abstract Systemic PTCL, with the exception of alk-positive anaplastic large cell lymphoma (ALCL), have a poor prognosis. ASCT has been shown to have a favourable impact on relapsed PTCL. Therefore, the NLG designed a prospective multicenter phase II study to evaluate the impact of a dose-intensified induction schedule (6 courses of two-weekly CHOEP) consolidated in 1st PR/CR with high-dose therapy (BEAM) followed by ASCT in previously untreated systemic PTCL. This is the largest prospective PTCL-specific trial published so far. Newly diagnosed non-primary cutaneous PTCL cases aged 18–67 yrs were eligible for enrollment. Cases of alk-positive ALCL were excluded. From Oct 2001 to Feb 2006, 99 histologically confirmed PTCL cases were included in the study: PTCL unspecified (n=41), alk-neg ALCL (n=24), AILT (n=15), enteropathy-type (n=12), panniculitis-like (n=3), T/NK nasal-type (n=2), hepatosplenic (n=2). The M/F ratio was 1.8 and the median age 55 yrs (range 20–67 yrs). Although almost 2/3 of the cases presented with advanced-stage disease (62%), B-symptoms (61%) and/or elevated s-LDH (63%), the majority of them (65%) had a good performance score (WHO 0–1) at diagnosis. Of the 77 patients, where information was available for all 6 induction courses, 68 (88%) were in CR (31) or PR (37) after the 3rd and 66 (86%) after the 6th course. A total of 58 patients (75%) went through ASCT indicating that at least a fourth of this younger patient cohort has a primary refractory disease and fails therapy before reaching the transplant. Treatment-related toxicity after both induction and high-dose treatment was manageable. Of the 58 transplanted patients, 50 (86%) were still in remission at re-evaluation short after transplant. In 39 patients follow-up data one year post-transplant were available: 30 are still in CR and 9 have relapsed, suggesting that post-transplant relapses probably account for another 25% of the original patient cohort. In conclusion, the present data indicate that a time- and dose-intensified schedule is feasible and effective in previously untreated systemic PTCL. Continuous remissions are not uncommon, but a longer follow-up is needed to further characterize long-term remission rates and evaluate their impact on time-to-treatment failure and overall survival.

Sequential Topoisomerase I (Topo I) and Topoisomerase II (Topo II) Inhibitors in Relapsed/Refractory Aggressive NHL: Results of CALGN 59906, a Phase II Study of Doxorubicin and Topotecan.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2500-2500 ◽  
Author(s):  
Sonali M. Smith ◽  
Jeffrey L. Johnson ◽  
Donna Niedzwiecki ◽  
J. Paul Eder ◽  
George P. Canellos ◽  
...  
Keyword(s):  
Phase Ii ◽  
Topoisomerase I ◽  
Phase Ii Study ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Large Cell ◽  
Cell Transplant ◽  
Histologic Subtype ◽  
Sequential Administration ◽  
Topo Ii

Abstract Topoisomerase enzymes are critical components of genomic replication and function to minimize torsional stress on DNA. Inhibition of topoisomerase function leads to DNA strand breaks followed by apoptosis. In malignant lymphomas, topo II inhibitors (anthracyclines, epidophyllotoxins) are part of many active regimens, and topo I inhibitors (camptothecins) show modest single agent activity. Supported by preclinical data, we hypothesized that the sequential administration of a topo II inhibitor followed by a topo I inhibitor would be potentially synergistic, with enhanced cytotoxicity of the topo I inhibitor due to increased target enzyme levels following topo II inhibition. The treatment regimen consisted of doxorubicin 25 mg/m2 IV on day 1 and topotecan 1.75 mg/m2/d IV on days 3–5, repeated at 21 day intervals. The primary objective of this phase II study was to determine the overall response rate, time to progression, and toxicity in patients with relapsed/refractory aggressive NHL. Eligible patients had recurrent or refractory aggressive NHL, no prior camptothecins, and limited prior anthracycline exposure (<400 mg/m2 prior doxorubicin; <96 mg/m2 prior mitoxantrone), and an ejection fraction ≥ 45% at baseline. Results: From July 2000 to August 2003, 26 patients were registered. One registered patient did not start protocol treatment and is excluded from analysis. Of 22 patients with a known histologic subtype, 18 had diffuse large B cell lymphoma and there was one case each of Burkitt’s, follicular grade III, anaplastic large cell, and anaplastic large cell, Hodgkin’s like lymphoma. The median age was 58 (range 23–74) years. All patients were heavily pretreated with a median of 2 (range 1–5) prior regimens, including 5 patients who had a prior stem cell transplant (SCT). A median of 2 cycles (range 1–6) were administered. Five patients (20%, 95% CI 0.07, 0.42) responded with 1 (4%) complete remission (CR) and 4 (16%) partial remissions (PR); an additional 3 (12%) patients had stable disease. 12 (48%) patients progressed during or after the first cycle and 5 (20%) progressed after the second cycle. The one patient achieving a CR had Burkitt’s lymphoma, and received a total of 6 cycles; this patient remains in remission 21 months following the end of treatment. Of the PR patients, 2 remain in PR at 1.5 and 12 months following therapy, and 2 patients have progressed at 1.5 and 6 months. Interestingly, 4 of the 5 responders had prior SCT. The main toxicity was hematologic, with 14 (63%) and 9 (41%) patients having grade 3 or 4 neutropenia and thrombocytopenia, respectively. Three patients had febrile neutropenia. There were no treatment-related deaths. Seven patients remain alive and 18 patients have died. The median follow-up time for surviving patients is 14 (range 7–27) months. The median event-free survival is 1.3 months and the median overall survival is 3.6 months. The combination of doxorubicin and topotecan is well-tolerated and has modest activity in relapsed/refractory NHL, with an occasional patient having a prolonged remission.

Holmium-166 (166Ho)-DOTMP Skeletal Targeted Radiotherapy (STR™) with Melphalan and Autologous Peripheral Stem Cell Transplant (PBSCT) for Multiple Myeloma (MM).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 922-922 ◽  
Author(s):  
Mark Goodman ◽  
William I. Bensinger ◽  
Sergio Giralt ◽  
Donna Salzman ◽  
Katherine L. Ruffner ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Hemorrhagic Cystitis ◽  
Conditioning Regimen ◽  
Complete Response ◽  
Phase Iii ◽  
High Dose ◽  
Cell Transplant ◽  
Red Marrow

Abstract Background: 166Ho-DOTMP is a beta-emitting radiophosphonate that localizes specifically to the bone surfaces and can deliver high dose radiation both to the bone and bone marrow. Follow-up data from 3 clinical trials with STR as conditioning for patients with MM undergoing autologous PBSCT are presented. Methods: In 2 Phase I/II dose-escalation trials, 83 patients received a dose of 166Ho-DOTMP STR calculated to deliver 20, 30, or 40 Gy to the red marrow; 82 pts received melphalan (140 or 200 mg/m2) ± 8 Gy TBI (n=25), followed by PBSCT. As of June, 2004, 77 subjects have been followed for at least 48 months. In a separate Phase II dosimetry trial, 12 patients received two 30 mCi tracer doses of 166Ho-DOTMP STR to determine the reproducibility of biodistribution and pharmacokinetics (PK). All pts received a 25 Gy therapy dose with concurrent IV hydration and continuous bladder irrigation, followed by 200 mg/m2 melphalan and PBSCT. These patients have been followed for at least 18 months. Results: Up to 2.3 Ci/m2, 166Ho-DOTMP STR was given in the Phase I/II trials; 29/83 (35%) patients achieved complete response (CR) and overall response rate (CR + PR) was 64% (7 pts not evaluable). The Kaplan-Meier estimate of median survival is 5.2 years for all 83 patients. In patients who are at least 4 years post transplant who achieved a CR, the survival is 74% (n=27). In patients who achieved less than a CR at least 4 years ago, the survival is 34% (n=44). Dose-related radiation-induced kidney toxicity presented in some patients more than 6 months post-therapy. The dose of 166Ho-DOTMP STR in the Phase II dosimetry trial was 550 to 860 mCi/m2, 166Ho-DOTMP. Currently, 18 months of follow-up reveals no occurrence of hemorrhagic cystitis or > Grade 2 elevated creatinine. A CR rate of 17% with an overall survival of 92%, was observed. In 10 patients who received 166Ho-DOTMP STR 750 mCi/m2 ± 10% in the Phase I/II trial, the CR rate was 40%, and the 4-year survival was 70%. Monitoring for safety and duration of response is ongoing in all 3 trials. Conclusion: Follow-up from the Phase I/II trials confirms that 166Ho-DOTMP STR provides favorable efficacy and safety as part of the conditioning regimen for patients with MM undergoing PBSCT. A Phase III, randomized multicenter study is now open to enrollment, comparing the safety and efficacy of 166Ho-DOTMP STR plus melphalan to melphalan alone as conditioning for PBSCT in subjects with primary refractory MM who have failed to respond to induction therapy, including high-dose dexamethasone, and are within 18 months of diagnosis.

Age-Stratified Treatment-Modalities for Patients with Primary CNS Lymphoma: Results of a Phase II Study and Two Pilot-Studies.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4683-4683
Author(s):  
Gerald Illerhaus ◽  
Reinhard Marks ◽  
Fabian Mueller ◽  
Friedrich Feuerhake ◽  
Christoph Ostertag ◽  
...  
Keyword(s):  
Overall Survival ◽  
Pilot Study ◽  
Phase Ii ◽  
Phase Ii Study ◽  
High Dose ◽  
Single Center ◽  
Pilot Phase ◽  
Multicenter Phase ◽  
New Treatment

Abstract Background: Primary NHL of the CNS (PCNSL) are associated with a dismal prognosis despite initial response to steroids and radiotherapy (RT). Addition of high-dose methotrexate (HD-MTX) to RT has improved the prognosis of patients (pts) with PCNSL. However, the majority of pts eventually relapse. To improve survival we performed a multicenter phase II study with early high-dose chemotherapy (HDT) and autologous stem-cell transplantation (ASCT) followed by hyperfractionated whole-brain radiation (WBRT) for 30 pts under 65yrs. Five-year overall survival rates of 69% for all pts and 87% for 23 pts receiving HDT and ASCT could be reported (Illerhaus et al., J Clin Oncol. 2006). Purpose: Here we present the results of 1) a pilot study for HDT and ASCT with WBRT restricted to residual disease in pts ≤65 years; 2) a multicenter phase II study for MTX-based CT and 3) a pilot-study for chemo-immunotherapy in pts &gt; 65 years. Methods and Results: New treatment regimen for pts ≤65 years: CT consists of 4 cycles HD-MTX (8g/m2), 2 cycles AraC (2×3g/m2) and thiotepa (40mg/m2) followed by HDT with BCNU (400mg/m2) and thiotepa (4×5mg/kg) before ASCT. To date, 12 pts have been treated in this single center pilot-study. After HDT and ASCT 7/10 pts (70%) responded with complete remission (CR), 2/10 pts with partial remission (PR), 1 pt showed progressive disease (PD) and died after refusing RT. The 2 pts with PR have been irradiated resulting in continuous CR. Two pts were off study due to refractory disease. After a median follow-up of 17 months (mo) (range 4–41) 9/12 pts are alive in continuous CR. One pt developed a systemic relapse and died 8 months after ASCT. Overall, the treatment was well tolerated without grade IV toxicity. Patients &gt;65 yrs, MCP-protocol: Thirty-two pts (17 female, 15 male, median age 71 yrs, range 57–79y) were treated in a phase II trial with 3 repetitive cycles of HD-MTX (3g/m2, d1, 15, 30) combined with procarbazine (60 mg/m2 p.o., d1-10) and CCNU (110 mg/m2 p.o., d 1). There was no lower limit of Karnofsky Performance Status. Thirty-two pts received 1 cycle, 17 pts received 2 cycles and 10 pts received 3 cycles. Best documented response in 25 evaluable pts were CR in 13/32 (41%), PR in 7/32 (22%) and PD 5/32 (16%) pts. Five of 32 pts developed severe renal impairment after MTX and were treated off-study. One patient died due to neutropenic fever. With a median follow-up of 64 mo (range 0–82 mo), the 5-year overall survival probability currently is 30.5%, the median survival is 15 mo. As of July 2006 9/32 (28%) pts are alive, 8 without evidence for leukoencephalopathy. New treatment regimen for pts &gt;65 years, R-MCP-Protocol: In a subsequent pilot-phase rituximab has been added before each MTX-application. In a single center pilot-phase, 9 pts were treated within the protocol. The response rates were CR in 4/7 (57%) evaluable pts, PR, SD and PD, each in one pt, respectively. One patient received only one dose of MTX due to liver toxicity and developed CR with rituximab as single agent. To date, after a median follow-up of 4 mo (range 0–11mo) 8 of 9 pts are alive. Conclusion: The protocols presented here are safe and show high efficacy in treating patients with PCNSL in both age-groups. The addition of rituximab to MTX-based chemotherapy is promising and warrants further investigation.

Final results of phase II study of S-1, oral leucovorin, oxaliplatin, and bevacizumab combination therapy (SOL+BV; SOLA) in metastatic colorectal cancer (mCRC).

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 574-574 ◽  
Author(s):  
Kentaro Yamazaki ◽  
Tomohiro Nishina ◽  
Takeshi Kato ◽  
Takayuki Yoshino ◽  
Yoshinori Miyata ◽  
...  
Keyword(s):  
Survival Rate ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Present Report ◽  
Sensory Neuropathy ◽  
Progression Free Survival ◽  
Target Lesion ◽  
Ecog Ps ◽  
The Impact

574 Background: The SOL regimen (S-1, Oral Leucovorin; LV, and Oxaliplatin) demonstrated a promising activity with tolerated toxicities compared to mFOLFOX6 in a randomized phase II study for mCRC. We previously reported the promising results of a phase II study of SOL+BV in Gastrointestinal Cancers Symposium 2012 (Kato T, et al.) focusing on early clinical outcomes, overall response rate (ORR), progression free survival (PFS) and safety. The final follow-up (cut-off date Dec 2012) has been completed, and we report up-dated overall survival (OS) and the impact of early objective tumor response (EOTR) on OS in the present report. Methods: The main inclusion criteria were; (1) metastatic colorectal adenocarcinoma, (2) age ≥20 years, (3) no prior chemotherapy, (4) target lesion (RECIST v1.0), (5) ECOG PS 0-1, 6) written informed consent. Patients (pts) received S-1 (40-60 mg bid) and LV (25 mg bid) orally for one week. Oxaliplatin (85 mg/m2) and BV (5 mg/kg) were administered on day 1. This treatment was repeated every 2 weeks. The primary endpoint was ORR confirmed by the independent review committee according to RECIST v1.0. This trial was supported by Taiho Pharmaceutical CO, LTD. (JAPIC Clinical Trials information Identifier: JapicCTI-090881). Results: From Oct 2009 to Apr 2010, 31 pts were enrolled. Of the eligible 29 pts, median age was 62; PS 0/1 was 24/5; number of metastatic organs 1/≥2 was 15/14. ORR was 86% (95%CI, 68-96), and the median PFS was 15 months (95%CI, 10-26). OS has not reached median with a median follow-up time of 34 months. Two-year survival rate was 72%. EOTR (RECIST sum ≥30% shrinkage) at 6-weeks was observed in 35% of pts. Two-year survival rate in these pts with an EOTR at 6-weeks was 80%, while in other pts without an EOTR at 6-weeks was 68%. The curative resection rate of metastatic lesions was 28%. The incidence (≥10%) of grade 3/4 adverse drug reactions were; neutropenia 20%, hypertension 23%, anorexia 20%, fatigue 17%, diarrhea 10%, and sensory neuropathy 53%. Conclusions: The SOL+BV regimen showed the promising activity for mCRC. The high proportion of EOTR might lead to long survival. Further evaluation of this regimen would be warranted. Clinical trial information: 090881.

scholarly journals Narcotic Use in Multiple Myeloma Patients at the Time of ASCT and One-Year Follow up

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4726-4726
Author(s):  
Matthew Danish ◽  
Tabitha Copeland ◽  
Joseph Ho ◽  
Mansi Shah ◽  
Dennis Cooper
Keyword(s):  
Multiple Myeloma ◽  
Clinical Response ◽  
Bone Pain ◽  
Novel Agents ◽  
Cell Transplant ◽  
Post Transplant ◽  
Opiate Use ◽  
The Impact

Background: Bone pain is one of the most common presentations of multiple myeloma and nearly all patients have skeletal involvement in the course of disease. Consequently, many patients require narcotics for symptom management at the time of diagnosis but the long term impact of MM treatment on pain control remains uncertain. With the advent of combination therapy for MM with novel agents followed by transplant and then maintenance therapy, clinical response is nearly universal and greater than 30% of patients achieve a serologic complete response. Therefore, we examined the impact of modern myeloma-directed therapy and high response rates on the use of narcotics up to 1 year after transplant in this group of patients. Methods: A retrospective review of data collected from the Rutgers-CINJ database was conducted. All patients who received induction inducing therapy (e.g. bortezomib, lenalidomide and dexamethasone or cyclophosphamide, bortezomib and dexamethasone) followed by high dose melphalan and autologous stem cell transplant (ASCT) and who had adequate post-transplant follow up (at least 100 days) were included. Morphine use was assessed at the time of transplant and at follow-up visits. All opiates (e.g. oxycodone, fentanyl, MS contin, etc.) where converted to morphine equivalents/day (ME/day) and recorded. Treatment responses were determined based on the International Myeloma Working Group Response Criteria. We compared the incidence and amount of narcotic use over time using one-way analysis of variance (ANOVA) and Dunn's multiple-comparison test. Results: 189 patients were included in the analysis. 38% were using opiates at the time of transplant. At 100 days post-transplant 35.5% were using opiates and at 1 year post transplant 30.9% were using opiates (p=0.04) . Average opiate use was 74.1 ME/day (95% CI: 55.2 to 92.9), 69.45 ME/day (95% CI: 50.5 to 88.3), and 70.78 ME/day (95% CI: 43.5 to 98) for each of the aforementioned time points (p=0.088) (Figure 1). For example, 74 ME/day would be equal to approximately 50 mg of Oxycodone daily. 74 patients were active opiate users at the time of transplant (Table 1). Response to myeloma treatment (remission, progression, relapse) was not different in opiate-using patients at the time of transplant or at 100 days and 1 year after transplant (Table 2). Conclusion : Early studies from the 1960's reported on the rapid reduction of bone pain in treatment responsive patients with MM (Hogstrata et al.). Recently, treatment modalities for MM have significantly improved, leading to markedly increased remission rates (>90%), progression-free and overall survival. With dramatically increased serologic responses, one would hypothesize that there would be a decline in pain and a subsequent decrease in opiate use. However, in this retrospective chart review we found that 30% of multiple myeloma patients continued to use opiates following transplant and that ongoing use of opiates appeared to be independent of clinical response. Interestingly, at the time of transplant active opiate users had a CR of 27.2% while the non-opiate using patients had a CR of 13.3%. Although there was a slight decline in the number of opiate users at the 1 year follow up, 33% of opiate users continued at their original level of opiate use and 22% increased their opiate use at 1 year post ASCT. Persistent long term use of opiates is of particular concern given that the survival of patients with MM has significantly improved with the use of novel agents and autologous transplant with an increasing number of patients surviving 10 years or more. In patients who have achieved an excellent response (e.g. serologic CR and negative PET scan), ongoing narcotic use should be addressed at each visit and other advanced pain management techniques should be considered. Disclosures No relevant conflicts of interest to declare.

L-mind: MOR208 combined with lenalidomide (LEN) in patients with relapsed or refractory diffuse large b-cell lymphoma (R-R DLBCL)—A single-arm phase II study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 7514-7514 ◽  
Author(s):  
Kami J. Maddocks ◽  
Eva González Barca ◽  
Wojciech Jurczak ◽  
Anna Marina Liberati ◽  
Johannes Duell ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
International Prognostic Index ◽  
Single Agent ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Cell Transplant ◽  
Cell Of Origin

7514 Background: The Fc-enhanced CD19 antibody MOR208 and the immunomodulatory drug LEN have demonstrated single agent activity in patients (pts) with R-R DLBCL. MOR208 and LEN have shown synergy in vitro and in vivo in preclinical lymphoma models. This ongoing phase II study assesses the safety and efficacy of MOR208 + LEN in pts with R-R DLBCL. Methods: Pts >18 years old with R-R DLBCL, ECOG 0–2, adequate organ function, having previously received ≥1 but not more than 3 prior therapies, including ≥1 CD20-targeting regimen and who are not candidates for autologous stem cell transplant (ASCT), are eligible. Treatment comprises up to 12, 28-day (d) cycles (C) of MOR208 12 mg/kg IV, weekly during C1–3 (loading dose d4 of C1); every second week C4–12 + LEN 25 mg po d1–21, C1–12. Pts progression-free after 12 cycles receive up to 12 additional cycles of MOR208 (every second week). The primary endpoint is the overall response rate (ORR) by central radiology assessment. Secondary endpoints include disease control, duration of response, progression-free and overall survival, safety, and response by cell of origin and other biomarkers. A preplanned safety evaluation was undertaken. Results: 31 of 80 planned pts were enrolled prior to data cutoff (3 January 2017). Median age was 74 years (range 47–82); 45% of pts received ≥2 prior lines of therapy; 23% had rituximab refractory disease; 74% had Ann Arbor stage ≥III disease; 65% had elevated lactate dehydrogenase level, and 52% had a poor revised International Prognostic Index (3-5). The most common treatment-emergent adverse events (any grade/grade ≥3 [% pts]) were neutropenia (39/26), anemia (23/0) thrombocytopenia (16/6), infections (26/10) diarrhea (13/0), pyrexia (13/0), and rashes (13/6). Of 26 response evaluable pts (median follow-up 3.3 months), ORR (investigator assessed) was 58% (15 pts), with 7 (27%) complete responses. Median time to response was 1.8 months. Conclusions: The combination of MOR208 + LEN is well tolerated and shows promising activity in pts with R-R DLBCL. Accrual and follow-up of pts is ongoing, as are cell of origin and other biomarker analyses. Clinical trial information: NCT02399085.

A Prospective Phase II Study on Tandem Autografting-Nonmyeloablative Allografting for Newly Diagnosed Myeloma: Final Results of the Gruppo Italiano Trapianto Midollo Osseo.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3026-3026
Author(s):  
B. Bruno ◽  
M. Rotta ◽  
F. Patriarca ◽  
D. Mattei ◽  
B. Allione ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Chronic Gvhd ◽  
New Drugs ◽  
Newly Diagnosed ◽  
Disease Response ◽  
Post Transplant ◽  
Primary Endpoints ◽  
Prospective Phase

Abstract The development of nonmyeloablative conditionings has recently reduced the transplant-related mortality (TRM) and extended the eligible age for transplantation up to 65–70 years. From January 2000 to June 2005, 106 newly diagnosed patients younger than 65 years were enrolled in a prospective phase II study at 15 Italian Centers. Fifty-eight were also previously described in a comparison of autografting with allografting based on a genetic randomisation (Bruno et al. N Engl J Med 2007). Here we report on a larger GITMO experience with a longer follow-up. Induction chemotherapy consisted of VAD-based regimens, followed by a cytoreductive autograft with melphalan 200 mg/m2, and by a non-myeloablative 2 Gy TBI-based allograft from an HLA-identical sibling. Graft-vs-host disease (GVHD) prophylaxis included cyclosporin and mycophenolate mofetil. Primary endpoints were overall (OS) and event-free (EFS) survivals. Secondary endpoint was TRM. One-hundred-two (96%) patients, median age 54 (30–65), completed the tandem program whereas 4 withdrew their consent. After a median follow-up of 54 (21–94) months, OS was not reached and median EFS was 35 (31–56) months post-transplant. Incidences of acute grade II-IV GHVD and extensive chronic GVHD were 40% and 50% respectively. Fourteen (13%) patients died from TRM, 14 (13%) from disease progression, 2 from lung cancer (2%) and 1 from lymphoma (1%). Overall response, defined as complete (CR) and partial remission, was 91% (93/102), with 53 patients achieving CR. Overall 39/102 patients relapsed, however only 8/53 of those who reached CR post-transplant. By multivariate-analysis disease response prior to allografting was significantly associated with longer OS (HR 0.27, CI 0.09–0.80, p<0.018) and longer EFS (HR 0.23, CI 0.11–0.49, p<0.001). Interestingly, chronic GVHD was not correlated with either the achievement of post-transplant CR (HR 0.87, CI 0.45–1.65, p<0.66) or its duration (HR 0.79, CI 0.45–1.40, p<0.42). Presence of del(13) was evaluated only in a subset of 39 patients: 13 carried del(13) and 26 did not. OS was not reached in the patients without del(13) and was 52 months in patients with del(13) (p=0.32), however EFS was not reached in the patients without del(13) whereas was 27 months for patients with del(13) (p=0.04). Given the encouraging results, the design of prospective studies that incorporate new drugs to cytoreduce the disease pre-transplant and enhance graft-vs.-myeloma are warranted to lower relapse rates and improve clinical outcomes.

A multicentric prospective study of intensive induction chemotherapy (API-AI) in localized osteosarcoma patients: Results of a phase II trial coordinated by the French Sarcoma Group (FSG) and the FNCLCC BECT

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 9521-9521 ◽  
Author(s):  
S. Piperno-Neumann ◽  
B. Bui ◽  
J. Blay ◽  
H. Roché ◽  
F. Pichon ◽  
...  
Keyword(s):  
Overall Survival ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Dose Intensity ◽  
Poor Responders ◽  
High Dose ◽  
Severe Toxicity ◽  
Salvage Regimen ◽  
The Impact

9521 Background: Based on the severe toxicity of high dose methotrexate (MTX) in adult patients, an alternative intensive chemotherapy (CT) was designed, associating doxorubicin, cisplatinum and ifosfamide in API-AI regimen. Promising results in 32 patients in a single institution study (Le Cesne ASCO 2004) led to a national multicenter phase II trial coordinated by the FSG of FNCLCC. Methods: Patients with a localized operable osteosarcoma were eligible. API-AI regimen consisted in 2 cycles every 28 days of doxorubicin 60 mg/m2 d1 and d15, cisplatinum 100 mg/m2 d1 and ifosfamide 5g/m2 d2 and d15, with equivalent dose of mesna and lenograstim after each course for 7 days. Good responders ≥95% necrosis (GR) received 2 postoperative API courses, and poor responders <95% necrosis (PR) a salvage regimen of 3 cycles of etoposide 100 mg/m2 d1 to d3 and ifosfamide 4 g/m2 d1 to d3. Results: From March 2001 to January 2004, 43 patients (male/female 28/15) with a median age of 23 years (range 17–50), were included. The median tumor size was 88 mm (13–280). All 43 patients received the preoperative API-AI regimen, with a dose intensity of ≥ 89% of the planned protocol. Toxicity was mainly haematological, with grade 3–4 sepsis, grade 4 neutropenia and thrombocytopenia observed in 12%, 79% and 49% of patients respectively. There was no severe renal and cardiac toxicity. All but 5 patients had a limb sparing surgery performed 77 days (median) after the first cycle (range 56–114 days). Intent to treat analysis showed 16/43 GR (37%). With a median follow-up of 36 months (25–48), the 2 year event-free and overall survival were 74% and 86% respectively. Conclusions: Despite the haematological toxicities, these results compare favorably with other previous induction CT schedules containing MTX in adults. A longer follow-up is required to evaluate the impact of this regimen on overall survival. No significant financial relationships to disclose.

Phase II study of lower-dose pracinostat plus azacitidine safety and efficacy in patients with high/very high-risk myelodysplastic syndromes.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 7556-7556
Author(s):  
Ehab L. Atallah ◽  
Samer K. Khaled ◽  
Brenda W. Cooper ◽  
Erica D. Warlick ◽  
David A. Ramies ◽  
...  
Keyword(s):  
High Risk ◽  
Phase Ii ◽  
Myelodysplastic Syndromes ◽  
Phase Ii Study ◽  
Standard Of Care ◽  
Cell Transplant ◽  
Open Label ◽  
Safety And Efficacy ◽  
Very High

7556 Background: Hypomethylating agents (HMA), such as azacitidine (AZA), are the standard of care for patients (pts) with higher-risk myelodysplastic syndromes (MDS). However, overall response rate (ORR=CR+PR) with HMA alone is approximately 30%, with a 2-year overall survival (OS) rate of 50.8%. Preclinical studies show that pracinostat (PRAN), an oral histone deacetylase inhibitor, synergizes with HMA. A study in pts with untreated IPSS intermediate-2/high-risk MDS receiving 60 mg PRAN plus AZA resulted in early discontinuations, mainly due to adverse events (AE), potentially leading to diminished clinical benefit. This follow-up phase II study evaluates a lower dose of PRAN (25% reduction) in combination with AZA in order to reduce toxicity, decrease early discontinuations, and improve outcomes. An interim analysis showed low discontinuation rate and promising efficacy, allowing trial expansion. Herein, we report preliminary safety and efficacy in the overall population. Methods: Open-label, II-stage, phase II trial (NCT03151304) in pts (≥18 years) naive to HMA therapy and with IPSS-R of high/very high-risk MDS. Planned enrollment was 60 pts. Pts received 45 mg PRAN 3 days/week for 3 consecutive weeks plus standard AZA dose for 7 days of each 28-day cycle. Primary objectives were to define the safety/tolerability of the combination and to assess the ORR (CR+PR). OS was a secondary endpoint. Results: Sixty-four pts were enrolled and received ≥1 dose of treatment. Most pts were male (67%), median age was 68 years (range 47–89), and the proportion of pts with high/very high-risk MDS was similar. After 17.6 months’ median follow-up, 31% of pts remain on treatment; 69% of pts discontinued treatment due to stem cell transplant (25%), disease progression (17%), AEs (11%), consent withdrawal (3%), pt noncompliance (3%), death (3%), lost to follow-up (2%), and other (5%). Most common nonhematologic AEs were constipation (55%), nausea (52%), fatigue (45%), decreased appetite (39%), peripheral edema (36%), diarrhea, and dyspnea (31% each). Frequent hematologic AEs were decreased neutrophil count (50%), anemia (39%), decreased platelet count (38%), febrile neutropenia (36%), and thrombocytopenia (30%). ORR was 33% (95% CI 22-46), with 33% achieving CR; 34% of pts had marrow CR. Median OS was 23.5 months (95% CI 16.4-nc), with an estimated 1-year OS of 77%. Conclusions: In pts with high/very high-risk MDS, a lower dose of pracinostat in combination with AZA demonstrated a tolerable safety profile and promising efficacy. Clinical trial information: NCT03151304 .

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