Second-Line Treatment with Imatinib (IM) after Crossover from Interferon Alfa Plus Cytarabine Yields High Rates of Durable Response: Results from the International Randomized Study of Interferon vs STI571 (IRIS).

Abstract Imatinib (IM) and interferon alfa plus cytarabine (IFN+Ara-C) were compared in the phase 3 IRIS trial, which enrolled 1106 patients (pts) with newly diagnosed CML-CP. Pts were allowed to cross over to the alternative treatment arm provided intolerance to treatment was indicated and/or efficacy landmarks were not met. All crossover requests required approval by the Study Management Committee according to strict criteria. Reasons for crossover were amended during the trial to include reluctance to continue IFN+Ara-C. The status of the 553 pts randomly assigned to receive 1st-line IFN+Ara-C and the reasons for crossover to IM are summarized in Table 1. Table 1: Status of IFN + Ara-C pts* Randomly assigned to 1st-line IFN + Ara–C N = 553 * Analysis as of 31-Jan-06 On 1st-line IFN + Ara-C 16 (2.9%) Discontinued from the study 178 (32.2%) Crossed over to IM 359 (64.9%) – Intolerance of treatment 144 (26%) – No CHR at 6 or 12 mos 44 (8.0%) – No MCyR at 12 or 24 mos 53 (9.6%) – Reluctance to continue on IFN + Ara-C 41 (7.4%) – Progression 77 (13.9%) = Increase in WBC 25 (4.5%) = Loss of CHR 29 (5.2%) = Loss of MCyR 23 (4.2%) On 2nd-line IM at 60 mos 251 (45.4%) The median time on IFN+Ara-C treatment before crossover was 9 months (mos), the median time since diagnosis was 13 mos at start of 2nd-line IM. The median time on 2nd-line IM was 45 mos (average 40 mos), with a maximum of 63 mos as per data cutoff 31-Jan-06. About one third of pts discontinued 2nd-line therapy: reasons were unsatisfactory therapeutic effect (13%), adverse events (4%), death (1%) and others (12%) including withdrawal of consent, BMT, loss to follow-up. A total of 251 pts remain on 2nd-line IM. Among 359 pts treated with 2nd-line IM, the best observed CHR rate was 93%, the best observed MCyR rate was 86%, and the best observed CCyR rate was 80%. The CCyR rate was 95% in pts who were reluctant to continue on IFN+Ara-C arm, 82% in intolerant pts, 78% in pts with lack of response on IFN+AraC and 71% in pts who progressed on 1st-line IFN+Ara-C. After 18 mos of 2nd-line IM therapy, the estimated rate of freedom from progression to AP/BC was 94%, and the estimated overall survival rate was 97%. These data are consistent with a previous trial of IM in pts with CML-CP after failure of prior IFN in which an estimated 89% of pts were free from progression to AP/BC, and an estimated 95% were alive, after 18 mos (Kantarjian NEJM 2002). In this trial, median time from diagnosis and median duration of prior IFN therapy were 34 and 14 mos, respectively. Table 2 compares 1st-line and 2nd-line IM results in the IRIS trial. Table 2: Comparison of Long-Term Results at 48 mos* 1st-line IM (N= 553) % [CI] 2nd-line IM (N=359) % [CI] * Analysis as of 31-Jan-06 Estimated survival w/o progression to AP/BC 93.3 % [91, 96] 90.3% [86, 94] Estimated overall survival 90.4% [87, 93] 89.2% [85, 93] The 48-mos rates of freedom from progression to AP/BC (overall survival) were 97% (96%) in pts who were reluctant to continue on IFN+Ara-C arm, 93% (90%) in intolerant pts, 90% (88%) in pts with lack of response on IFN+Ara-C and 80% (85%) in pts who progressed 1st-line IFN+Ara-C. The adverse event profile was similar between 1st- and 2nd-line IM therapy. CML-CP pts treated with 2nd-line IM after IFN+Ara-C achieved high response rates that are durable; the vast majority of pts remain free from progression to AP/BC after median follow-up of nearly 4 years. However, the overall efficacy results were better for 1st-line IM pts in newly diagnosed CML-CP.

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RTOG 0131: Phase II trial of pre-irradiation and concurrent temozolomide in patients with newly diagnosed anaplastic oligodendrogliomas and mixed anaplastic oligodendrogliomas: Relationship between 1p/19q status and progression-free survival

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.1517 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 1517-1517 ◽

Cited By ~ 1

Author(s):

M. A. Vogelbaum ◽

B. Berkey ◽

D. Peereboom ◽

C. Giannini ◽

R. Jenkins ◽

...

Keyword(s):

Overall Survival ◽

Radiation Therapy ◽

Median Time ◽

Phase Ii ◽

Progression Free Survival ◽

Chromosome 8 ◽

Newly Diagnosed ◽

Time To Progression ◽

Durable Response ◽

Free Survival

1517 Background: In a previous report, we showed in patients with newly diagnosed anaplastic oligodendrogliomas (AOs) and mixed anaplastic oligoastrocytomas (MAOs) that temozolomide (TMZ) can be given concurrently with radiation therapy (RT) with acceptable toxicity. We have now evaluated the efficacy of this regimen and correlated durability of response with tumor 1p/19q genotype. Methods: A phase II study was performed to evaluate the use of pre-RT TMZ followed by concurrent RT and TMZ in patients with newly diagnosed AO or MAO. The primary endpoint was to determine the pre-RT TMZ six-month progression rate, and secondary endpoints included progression-free survival and overall survival. Results: 40 eligible patients were entered into the trial. Thirty-two patients completed 6 months of pre-RT TMZ and concurrent RT and TMZ. Of the remaining eight patients, 4 withdrew due to toxicity and 4 other patients withdrew from study without evidence of toxicity or pre-RT progression. 1p/19q data are available in 37 cases; 23 tumors had loss of heterozygosity (LOH) of both 1p and 19q (double-deleted) while 14 tumors had LOH of either 1p or 19q (n = 3), or no LOH (n = 11). To date, 11 patients have experienced tumor progression; 1p/19q data are available for 10 of these cases (2 are double-deleted (2/23 = 9%), 8 have at least one intact chromosome (8/14 = 57%). Kaplan-Meier analysis demonstrates that progression free survival is significantly better for the double-deleted group (median time to progression not reached) than for the intact group (median time to progression = 15.2 months, p = 0.001). Overall survival is 98% (39/40) with a median follow-up of 17.5 months (2.8 - 31.1 months). Conclusions: LOH of both 1p and 19q is strongly correlated with a durable response of AO and MAO to a combined regimen of chemotherapy and radiation therapy. Tumors that are intact at 1p and/or 19q progress early despite an aggressive therapeutic regimen. These results suggest that future clinical trials should be prospectively stratified by tumor 1p/19q genotype. [Table: see text]

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ATIM-46. A MULTICENTER, PHASE I, TRIAL OF RADIATION, TEMOZOLOMIDE AND RRx-001 FOLLOWED BY MAINTENANCE TEMOZOLOMIDE WITH OR WITHOUT RRx-001 IN NEWLY DIAGNOSED GLIOBLASTOMA PATIENTS

Neuro-Oncology ◽

10.1093/neuonc/noz175.044 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi11-vi12

Author(s):

Robert Aiken ◽

Howard Fine ◽

Nicholas Butowski

Keyword(s):

Overall Survival ◽

Confidence Interval ◽

Survival Time ◽

Median Time ◽

Lower Limit ◽

Dose Range ◽

Newly Diagnosed ◽

Overall Survival Time ◽

Newly Diagnosed Glioblastoma

Abstract BACKGROUND RRx-001 is an aerospace-derived radiochemosensitizer with minimal toxicity. The purpose of this trial was to establish the safety of RRx-001 plus radiotherapy and temozolomide and to look for signals of enhanced anti-tumor activity in patients with newly diagnosed glioblastoma. METHODS In this non-randomized trial called G-FORCE-1 (NCT02871843), 18 newly diagnosed, histologically verified glioblastoma patients were enrolled. The treatment plan included 6 weeks of temozolomide and radiotherapy with RRx-001 followed by maintenance temozolomide with or without RRx-001. Four cohorts of 3 patients received intravenous RRx-001 at doses of 0.5,1,2, or 4 mg/week during radiotherapy only. An additional two cohorts of 3 patients received 4 mg/week of RRx-001 during radiotherapy and 0.5 mg/week of RRx-001 during temozolomide maintenance. RESULTS There were no grade 3 or 4 dose-limiting toxicity events (DLT) that appeared related to RRx-001 for the dose range of 0.5 to 4 mg/week. A maximum tolerated dose was not defined. The main adverse event related to RRx-001 was injection-site reaction. The overall response rate was 16.7% (3 PR out of 18) pending confirmation since pseudoprogression was prevalent, and the disease control rate was 61.1% (3 PR, 8 SD out of 18). The median time to tumor progression (95% confidence interval lower limit of 9.2 months to NR) and the median overall survival time (95% confidence interval lower limit of 12.9 months to NR) have not been reached after a median follow-up time of 10.3 months (range: 2.7 to 25 months.). CONCLUSION RRx-001 was well tolerated with concurrent temozolomide and radiotherapy and with temozolomide maintenance in 18 newly diagnosed glioblastoma patients. The primary objective to determine the MTD of RRx-001 was not met, since no DLTs occurred. The median time to progression and overall survival time have not been met after a median follow up time of 10.3 months.

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Prophylactic levofloxacin to prevent infections in newly diagnosed symptomatic myeloma: the TEAMM RCT

Health Technology Assessment ◽

10.3310/hta23620 ◽

2019 ◽

Vol 23 (62) ◽

pp. 1-94 ◽

Cited By ~ 1

Author(s):

Mark T Drayson ◽

Stella Bowcock ◽

Tim Planche ◽

Gulnaz Iqbal ◽

Guy Pratt ◽

...

Keyword(s):

Overall Survival ◽

Cost Effectiveness ◽

Health Technology Assessment ◽

Technology Assessment ◽

Health Technology ◽

Newly Diagnosed ◽

Double Blind ◽

Double Blind Placebo ◽

Febrile Episodes

Background Myeloma causes profound immunodeficiency and recurrent serious infections. There are approximately 5500 new UK cases of myeloma per annum, and one-quarter of patients will have a serious infection within 3 months of diagnosis. Newly diagnosed patients may benefit from antibiotic prophylaxis to prevent infection. However, the use of prophylaxis has not been established in myeloma and may be associated with health-care-associated infections (HCAIs), such as Clostridium difficile. There is a need to assess the benefits and cost-effectiveness of the use of antibacterial prophylaxis against any risks in a double-blind, placebo-controlled, randomised clinical trial. Objectives To assess the risks, benefits and cost-effectiveness of prophylactic levofloxacin in newly diagnosed symptomatic myeloma patients. Design Multicentre, randomised, double-blind, placebo-controlled trial. A central telephone randomisation service used a minimisation computer algorithm to allocate treatments in a 1 : 1 ratio. Setting A total of 93 NHS hospitals throughout England, Northern Ireland and Wales. Participants A total of 977 patients with newly diagnosed symptomatic myeloma. Intervention Patients were randomised to receive levofloxacin or placebo tablets for 12 weeks at the start of antimyeloma treatment. Treatment allocation was blinded and balanced by centre, estimated glomerular filtration rate and intention to give high-dose chemotherapy with autologous stem cell transplantation. Follow-up was at 4-week intervals up to 16 weeks, with a further follow-up at 1 year. Main outcome measures The primary outcome was to assess the number of febrile episodes (or deaths) in the first 12 weeks from randomisation. Secondary outcomes included number of deaths and infection-related deaths, days in hospital, carriage and invasive infections, response to antimyeloma treatment and its relation to infection, quality of life and overall survival within the first 12 weeks and beyond. Results In total, 977 patients were randomised (levofloxacin, n = 489; placebo, n = 488). A total of 134 (27%) events (febrile episodes, n = 119; deaths, n = 15) occurred in the placebo arm and 95 (19%) events (febrile episodes, n = 91; deaths, n = 4) occurred in the levofloxacin arm; the hazard ratio for time to first event (febrile episode or death) within the first 12 weeks was 0.66 (95% confidence interval 0.51 to 0.86; p = 0.002). Levofloxacin also reduced other infections (144 infections from 116 patients) compared with placebo (179 infections from 133 patients; p-trend of 0.06). There was no difference in new acquisitions of C. difficile, methicillin-resistant Staphylococcus aureus and extended-spectrum beta-lactamase Gram-negative organisms when assessed up to 16 weeks. Levofloxacin produced slightly higher quality-adjusted life-year gains over 16 weeks, but had associated higher costs for health resource use. With a median follow-up of 52 weeks, there was no significant difference in overall survival (p = 0.94). Limitations Short duration of prophylactic antibiotics and cost-effectiveness. Conclusions During the 12 weeks from new diagnosis, the addition of prophylactic levofloxacin to active myeloma treatment significantly reduced febrile episodes and deaths without increasing HCAIs or carriage. Future work should aim to establish the optimal duration of antibiotic prophylaxis and should involve the laboratory investigation of immunity, inflammation and disease activity on stored samples funded by the TEAMM (Tackling Early Morbidity and Mortality in Myeloma) National Institute for Health Research Efficacy and Mechanism Evaluation grant (reference number 14/24/04). Trial registration Current Controlled Trials ISRCTN51731976. Funding details This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 62. See the NIHR Journals Library website for further project information.

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Routine Use of Gemtuzumab Ozogamicin in 7+3-Based Inductions for All "Non-Adverse" Risk AML

Blood ◽

10.1182/blood-2020-142691 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 36-37

Author(s):

Gavin Hui ◽

Abdullah Ladha ◽

Edna Cheung ◽

Caroline Berube ◽

Steven Coutre ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Gemtuzumab Ozogamicin ◽

Intermediate Risk ◽

Newly Diagnosed ◽

Myeloablative Conditioning ◽

Advisory Committees ◽

Monosomy 7

Introduction: The addition of gemtuzumab ozogamicin (GO) to 7+3 chemotherapy for newly diagnosed acute myeloid leukemia (AML) has been shown to significantly improve event-free survival (EFS) for cytogenetically favorable-risk AML, with marginal benefit for intermediate-risk AML, and no benefit for cytogenetically adverse-risk AML. Of note, with the exception of mutated FLT3-ITD, little is known about the impact of GO in ELN 2017-defined genotypically adverse-risk AML, and a recent randomized trial found no EFS benefit for 7+3+GO in patients (pts) with genotypically favorable-risk, NPM1-mutated AML. Since 2017, our institution incorporated GO into 7+3-based inductions for all "non-adverse" risk AML pts, as defined by wild-type FLT3 and no abnormalities on rapid FISH analysis for del(5q)/monosomy 5, del(7q)/monosomy 7, and del(20q). We report our experience treating all pts with "non-adverse" risk AML-as defined by this algorithm-with 7+3+GO. Methods: An institutional database was queried in order to identify all pts ≥18 years old who received 7+3-based chemotherapy for newly diagnosed AML between 2017 and 2020; pts who received the FDA-approved fractionated dose of GO were included in the analysis. Data collection included demographic variables, karyotype/FISH, targeted PCR analyses, and multigene NGS panels for AML-related mutations including, but not limited to, mutations in FLT3, NPM1, CEBPA, TP53, RUNX1, and ASXL1. Outcome data included response to induction, relapse, and death, as well as hematopoietic cell transplant (HCT) rates, conditioning regimens, and post-transplant complications. Results: Between January 2017 and July 2020, 96 pts received 7+3-based induction at our institution. Of these, 29 (30%) received 7+3 in combination with GO. Median age at diagnosis was 46 years (range 23-66), with 17 (59%) males. Sixteen (55%) pts had ELN favorable-risk AML (5 [31%] by cytogenetics and 11 [69%] by genotype), 6 (21%) pts had ELN intermediate-risk AML, and 7 (24%) pts had ELN adverse-risk AML (4 [57%] by cytogenetics and 3 [43%] by genotype). Median time from diagnosis to start of induction was 4 days (range 0-43). For cytogenetically adverse-risk pts, median time from diagnostic bone marrow biopsy to receipt of adverse karyotype results was 8 days (7-14). Median time from start of induction to receipt of multigene NGS results for all pts was 15 days (3-32). Overall, 22 (76%) pts achieved remission. All genotypically adverse-risk pts (1 with mutated TP53 and 2 with mutated RUNX1) were refractory to induction, while 3 of 4 (75%) cytogenetically adverse-risk pts (1 with t(6;9), 1 with monosomy 7, and 2 with 11q23 abnormalities) achieved remission. Eight of the 29 (28%) pts proceeded to HCT, including 4 adverse-risk pts. Of the adverse-risk pts, all received myeloablative conditioning prior to HCT and 3 (75%) developed veno-occlusive disease (VOD), with 2 (50%) requiring defibrotide therapy. In favorable/intermediate-risk pts, 4 (18%) proceeded to HCT (2 intermediate-risk pts in first remission and 2 favorable-risk pts in second remission). Of these, 2 (50%) received myeloablative conditioning and 1 (25%) developed VOD. At last follow-up, 23 of 29 pts (79%) remained alive, with a median overall survival not reached (range 1-29 months) and a median EFS of 20 months (9-31). The percentage of ELN favorable-, intermediate-, and adverse-risk pts who remained event-free at last follow-up was 75%, 33%, and 43%, respectively. Discussion: This single-center, retrospective cohort describes the outcomes of pts with "non-adverse" risk AML who received induction chemotherapy with 7+3+GO according to a pre-defined algorithm. Using this algorithm, 30% of all pts receiving 7+3-based inductions received GO. Of these, nearly 25% were ultimately found to have adverse-risk AML as defined by ELN 2017 criteria, largely driven by long turn-around times for karyotyping and NGS multigene panel results. No patient with genotypically adverse-risk AML by ELN criteria responded to induction chemotherapy, and 75% of cytogenetically adverse-risk pts who proceeded to HCT developed VOD. Routine use of 7+3+GO induction outside of the context of cytogenetically favorable-risk AML remains controversial, and further study is needed to define the role of GO, particularly for pts with ELN genotypically adverse-risk AML. Table Disclosures Gotlib: Blueprint Medicines Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Chair of the Response Adjudication Committee and Research Funding, Research Funding; Deciphera: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: co-chair of the Study Steering Committee and Research Funding. Liedtke:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; GSK: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Muffly:Adaptive: Research Funding; Amgen: Consultancy; Servier: Research Funding. Mannis:AbbVie, Agios, Bristol-Myers Squibb, Genentech: Consultancy; Glycomimetics, Forty Seven, Inc, Jazz Pharmaceuticals: Research Funding.

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Efficacy of Melphalan and Prednisone Plus Thalidomide in Patients Older Than 75 Years With Newly Diagnosed Multiple Myeloma: IFM 01/01 Trial

Journal of Clinical Oncology ◽

10.1200/jco.2008.21.0948 ◽

2009 ◽

Vol 27 (22) ◽

pp. 3664-3670 ◽

Cited By ~ 284

Author(s):

Cyrille Hulin ◽

Thierry Facon ◽

Philippe Rodon ◽

Brigitte Pegourie ◽

Lotfi Benboubker ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Elderly Patients ◽

Progression Free Survival ◽

Phase Iii ◽

Standards Of Care ◽

Newly Diagnosed ◽

Grade 3 ◽

To Receive

Purpose Until recently, melphalan and prednisone were the standards of care in elderly patients with multiple myeloma. The addition of thalidomide to this combination demonstrated a survival benefit for patients age 65 to 75 years. This randomized, placebo-controlled, phase III trial investigated the efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed myeloma. Patients and Methods Between April 2002 and December 2006, 232 previously untreated patients with myeloma, age 75 years or older, were enrolled and 229 were randomly assigned to treatment. All patients received melphalan (0.2 mg/kg/d) plus prednisone (2 mg/kg/d) for 12 courses (day 1 to 4) every 6 weeks. Patients were randomly assigned to receive 100 mg/d of oral thalidomide (n = 113) or placebo (n = 116), continuously for 72 weeks. The primary end point was overall survival. Results After a median follow-up of 47.5 months, overall survival was significantly longer in patients who received melphalan and prednisone plus thalidomide compared with those who received melphalan and prednisone plus placebo (median, 44.0 v 29.1 months; P = .028). Progression-free survival was significantly prolonged in the melphalan and prednisone plus thalidomide group (median, 24.1 v 18.5 months; P = .001). Two adverse events were significantly increased in the melphalan and prednisone plus thalidomide group: grade 2 to 4 peripheral neuropathy (20% v 5% in the melphalan and prednisone plus placebo group; P < .001) and grade 3 to 4 neutropenia (23% v 9%; P = .003). Conclusion This trial confirms the superiority of the combination melphalan and prednisone plus thalidomide over melphalan and prednisone alone for prolonging survival in very elderly patients with newly diagnosed myeloma. Toxicity was acceptable.

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Initial Gamma Knife Radiosurgery for Large or Documented Growth Asymptomatic Meningiomas: Long-Term Results From a 27-Year Experience

Frontiers in Oncology ◽

10.3389/fonc.2020.598582 ◽

2020 ◽

Vol 10 ◽

Author(s):

Junyi Fu ◽

Lisha Wu ◽

Chao Peng ◽

Xin Yang ◽

Hongji You ◽

...

Keyword(s):

Median Time ◽

Gamma Knife ◽

Gamma Knife Radiosurgery ◽

Long Term Results ◽

Tumor Control ◽

Long Term Outcomes ◽

Radiological Progression ◽

Design And Methods

ObjectiveThe aims of this study were to investigate the long-term outcomes of initial Gamma Knife radiosurgery (GKRS) for large (≥20 mm) or documented growth asymptomatic meningiomas.Design and MethodsThis was a single-center retrospective study. Fifty-nine patients with large (≥20 mm) or documented growth asymptomatic meningiomas undergoing initial GKRS were enrolled. The median age was 56 (range, 27–83) years. The median time of follow-up was 66.8 (range, 24.6–245.6) months, and the median tumor margin dose was 13.0 Gy (range, 11.6–22.0 Gy).ResultsTumors shrunk in 35 patients (59.3%) and remained stable in 23 (39.0%). One patient (1.7%) experienced radiological progression at 54 months after GKRS. The PFS was 100%, 97%, and 97% at 3, 5, and 10 years, respectively. Nine patients (15.3%) occurred new neurological symptoms or signs at a median time of 8.1 (range, 3.0–81.6) months. The symptom PFS was 90% and 78% at 5 and 10 years, respectively. Fifteen patients (25.4%) occurred peritumoral edema (PTE) at a median time of 7.2 (range, 2.0–81.6) months. One patient underwent surgical resection for severe PTE. In univariate and multivariate analysis, Only tumor size (≥25 mm) and maximum dose (≥34 Gy) were significantly associated with PTE [hazard ratio (HR)= 3.461, 95% confidence interval (CI)=1.157-10.356, p=0.026 and HR=3.067, 95% CI=1.068-8.809, P=0.037, respectively].ConclusionsIn this study, initial GKRS can provide a high tumor control rate as well as an acceptable rate of complications in large or documented growth asymptomatic meningiomas. GKRS may be an alternative initial treatment for asymptomatic meningiomas.

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Continued Excellent Outcomes in Previously Untreated Patients With Follicular Lymphoma After Treatment With CHOP Plus Rituximab or CHOP Plus 131I-Tositumomab: Long-Term Follow-Up of Phase III Randomized Study SWOG-S0016

Journal of Clinical Oncology ◽

10.1200/jco.2017.74.5083 ◽

2018 ◽

Vol 36 (7) ◽

pp. 697-703 ◽

Cited By ~ 24

Author(s):

Mazyar Shadman ◽

Hongli Li ◽

Lisa Rimsza ◽

John P. Leonard ◽

Mark S. Kaminski ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Randomized Study ◽

Phase Iii ◽

Second Malignancies ◽

Long Term Follow Up ◽

Acute Myeloid

Purpose SWOG S0016 was a phase III randomized study that compared the safety and efficacy of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) with CHOP-RIT (CHOP followed by consolidation with iodine-133–tositumomab radioimmunotherapy) for previously untreated patients with follicular lymphoma. Understanding the long-term outcome of patients provides a benchmark for novel treatment regimens for FL. Patients and Methods Between 2001 and 2008, 531 previously untreated patients with FL were randomly assigned to receive either six cycles of R-CHOP or six cycles of CHOP-RIT. Patients with advanced-stage disease (bulky stage II, III, or IV) of any pathologic grade (1, 2, or 3) were eligible. Results After a median follow-up of 10.3 years, 10-year estimates of progression-free and overall survival were 49% and 78% among all patients, respectively. Patients in the CHOP-RIT arm had significantly better 10-year progression-free survival compared with patients in the R-CHOP arm (56% v 42%; P = .01), but 10-year overall survival was not different between the two arms (75% v 81%; P = .13). There was no significant difference between the CHOP-RIT and R-CHOP arms in regard to incidence of second malignancies (15.1% v 16.1%; P = .81) or myelodysplastic syndrome or acute myeloid leukemia (4.9% v 1.8%; P = .058). The estimated 10-year cumulative incidences of death resulting from second malignancies were not different (7.1% v 3.2%; P = .16), but cumulative incidence of death resulting from myelodysplastic syndrome or acute myeloid leukemia was higher in the CHOP-RIT arm compared with the R-CHOP arm (4% v 0.9%; P = .02). Conclusion Given these outstanding outcomes, immunochemotherapy should remain the standard induction approach for patients with high-risk FL until long-term follow-up of alternative approaches demonstrates superiority.

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ATIM-35. THE ASSOCIATIONS BETWEEN TOTAL LYMPHOCYTE COUNTS AFTER CONCOMITANT CHEMORADIATION WITH OVERALL SURVIVAL IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noz175.034 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi9-vi9

Author(s):

Stephen Ahn ◽

Jae-Sung Park ◽

Yong Kil Hong ◽

Seung Ho Yang ◽

Sin-Soo Jeun

Keyword(s):

Overall Survival ◽

Complete Blood Count ◽

Malignant Tumors ◽

P Value ◽

Newly Diagnosed ◽

Total Lymphocyte ◽

Concomitant Chemoradiation ◽

Newly Diagnosed Glioblastoma ◽

The Relationship

Abstract Several studies have been conducted to determine the relationship between post-treatment total lymphocyte count (TLC) and overall survival (OS) in patients with malignant tumors including glioblastomas (GBMs). In this retrospective study, whether patients with newly diagnosed GBM experience significant lymphopenia after concomitant chemoradiation (CCRT) was evaluated, and whether TLC after this treatment is associated with OS in the treated population was examined. Using electronic medical records, all patients newly diagnosed with GBM between 2008 and 2016 at Seoul St. Mary’s Hospital were retrospectively examined. The eligible criteria included the following: 1) craniotomy with surgical resection or biopsy, 2) completion of CCRT, 3) accessible baseline and/or follow-up complete blood count (CBC). Median TLC significantly decreased after completion of CCRT, compared to TLC at baseline (1,742 versus 1,319 cells/mm3, P-value < 0.001). Patients with TLC < 1,200 cells/mm3 at 4 weeks after the completion of CCRT showed shorter survival than those with TLC ≥ 1,200 cells/mm3 with median OS of 14.5 versus 21.0 months (P-value = 0.017). Also, in multivariate analysis for OS, TLC < 1,200 cells/mm3 at 4 weeks after the completion of CCRT (HR 1.97, 95% CI 1.61 – 2.25, P-value = 0.004) were significantly associated with shorter survival. The results from the present study indicate that treatment-related total lymphocyte counts after CCRT is associated with worse survival in patients with newly diagnosed GBM.

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Frequency of Clonal Evolution by FISH in Untreated, Early Stage Patients with CLL: A Prospective, Longitudinal Study with Long Clinical Follow-Up.

Blood ◽

10.1182/blood.v106.11.2098.2098 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2098-2098 ◽

Cited By ~ 3

Author(s):

Tait D. Shanafelt ◽

Stephanie Fink ◽

Tom E. Witzig ◽

Sarah F. Paternoster ◽

Stephanie Smoley ◽

...

Keyword(s):

Overall Survival ◽

Median Time ◽

Early Stage ◽

Clonal Evolution ◽

Normal Karyotype ◽

Risk Category ◽

Fish Analysis ◽

Cytogenetic Abnormalities ◽

Study Participants

Abstract Background: Using fluorescent in-situ hybridization (FISH), a number of investigators have identified specific cytogenetic abnormalities that identify CLL patients with a more aggressive (17p-, 11q-) or indolent (13q-) disease course. Some have suggested patients who initially have a normal karyotype may acquire new chromosome abnormalities during the course of their disease. Since patients with specific cytogenetic abnormalities (17p-, 11q-) are less likely to respond to purine nucleoside analogues, such clonal evolution has potential implications for treatment as well as prognosis. No study has prospectively investigated the frequency of clonal evolution in a cohort of patients with newly diagnosed untreated CLL. Methods: Between 1994 and 2000, we enrolled 167 patients with previously untreated CLL seen at Mayo Clinic in a prospective trial evaluating the prognostic importance of cytogenetic abnormalities and clonal evolution detected by FISH. All patients provided a baseline blood specimen for FISH testing and follow-up specimens over the following 24 months. Other research samples from later timepoints were tested where available. Study participants were contacted by mail in 2004 to update vital and treatment status. Of 83 living responders, 70 (84%) indicated they would be willing to provide an additional follow-up sample for cytogenetic analysis of whom 48 have returned a sample to date. Results of clinical FISH testing during the follow-up interval were also abstracted. FISH was performed on interphase nuclei from blood as we have previously described (BJH 121:287). Results: Median age at diagnosis was 64. Median time from diagnosis to study enrollment was 3.3 months. 94% of patients had early stage disease at enrollment (88 Rai 0; 48 Rai I, 18 Rai II, 2 Rai III; 8 Rai IV). Median follow-up time from diagnosis for all 164 eligible study participants was 8.5 years (range: 0.33–22.9 yrs). As of last follow-up, 48% of patients have received treatment and 57 (35%) have died. 75% of patients had chromosome abnormalities on FISH testing at baseline. The frequency of individual cytogenetic abnormalities on baseline FISH analysis along with overall survival by hierarchical FISH risk category are shown in Table I. 106 patients had sequential samples for FISH analysis at least 2 years apart, 61 had samples at least 5 years apart, and 22 had samples at least 10 years apart. 15 patients had evidence of clonal evolution during follow up as evidenced by a new FISH anomaly not present on the baseline specimen. No clonal evolution was observed in the first 2 years of follow-up (n=106), however of 61 patients with samples at least 5 years apart, 14 (23%) had evidence of clonal evolution. Median time for development of a new cytogenetic abnormality among these patients was 9.3 years. Conclusions: Clonal evolution occurs during the course of disease for approximately 25% of patients with early stage CLL. Clonal evolution appears to occur at low frequency during the first 2 years of follow-up but increases in frequency after 5 years. This finding has potentially significant implications for prognosis and treatment of patients with CLL. FISH Risk Category* N (Baseline) Median Overall Survival (Years) * Difference between groups significant p=0.0038 13q- x 1 37 14.4 13q- x2 35 17 Normal Karyotype 40 13.2 12+ 24 11.1 11q- 12 8.6 17p- 10 10.5 6q- 2 4.1 Other 2 Not reached

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Imatinib Dose Escalation Is Effective in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP).

Blood ◽

10.1182/blood.v110.11.1047.1047 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1047-1047

Author(s):

Hagop M. Kantarjian ◽

Brian J. Druker ◽

Francois Guilhot ◽

Jorge Cortes ◽

Stephen G. O’Brien ◽

...

Keyword(s):

Dose Escalation ◽

Randomized Study ◽

Chronic Phase ◽

Cytogenetic Response ◽

Separate Analysis ◽

Inadequate Response ◽

Durable Response ◽

Entire Cohort ◽

The Impact

Abstract Background: Imatinib mesylate (IM) 400 mg/d is the standard of care for newly diagnosed patients (pts) with CML-CP. Dose escalation to 600 or 800 mg IM has been shown to be beneficial in patients with either an inadequate response or disease progression while on standard therapy (Kantarjian et al Blood 2003). In the International Randomized study of Interferon versus STI571 (IRIS) trial, initiated in 2000, dose escalation was allowed for patients who did not achieve a complete hematologic response (CHR) by 3 months or a minor cytogenetic response (minCyR) by 12 months, lost a major cytogenetic response (MCyR) at any time, or progressed (including increase in WBC); no dose escalation in cases of loss of CCyR were specified. The impact of IM dose escalation for patients on IRIS is presented in this post-hoc analysis. Methods: Patients were evaluated for hematologic and cytogenetic responses, progression (to accelerated or blast phase) free survival (PFS), and overall survival (OS) following dose escalation. Patients were included if their dose was increased within −0.5 to 3 months following the respective landmark evaluation. Instances of dose escalation (to ≥600 mg/d) on the IM arm were reviewed and classified, where possible, based on either criteria established by IRIS protocol or the European LeukemiaNet recommendations Results: Of 551 patients receiving first line IM, 106 pts (19%) had dose escalation to 600–800 mg/d. Median time to dose escalation was 22 months (range:3–74 months; 25th–75th percentile: 13–45 months). After dose escalation the median imatinib dose delivered was 604 mg/d (range: 294–800 mg/d; 25th–75th percentile:600–739 mg/d) and remained on treatment for a median of 19.4 months based on current follow-up. Last recorded dose was ≥600mg/d in 85% of these patients. Dose increases in 39 patients were based on the IRIS protocol criteria. Responses among these patients included: 6 of 7 who had not achieved CHR at 3 months achieved a CHR with dose escalation, 2 of these patients subsequently achieved a CCyR. Of 8 patients who had not achieved a minCyR at 12 months, 4 improved to a CCyR, and of 18 patients who lost their MCyR, 9 subsequently re-achieved an MCyR within 12.5 months after dose escalation, of whom 3 also attained a CCyR by 30-months after dose escalation. The 6 patients who received dose escalations upon progression, had an OS of 83% at 2 years after dose escalation. At 36-months after dose escalation the 39 patients dose escalated per IRIS protocol criteria achieved an estimated PFS and OS of 81%. In a separate analysis of these 106 pts, dose escalations in 48 pts were retrospectively classified according to the ELN recommendations. At 36-months follow-up after dose escalation these 48 patients achieved a 90% PFS and 89% OS. For the entire cohort of 106 patients who were dose escalated, estimated PFS was 89% and OS was 84% at 36 months after dose escalation. Conclusion: Based on these data, IM dose escalation to 600 and/or 800 mg allows poorly responding patients to achieve a clinically important durable response or re-gain responses. These slower responding or progressing patients benefited from IM dose escalation and thus, the data support dose escalation for these patients.

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