Multicenter Phase II Study of Fertility-Sparing Treatment With Medroxyprogesterone Acetate for Endometrial Carcinoma and Atypical Hyperplasia in Young Women

2007 ◽  
Vol 25 (19) ◽  
pp. 2798-2803 ◽  
Author(s):  
Kimio Ushijima ◽  
Hideaki Yahata ◽  
Hiroyuki Yoshikawa ◽  
Ikuo Konishi ◽  
Toshiharu Yasugi ◽  
...  
Keyword(s):  
Endometrial Carcinoma ◽  
Young Women ◽  
Medroxyprogesterone Acetate ◽  
Prospective Trial ◽  
Pathologic Complete Response ◽  
Fertility Treatment ◽  
High Dose ◽  
Fertility Sparing ◽  
Grade 3

Purpose To assess the efficacy of fertility-sparing treatment using medroxyprogesterone acetate (MPA) for endometrial carcinoma (EC) and atypical endometrial hyperplasia (AH) in young women. Patients and Methods This multicenter prospective study was carried out at 16 institutions in Japan. Twenty-eight patients having EC at presumed stage IA and 17 patients with AH at younger than 40 years of age were enrolled. All patients were given a daily oral dose of 600 mg of MPA with low-dose aspirin. This treatment continued for 26 weeks, as long as the patients responded. Histologic change of endometrial tissue was assessed at 8 and 16 weeks of treatment. Either estrogen-progestin therapy or fertility treatment was provided for the responders after MPA therapy. The primary end point was a pathologic complete response (CR) rate. Toxicity, pregnancy rate, and progression-free interval were secondary end points. Results CR was found in 55% of EC cases and 82% of AH cases. The overall CR rate was 67%. Neither therapeutic death nor irreversible toxicities were observed; however, two patients had grade 3 body weight gain, and one patient had grade 3 liver dysfunction. During the 3-year follow-up period, 12 pregnancies and seven normal deliveries were achieved after MPA therapy. Fourteen recurrences were found in 30 patients (47%) between 7 and 36 months. Conclusion The efficacy of fertility-sparing treatment with a high-dose of MPA for EC and AH was proven by this prospective trial. Even in responders, however, close follow-up is required because of the substantial rate of recurrence.

scholarly journals Shortened Immunosuppression Following Peripheral Blood (PB) Haploidentical (haplo) Transplantation with Post-Transplant Cyclophosphamide (PTCy) Is Associated with Tolerable Rates of Graft-Vs-Host Disease (GVHD)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3320-3320
Author(s):  
Amy E. DeZern ◽  
Marianna Zahurak ◽  
Javier Bolanos-Meade ◽  
Richard J. Jones
Keyword(s):  
Graft Failure ◽  
Acute Gvhd ◽  
Risk Index ◽  
Chronic Gvhd ◽  
Prospective Trial ◽  
Stopping Rules ◽  
High Dose ◽  
Gvhd Prophylaxis ◽  
Grade 3

With PTCy as GVHD prophylaxis, nonmyeloablative (NMA) HLA- haplo and HLA-matched blood or marrow (BMT) have comparable outcomes. Previous reports showed that discontinuation of immunosuppression (IST) as early as day 60 after infusion of bone marrow (BM) haplo allograft with PTCy is feasible. However, there are certain diseases in which PB may be favored over BM grafts to augment engraftment rates; however, given the higher rates of GVHD with PB, excessive GVHD becomes a concern with early discontinuation of IST. We present a completed, prospective single-center trial of stopping IST at days 90 and 60 after NMA haplo PB. (NCT02556931) From 12/2015-7/2018, 117 evaluable patients (pts) with hematologic malignancies associated with higher rates of graft failure with PTCy (MDS, MPN, overlap syndromes, 2o AML, AML with MRD, MM, and CLL) received NMA PB allografts on trial. Haplo donors were preferred, but in patients lacking suitable haplo relatives, unrelated donors were employed with 6 in each IST cohort. The primary objective was to evaluate the safety and feasibility of reduced‐duration IST (from Day 5 through Day 90 in cohort 1 and through Day 60 in cohort 2.) Transplant inclusion criteria were standard and the conditioning included Cy (14.5 mg/kg IV D -6 and -5), fludarabine (D -6 to -2), TBI (200 cGy D -1) and T-cell replete PB. GVHD prophylaxis consisted of high-dose PTCy (50 mg/kg IV D 3 and 4), mycophenolate mofetil (D 5-35) and IST (tacrolimus/sirolimus) from D 5 forward. Priot to transplantation, pts were assigned to stop IST early if eligible, as defined by having ≥ 5% donor T cells at ~D 56 onward, no relapse, and no grade 2-4 acute or significant chronic GVHD. If ineligible to discontinue IST early, it continued through D 180. Monitoring rules declared reduced IST feasible if ≥ 33% of pts stopped IST early as planned. Safety stopping rules for early IST cessation were based on ≥ 5% graft failure, ≥ 5% NRM, ≥ 50% relapse, and ≥ 10% combined grade 3-4 acute GVHD and severe chronic GVHD, measured from the IST stop date to ~D 180. Historical data from 55 haplo transplants for MDS, CLL, and MPNs at our center using the same regimen and PB grafts informed safety calculations. Of the 117 pts (median age 64 years, range 24-78), the most common diagnoses were MDS (33%), AML (with MRD or arising from antecedent disorder) (31%), MPNs (21%) myeloma (10%), and CLL (6%). By refined Disease Risk Index, 13% were low risk, 69% intermediate and 18% high. Shortened IST was feasible in 75 pts (64%) overall. Ineligibility for shortened IST was due most commonly to GVHD (17 pts), followed by early relapse (11 pts), NRM (7 pts), patient/ physician preference (4 pts) or graft failure (3 pts). Of the 57 patients in the D90 cohort (median follow up 35 mos), 33 (58%) stopped IST early as planned. Of the 60 patients in the D60 cohort (median follow up 20 mos), 42 (70%) stopped IST early as planned. The graft failure rate was 2.6%. NRM was very similar in the two arms, 12% at both 12 and 18 months in the D90 cohort and 10% and 13% at 12 and 18 months in the D60 cohort. Relapse in D90 cohort is 40% at 18 months compared to 33% at 18 months in the D60 cohort. Figure 1 shows cumulative incidence (CI) of acute grade 2-4 and grade 3-4 GVHD. Although the CI of grade 1-2 GVHD may be slightly higher in day 60 cohort, it is only 40% at D180. Severe chronic GVHD was 12% (D90) and 11% (D60) at 540 days. One year OS is 75% and 78% for the D90 and D60 cohorts, respectively. At 12 months PFS is 54% in the D90 group and 67% in the D60. At 12 months, the GRFS is 33% in the D90 group, and 38% in the D60 group. (Figure 2) These data suggest that reduced-duration IST in pts receiving NMA haplo PB with PTCy is feasible and carries an acceptable safety profile. Risks of acute GVHD, chronic GVHD, graft failure and NRM appear similar to historical outcomes with IST until D180 and between the two cohorts. When comparing the D90 and D60 arms, grade 3-4, severe chronic GVHD, GRFS, OS and PFS were similar. Although a larger, prospective trial would be needed to uncover potential small differences in outcomes based on IST duration, these data show that similar to our findings with BM, many PB pts (64% in this trial) can discontinue IST as early as D60 without undue toxicity. The favorable toxicity profile of the PTCy platform, coupled with the feasibility and safety of early IST cessation, provides an ideal setting to incorporate novel post-transplantation approaches for relapse reduction. Figure 1 Disclosures DeZern: Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. Bolanos-Meade:Incyte Corporation: Other: DSMB fees.

Predictability of later developed relapse in endometrial carcinoma in young women with functional imaging parameters of fes/FDG SUV ratio after fertility-sparing hormone treatment.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e16502-e16502
Author(s):  
Yoshio Yoshida ◽  
Hidehiko Okazawa ◽  
Akiko Shinagawa ◽  
Yasushi Kiyono ◽  
Tetsuya Mori ◽  
...  
Keyword(s):  
Endometrial Carcinoma ◽  
Young Women ◽  
Young Patients ◽  
Complete Response ◽  
Hormone Treatment ◽  
Tracer Uptake ◽  
High Dose ◽  
Standardized Uptake Values ◽  
Fertility Sparing ◽  
Significant Difference

e16502 Background: Even in responders of fertility-sparing hormone treatment for uterine endometrial carcinoma (EC) and atypical endometrial hyperplasia (AH) in young women, there have been high potential risks of later developed relapse. The aim of this study was whether changes in FDG and fluoroestradiol (FES) PET parameters following hormone treatment have the prognostic factor in prediction of later developed relapse. Methods: Eight young patients with EC and AH were treated by fertility-sparing treatment with a high-dose of medroxyprogesterone acetate (MPA) for 26 weeks. All patients underwent two FDG and FES-PET scans at baseline and 8 weeks after the beginning of MPA treatment, respectively. For each lesion, metabolic indices were calculated by standardized uptake values (SUV). All patients were followed up for 2 years. Values of FDG-SUV, FES-SUV and FES/FDG SUV ratio of tumors were retrospectively reviewed. The correlation between these parameters and clinical outcome of EC and AH for 2 years was evaluated. Results: An initial complete response was achieved in all patients. Two of 5 responders (40%) with AH and one of three (33%) responders with EC later developed (72-88weeks) relapse. One of those three patients underwent hysterectomy due to no response for additional MPA therapy. The tracer uptake of FDG and FES was decrease in all eight patients after 8 weeks. The FES/FDG ratio was increased in all three patients with later developed relapse, but the FES/FDG ratio was decrease in all patients without recurrence for 8 weeks. There was a significant difference of the change in FES/FDG ratio between later developed relapse patients and no relapse patients (0.113 vs -0.392; p = 0.044). Conclusions: This study suggests that an increase in the FES/FDG ratio after 8 weeks fertility-sparing hormone treatment with a high-dose of MPA may be a useful biomarker for predicting later developed relapse in EC and AH in young women.

Fertility-Preserving Treatment in Young Women With Endometrial Adenocarcinoma: A Long-Term Cohort Study

2014 ◽  
Vol 24 (4) ◽  
pp. 718-728 ◽  
Author(s):  
Chin-Jung Wang ◽  
Angel Chao ◽  
Lan-Yan Yang ◽  
Swei Hsueh ◽  
Yu-Ting Huang ◽  
...  
Keyword(s):  
Endometrial Carcinoma ◽  
Young Women ◽  
Endometrial Adenocarcinoma ◽  
Myometrial Invasion ◽  
Megestrol Acetate ◽  
Published Data ◽  
High Dose ◽  
Low Grade

ObjectiveGrowing evidence suggests that fertility-preserving treatment is feasible for young women with early-stage, low-grade endometrial carcinoma. However, published data on their long-term outcomes and prognostic factors remain scanty. We aimed to investigate the outcomes of young women receiving fertility-preserving treatment.MethodsBetween 1991 and 2010, the outcomes of young women with grade 1 endometrioid endometrial carcinoma at presumed stage IA (without myometrial invasion) who underwent fertility-preserving treatment of megestrol acetate 160 mg/d with or without other hormonal agents were retrospectively analyzed.ResultsWe identified 37 eligible patients (median age, 32 years; range, 18–40 years). The median follow-up time was 78.6 months (range, 19.1–252.8 months). Complete response (CR) lasting more than 6 months was achieved in 30 (81.1%) women. Responders were significantly younger than nonresponders (P= 0.032). Of the 30 women who had a CR, 15 (50.0%) had disease recurrence. The 5-, 10-, and 15-year cumulative recurrence-free survival rates were 51.0%, 51.0%, and 34.0%, respectively. Notably, those recurred were significantly older (P= 0.003), and the time to CR was significantly longer (P= 0.043) than those without recurrence. One patient developed late recurrences at 156 months, and 2 patients developed ovarian metastasis (6 and 137 months from diagnosis). All the patients are currently alive.ConclusionsThis study demonstrates the feasibility of high-dose megestrol acetate–based therapy for fertility preservation. The substantial risk of late recurrences highlights the need for long-term follow-up studies of large sample sizes with in-depth tumor and host molecular signatures.

Controversies in the management of early endometrial carcinoma: an update

2017 ◽  
Vol 6 (6) ◽  
pp. 2124 ◽  
Author(s):  
P. Reddi Rani ◽  
Jasmina Begum ◽  
K. Sathyanarayana Reddy
Keyword(s):  
Developing Countries ◽  
Endometrial Carcinoma ◽  
Young Women ◽  
Genital Tract ◽  
Best Practice ◽  
Management Strategies ◽  
Evidence Based ◽  
Fertility Sparing Surgery ◽  
Fertility Sparing ◽  
Cure Rates

Endometrial carcinoma (EC) is the commonest genital tract malignancy in developing countries and is usually confined to the uterus at the time of diagnosis with excellent prognosis and high cure rates. But the management is associated with lot of controversies like in staging, best surgical approach, extent of lymphadenectomy, adjuvant therapy, fertility sparing surgery in young women etc. A thorough surgical staging is important to determine uterine and extrauterine spread and also understanding of the pathophysiology and management strategies to identify women who are at high risk and tailoring the adjuvant treatment if necessary without increasing the morbidity. This evidence based narrative review conducted by searching Medline (1994- 2015) and other online articles from Pubmed, Google scholar. Articles were selected based on their currency and relevance to the discussion they summarize the current literature to provide an approach to best practice management of early endometrial carcinoma.

Long-term weekly treatment of colorectal metastatic cancer with fluorouracil and leucovorin: results of a multicentric prospective trial of fluorouracil dosage optimization by pharmacokinetic monitoring in 152 patients.

1998 ◽  
Vol 16 (4) ◽  
pp. 1470-1478 ◽  
Author(s):  
E Gamelin ◽  
M Boisdron-Celle ◽  
R Delva ◽  
C Regimbeau ◽  
P E Cailleux ◽  
...  
Keyword(s):  
Therapeutic Range ◽  
Plasma Levels ◽  
Dose Adjustment ◽  
Metastatic Cancer ◽  
Prospective Trial ◽  
High Dose ◽  
High Survival ◽  
Time Curve ◽  
Minor Response ◽  
Grade 3

PURPOSE A relationship between fluorouracil (5-FU) dose and response has been previously shown in advanced colorectal cancer. In a previous study with 5-FU stepwise dose escalation in a weekly regimen, and pharmacokinetic monitoring, we defined a therapeutic range for 5-FU plasma levels: 2,000 to 3,000 microg/L (area under the concentration-time curve at 0 to 8 hours [AUC0-8], 16 to 24 mg x h/L). The current study investigated 5-FU therapeutic intensification with individual dose adjustment in a multicentric phase II prospective trial. PATIENTS AND METHODS Weekly high-dose 5-FU was administered by 8-hour infusion with 400 mg/m2 leucovorin. The initial dose of 5-FU (1,300 mg/m2) was adapted weekly according to 5-FU plasma levels, to reach the therapeutic range previously determined. RESULTS A total of 152 patients entered the study from December 1991 to December 1994: 117 patients with measurable metastatic disease and 35 with assessable disease. Toxicity was mainly diarrhea (39%, with 5% grade 3) and hand-foot syndrome (30%, with 2% grade 3). Among 117 patients with measurable disease, 18 had a complete response (CR), 48 a partial response (PR), 35 a minor response (MR) and stable disease (SD), and 16 progressive disease (PD). Median overall survival time was 19 months. The 5-FU therapeutic plasma range was rapidly reached with a variable 5-FU dose in the patient population: mean, 1,803 +/- 386 mg/m2/wk (range, 950 to 3,396). Thirteen patients were immediately in the toxic zone, whereas 51 required a > or = 50% dose increase. CONCLUSION Individual 5-FU dose adjustment with pharmacokinetic monitoring provided a high survival rate and percentage of responses, with good tolerance.

High-Dose Cytoxan, Etoposide, and Cisplatin Followed by Autologous Hematopoietic Cell Transplantation for the Treatment of Hodgkin Lymphoma: A 20-Year Single-Institutional Experience.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1913-1913
Author(s):  
Thomas R. Klumpp ◽  
Moshe C. Chasky ◽  
Robert V. Emmons ◽  
Mary E. Martin ◽  
James L. Gajewski ◽  
...  
Keyword(s):  
Complete Remission ◽  
Total Dose ◽  
Hodgkin Lymphoma ◽  
Pulmonary Toxicity ◽  
Median Number ◽  
High Dose ◽  
Post Transplant ◽  
Grade 3 ◽  
Active Disease

Abstract Since 1988 we have treated 66 patients with relapsed, refractory, or high-risk Hodgkin lymphoma (HD) with high-dose CEP consisting of cyclophosphamide 1,500 mg/m2/day × 4 (total dose, 6,000 mg/m2), etoposide 400 mg/m2 twice daily × 6 doses (total dose, 2,400 mg/m2), and cisplatin 50 mg/m2/day × 3 by continuous i.v. infusion (total dose 150 mg/m2) followed by infusion of autologous peripheral blood stem cells (n=49), bone marrow (n=16), or both (n=1). The patient population included 41 males and 25 females. The median age at transplant was 33 years (range, 17–64 years). Twenty-three patients (35%) had never achieved complete remission prior to transplant, 36 (55%) had previously achieved a complete remission but subsequently relapsed, and 3 (5%) were in first complete remission. Information regarding the disease status at transplant was unavailable for 4 patients (6%). Twenty-seven patients (41%) remain alive and free of any post-transplant relapse or progression as of the most recent follow-up, and an additional 10 patients (15%) manifested active disease post-transplant but are currently in remission following additional post-transplant therapy, yielding a total of 37 patients (56%) currently in CR. In addition, 5 patients (8%) remain alive with active disease, 23 patients (35%) died of progressive disease, and only 2 patients (3%) died of treatment-related causes including diffuse alveolar hemorrhage (1 patient) and hepatic veno-occlussive disease (1 patient). With a median follow-up of 4.4 years among surviving patients, the Kaplan-Meier 5-year estimates for event-free survival and overall survival are 34% and 60%, respectively, and five-year survival was superior among patients who had achieved at least one CR prior to transplant versus patients who had never been in CR prior to transplant (71% versus 43%, p = 0.03). Detailed adverse events data is available regarding all patients transplanted since September 1996: Of these, only 3 (7%) suffered grade 3 or greater pulmonary toxicity, 12 (29%) exhibited grade 3 or higher mucositis, and 10 (24%) had grade 3 or higher nausea or vomiting. The median number of days from transplant to neutrophil recovery (500 cells/uL) was 10 days, whereas the median number of days to platelet recovery (20,000 cells/uL) was 12 days. We conclude that high- dose CEP followed by autologous transplant is an active and well-tolerated treatment program in patients with relapsed or refractory HD. The low incidence of pulmonary toxicity is noteworthy given that a high percentage of patients had been exposed to bleomycin and/or thoracic XRT prior to transplant, and appears to be superior to that reported with conventional CBV-conditioned transplants in patients with HD.

Phase I/II Trial of High-Dose Melphalan (M) and Topotecan (T) Followed by Autologous Stem Cell Rescue in Patients ≤ 60 and > 60 Years of Age with Multiple Myeloma (MM).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 943-943
Author(s):  
Daniel Sullivan ◽  
Melissa Alsina ◽  
Claudio Anasetti ◽  
Teresa Field ◽  
Mohamed Kharfan-Dabaja ◽  
...  
Keyword(s):  
Stem Cell ◽  
Total Dose ◽  
Dose Level ◽  
Topoisomerase I ◽  
Plasma Cells ◽  
The Elderly ◽  
High Dose ◽  
Stem Cell Rescue ◽  
Grade 3

Abstract MM is the most common indication for high-dose chemotherapy (HDC) and autologous stem cell rescue. Among 13,431 pts receiving HDC for MM, the 3-year probability of survival is 67% ± 1% with autotransplantation (IBMTR data). Pre-clinical data from our lab demonstrate a synergistic cytotoxic interaction from sequential M and topoisomerase I inhibitors in human MM cell lines. Thus, we conducted a trial where poor prognosis chemosensitive, relapsed, and primary refractory pts were primed for stem cell collection with cyclophosphamide (50 mg/kg/d X 2d) and GCSF. Pts were then treated with fixed doses of M (50 mg/m2/d X 3d; total dose = 150 mg/m2) followed immediately by dose-escalated T (6.7–56.7 mg/m2/d X 3d; total dose = 20–170 mg/m2) in separate cohorts of younger (≤ 60) and elderly (> 60) patients with MM. The standard dose of M was decreased to allow for dose-escalation of T. One hundred nineteen patients are evaluable for toxicity, response and survival (54 elderly and 65 younger). The maximum tolerated dose (MTD) in the elderly cohort is 30 mg/m2 total dose T (dose level 2); dose-limiting toxicity (DLT) at 40 mg/m2 was grade 3 musculoskeletal toxicity. The median age of the elderly pts was 65 yrs (range 61–77). The MTD in younger patients was a total T dose of 127.3 mg/m2 (dose level 7); DLT at 170 mg/m2 was grade 4 transaminitis. The median age of the younger pts was 53 yrs (range 33–60). The response rate (CR + PR) in elderly subjects (includes 38 pts enrolled at the MTD) was 65%, and 77% in those ≤ 60 (7 pts enrolled at the MTD thus far). Grade 3–4 mucositis was common at all dose levels of T and increased in incidence with T dose-escalation. Median days to ANC ≥ 500/ml X 3d for all patients was d+11, and for platelets ≥ 20K X 7d was d+16. No correlation between time of engraftment and dose level was observed. The 100 day non-relapse mortality was 1.7% (one patient died from sepsis and one from ARDS). At a median follow up of 25.3 and 35.3 months for the elderly and young cohorts, respectively, the 3-year overall survival is 70% for both groups. At a median follow up of 15.3 months for the elderly and 14 months for the young cohort, the 3-year event-free survival is 32% and 40%, respectively. The pharmacokinetics of high-dose M and T have been determined in all patients on this trial, and the AUC and CMAX of T appear to be linear with dose. Pts with stable disease after transplant were found to have an increased clearance of melphalan and a lower AUC of T lactone and T total drug. SNP analyses of 71 pts using the Nanogen DrugMet SNP genotyping assay showed that CYP3A5*3 carriers appear to have increased T metabolism that is associated with a poorer response to MT. The relative risk a CYP3A5*3 allele carrier would have a PR or SD was 1.77 with a 95% CI of 1.37–2.28. The remaining goals of this trial are to enroll 43 pts at the MTD for both the young and elderly cohorts, to determine topoisomerase I levels and distribution in CD138-selected plasma cells, and to define the levels and function of the ABCG2/BCRP pump in plasma cells (for which T is the best substrate). This trial was supported in part by NCI grant CA082533 and GlaxoSmithKline.

Alemtuzumab Plus Oral Dexamethasone, Followed by Alemtuzumab Maintenance or Allogeneic Transplantation in Ultra High-Risk CLL: Interim Analysis of a Phase II Study of the GCLLSG and fcgcll/MW

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2854-2854 ◽  
Author(s):  
Stephan Stilgenbauer ◽  
Florence Cymbalista ◽  
Véronique Leblond ◽  
Alain Delmer ◽  
Dirk Winkler ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Response Rates ◽  
Long Term Results ◽  
High Dose ◽  
Significant Difference ◽  
Ultra High Risk ◽  
Grade 3 ◽  
The Impact

Abstract Abstract 2854 Alemtuzumab (A) proved to be efficacious in CLL patients (pts) with very poor prognosis, either due to fludarabine (F) refractoriness or due to unfavorable cytogenetics (17p-). However, rate and duration of remissions still remain unsatisfactory. Therefore, the French and German CLL study groups jointly embarked on this trial, trying to achieve higher overall response rates (ORR) by adding high-dose dexamethasone (D) to A and, simultaneously, investigating the consolidation effect of prolonged A maintenance or allogeneic stem-cell transplantation (allo-SCT), respectively. Induction treatment consisted of subcutaneous A 30 mg weekly × 3 for 28 days, combined with oral D 40 mg on days 1–4 and 15–18, and prophylactic pegfilgrastim 6 mg on days 1 and 15. Depending on the remission status, pts were treated for up to 12 weeks. If CR was documented at 4 or 8 weeks, or at least SD was achieved at 12 weeks, consolidation was scheduled with either allo-SCT or A maintenance with 30 mg every 14 days for up to 2 years (y), at the discretion of pt and physician. Between January 2008 and July 2011, 124 pts were recruited at 26 centers, 120 of whom were eligible. Pts were generally subdivided into three cohorts: 55 pts were refractory (i.e. no response or relapse within 6 months) to regimens containing F or a similar drug (i.e. pentostatin, cladribine, bendamustine). Non-refractory pts all exhibited 17p- and had either untreated (n=39) or relapsed CLL (n = 26) requiring therapy. The median age was high with 66/64/66 y in 17p- 1st line, 17p- relapse, and F-refractory pts, respectively. The three cohorts had 46/54/75% Binet C disease, 41/35/27% B symptoms, 38/42/53% reduced performance status (ECOG 1/2), median thymidine kinase levels of 35/49/24 U/L, median ß2MG levels of 3.8/5.5/4.6 mg/L, and IGHV was unmutated in 89/96/87%. In the F-refractory group, 53% exhibited 17p deletion and 22% had 11q deletion. Pretreated patients had received a median of 3 (F-refractory) or 2 prior lines (17p- relapse). 5 pts had previously undergone autologous and 1 pt allo-SCT. Treatment and efficacy data are currently available for 87 pts who completed induction therapy :17p- 1st-line (n=30), 17p- relapse (n=17), and F-refractory (n=40). Of these, 80/53/55% received the full induction of 12 weeks. ORR (best observed status) was generally high with 97/76/70%. CR was achieved in 20/0/5%. After a median follow-up of 11.8 months (mo), median progression-free survival (PFS) was 16.9/10.4/8.4 mo. Deaths are recorded in 13/27/36% of pts, with median overall survival (OS) not yet reached (>24 mo) in the 17p- 1st line group, and 15/12 mo in 17p- relapse/F-refractory pts. Consolidation treatment was performed as maintenance A (median duration 32 weeks, range 2 – 89) in 34%, and allo-SCT in 30%, with a median age of 66 and 61 y in these subgroups. The main reasons for going off-study without consolidation were death due to infection (14%, n=11, of these 6 without response, and 10 in the F-refractory cohort), CLL progression (12%), and other toxicity (5%). Among the 28 pts not receiving consolidation, there were 19 (68%) deaths, 15 of them in the F-refractory cohort. When comparing A maintenance and allo-SCT for consolidation, there were 9 (35%) and 7 (30%) PD events, respectively and there was so far no significant difference in PFS (median 17 mo in both groups) or OS. During induction, grade 3/4 hematotoxicity consisted of anemia in 28%, neutropenia in 47%, and thrombopenia in 44%. Grade 3/4 non-CMV infection occurred in 29% of 17p- 1st-line, 15% of 17p- relapsed, and 56% of F-refractory pts. CMV reactivation was observed in 54/25/40%, without severe sequelae recorded. During A maintenance, grade 3/4 toxicity consisted of neutropenia in 39% pts and thrombopenia in 4% pts with 6 SAEs (ITP, diarrhea, infection, erythema, tachycardia, and thrombosis). Conclusions: The combination of A and D shows high response rates in ultra high-risk CLL, with promising preliminary findings for PFS and OS, despite the high median age of the pts. The results compare favorably to ORR/CR of 68%/5%, and median PFS of 11.3 mo in the 17p- subgroup of the CLL8 study treated with FCR, consisting of younger pts (median 61 y). In F-refractory CLL however, when compared to the preceding CLL2H study with single agent A, the improved initial response by adding dexamethasone does not seem to translate into improved long-term results. More mature follow-up is needed, especially with respect to the impact of allo-SCT. Disclosures: Stilgenbauer: Amgen: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding. Off Label Use: Alemtuzumab in 1st line CLL treatment. Cymbalista:Roche (d) Mundipharma (e) Genzyme (e): Honoraria, Research Funding. Hinke:WiSP (CRO): Employment.

Effects of Dexamethasone (DEX) Vs Prednisone (PDN) and High-Dose Methotrexate (HD-MTX) Vs Capizzi Methotrexate/Asparaginase (C-MTX/ASNase) On Osteonecrosis (ON) Incidence in Children and Young Adults with High Risk Acute Lymphoblastic Leukemia (HR-ALL): A Report From the Children's Oncology Group (COG) Study AALL0232

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 665-665 ◽  
Author(s):  
Leonard A. Mattano ◽  
Meenakshi Devidas ◽  
Naomi Winick ◽  
Elizabeth Raetz ◽  
Stephen P. Hunger ◽  
...  
Keyword(s):  
Lymphoblastic Leukemia ◽  
Significant Risk ◽  
Pairwise Comparison ◽  
Clinical Severity ◽  
High Dose ◽  
Additional Risk ◽  
History Of ◽  
Children And Young Adults ◽  
Grade 3

Abstract Abstract 665 Improved treatment outcomes for HR-ALL are associated with a significant risk of symptomatic ON, particularly in adolescents. Causes are multifactorial, including exposure to DEX, MTX and ASNase. This was first noted on CCG-1882 (1991–1995), which showed more ON in slow early responders (SER) given 2 vs 1 interim maintenance/delayed intensification (IM/DI) phases as part of therapy that included C-MTX/ASNase during IM and continuous DEX (d1-21) during DI (Mattano, JCO 2000). Since 1996 the COG has prospectively monitored the occurrence of symptomatic ON in HR ALL trials. CCG-1961 (1996–2002) showed that alternate-week DEX (AWD) (d1-7, 15–21) during 2 DIs reduced ON compared with continuous DEX during 1 DI in rapid early responders (RER) (Mattano, Lancet Oncol 2012). AALL0232 (2003–2011) enrolled a total of 3154 HR-ALL patients (pts) 1–30 yr and included COG augmented therapy with a 2×2 randomization to DEX (10 mg/M2 d1-14) vs PDN (60 mg/M2 d1-28) during induction (IND) and HD-MTX vs escalating-dose C-MTX plus pegaspargase during IM. RER pts received 1 IM/DI, SER pts received 2 IM/DI; all initially received monthly DEX maintenance (MTC) pulses (6 mg/M2 d1-5). To limit ON, pts 13+ yr received AWD during 1 or 2 DI, while pts <13 yr received continuous DEX. Based on interim analyses, the study was amended twice to address unexpectedly high ON rates. After 10/2006 all pts 10+ yr received AWD during DI; after 6/2008 all pts 10+ yr were non-randomly assigned to PDN during IND, and pts of all ages received AWD during DI and PDN pulses in MTC. Detailed analyses of 2701 pts with reportable data (1405 with 24+ month follow-up) showed ON in 249 pts (228 10+ yr, 21 1–9 yr; 119 males, 130 females). Symptom onset was pre-MTC in 17.7%, during MTC in 77.9%, after therapy completion in 4.4%, and within 36 months from ALL diagnosis in 98.0%. The 36-month cumulative ON incidence was 13.5±1.1%, was higher for pts 10+ yr (19.6±1.6 vs 3.1±0.9%, RHR 6.7, p<0.0001), and increased with age (1–9 yr 3.1±0.9%, 10–12 yr 17.2±2.5%, 13–15 yr 21.9±2.7%, 16+ yr 21.2±3.3%, p<0.0001). For pts 10+ yr, ON incidence was higher in females (22.2±2.5 vs 17.4±2.1%, RHR 1.4, p=0.01). Among randomized RER pts 10+ yr (Table), ON incidence was higher for DEX vs PDN (RHR 1.8); for pts 1–9 yr, rates were similarly low but modestly higher for PDN (borderline significance). There was no difference between C-MTX/ASNase vs HD-MTX overall. However, for pts 10+ yr randomized to PDN, pairwise comparison showed a higher ON rate for C-MTX/ASNase (17.2±3.8 vs 10.3±2.7%, RHR=1.7, p=0.01). Comparison of ON incidences between randomized RER regimens showed significant differences in pts 1–9 yr (DC 1.5±1.4, DH 0.7±1.0, PC 5.6±2.6, PH 1.9±1.6%, p=0.04) and 10+ yr (DC 23.9±4.0, DH 24.7±3.7, PC 20.9±4.0, PH 9.8±2.7%, p=0.0004). Comparison of ON incidences for pts 10–12 yr given continuous DEX vs AWD in DI (pre- vs post-2006 amendment) confirmed a significantly lower rate with AWD (28.9±3.8 vs 10.3±3.1%, RHR 3.1, p<0.0001). Maximum patient ON clinical severity (CTCAE v3.0) reported for 210 of 249 pts: 6.7% grade 1, 63.3% grade 2, 29% grade 3, 1.0% grade 4. The most common sites were knee > hip > ankle. In conclusion, DEX is associated with a higher incidence of ON among pts 10+ yr receiving augmented therapy. Children 1–9 yr appear to tolerate DEX and PDN during IND with similar low ON rates. ON risk can be significantly reduced by using AWD during DI, and by using HD-MTX rather than C-MTX/ASNase with PDN based regimens. Studies are presently underway that include prospective MRI screening to further define the natural history of ON in HR ALL and to identify additional risk factors for this common toxicity. Randomized RER, 36-Month Incidence Rate (% ± SE) DEX PDN P 1-9 yr 1.1 ± 0.9 3.7 ± 1.5 0.05 10+ yr 24.3 ± 2.7 15.1 ± 2.4 0.0007 16+ yr 25.6 ± 6.0 13.7 ± 4.9 0.04 C-MTX HD-MTX P 1-9 yr 3.6 ± 1.4 1.6 ± 0.9 0.09 10+ yr 19.1 ± 2.4 18.3 ± 2.2 0.4 16+ yr 16.4 ± 4.7 24.0 ± 4.5 0.2 Disclosures: Mattano: Pfizer: Employed 2009–2012 Other, Equity Ownership.

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