Independent role of dose-escalation and prophylactic lymph-nodal irradiation in salvage radiotherapy after prostatectomy. A retrospective, multi-institute analysis on 725 men treated with high-dose radiotherapy and eight years follow-up

Abstract Abstract 3775 Background. In chronic myeloid leukemia (CML), achievement of optimal responses by time point has improved long-term outcomes. In contrast, several clinical studies investigating the clinical implications of suboptimal response showed that patients with suboptimal responses tend to have poor long-term outcomes. In IRIS study, patients who achieved major molecular response (MMR) at 18 months had event-free survival (EFS) benefit, compared to those who achieved complete cytogenetic response (CCyR) without MMR. However, the best treatment for these patients is still not confirmed. By the previous studies, sustaining standard-dose of imatinib (IM) is expected to yield less than 20 percent of additive MMR. In this prospective study, we investigated whether switching to nilotinib (NIL) or high-dose IM may be more effective for patients with suboptimal molecular response to IM as first-line therapy. Methods. Early chronic phase (CP) CML patients who have achieved CCyR but no MMR after at least 18 months and up to 24 months (≤ 18 to ≥24 months) on first-line IM therapy at a daily dose of 400 mg were enrolled in this clinical trial, and informed consents were obtained from all patients. In NIL arm, patients received oral dose of 400 mg BID (800 mg/day) and in high-dose IM arm, patients received 800 mg/day administrated as 400 mg BID. Primary endpoint is to evaluate the cumulative MMR rates by 12 months, and secondary endpoints are to evaluate the cumulative MMR, MR4.0 and undetectable molecular residual disease (UMRD) rates during further 24 month follow-up. Safety profiles will also be assessed. Patients showing lack of response (lack of complete hematologic response (CHR) at 6 months, increasing WBC, no major cytogenetic response (MCyR) at 24 months), loss of response (loss of CHR or MCyR) or severe intolerance to treatment were allowed to crossover to the alternative treatment. Results. With a data cut-off date of 10 Jul 2012, a total of 43 patients were randomized into NIL arm (n = 22) or high-dose IM arm (n = 21). With a median follow-up of 15 months (range, 1–36), all patients have maintained CCyR without progression to advanced disease, and progressive decrease in BCR-ABL1 transcript levels was observed in all patients. Cumulative incidence (CI) of MMR by 12 months showed no significant difference between NIL arm and high-dose IM arm (37.8 ± 11.9% vs 34.8 ± 10.6%, P = 0.789). In NIL arm, 3 in 22 (14%) and 2 in 22 (9%) patients achieved MR4.0 and UMRD, respectively, and in high-dose IM arm, 1 in 21 (5%) patients achieved MR4.0. Overall, the patients treated with high-dose IM showed toxicities more frequently, such as fatigue, dyspnea and decreased phosphate. In addition, 10 patients in high-dose IM arm have cross-over to NIL treatment due to lack of response (n=9) and intolerance (n=1), and the median duration of NIL treatment was 14 months (range, 7–26 months). Among them, 5 (50%) patients have achieved MMR with a median NIL treatment duration of 12 months (range, 3–18). Conclusions. These results demonstrate that early switching to NIL or dose escalation of IM could be recommended, considering the results of standard dose of IM in suboptimal molecular responders. When the tolerability of treatment was considered for switching to NIL or high-dose IM, NIL may be preferred. Through further clinical investigation on a large patient population and longer period observation, the efficacy and safety of early intervention of suboptimal molecular response using NIL or dose escalation of IM will be needed. Updated data with longer follow-up duration will be presented in the meeting. Disclosures: No relevant conflicts of interest to declare.

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Liposarcoma of the Thyroid

Sarcoma ◽

10.1155/2004/972706 ◽

2004 ◽

Vol 8 (2-3) ◽

pp. 91-96 ◽

Cited By ~ 7

Author(s):

A. Mitra ◽

C. Fisher ◽

P. Rhys-Evans ◽

C. Harmer

Keyword(s):

Radical Surgery ◽

English Literature ◽

External Beam Radiotherapy ◽

Myxoid Liposarcoma ◽

High Dose ◽

Pleomorphic Liposarcoma ◽

Positive Margins ◽

Margins Of Excision

Liposarcoma of the thyroid gland is rare with only 3 cases reported in the English literature. We present a further two patients whom we have recently treated: a 49 year old lady with a myxoid liposarcoma and a 71 year old man with a pleomorphic liposarcoma. Both underwent macroscopic excision of tumour but had positive margins, so were then treated with external beam radiotherapy. The former patient died from metastases 10 months after presentation, the latter remains alive but has developed metastatic disease on follow up at 24 months.We recommend the use of high dose radiotherapy following radical surgery as margins of excision are usually narrow in this most difficult region. The role of chemotherapy is yet to be established.

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Role of high-dose salvage radiotherapy for oligometastases of the localised abdominal/pelvic lymph nodes: a retrospective study

BMC Cancer ◽

10.1186/s12885-020-07033-7 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Makoto Ito ◽

Takeshi Kodaira ◽

Yutaro Koide ◽

Takahito Okuda ◽

Shinichiro Mizumatsu ◽

...

Keyword(s):

Retrospective Study ◽

Lymph Nodes ◽

Salvage Radiotherapy ◽

High Dose ◽

Pelvic Lymph Nodes

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ICHD-II Diagnostic Criteria for Tolosa—Hunt Syndrome in Idiopathic Inflammatory Syndromes of the Orbit and/or the Cavernous Sinus

Cephalalgia ◽

10.1111/j.1468-2982.2008.01569.x ◽

2008 ◽

Vol 28 (6) ◽

pp. 577-584 ◽

Cited By ~ 62

Author(s):

S Colnaghi ◽

M Versino ◽

E Marchioni ◽

A Pichiecchio ◽

S Bastianello ◽

...

Keyword(s):

Diagnostic Criteria ◽

Response To Treatment ◽

High Dose ◽

Inclusion Criteria ◽

Resonance Imaging ◽

Hunt Syndrome ◽

Magnetic Resonance Imaging Mri

A bibliographical search was conducted for papers published between 1999 and 2007 to verify the validity of International Classification of Headache Disorders (ICHD)-II criteria for the Tolosa-Hunt syndrome (THS) in terms of (i) the role of magnetic resonance imaging (MRI); (ii) which steroid treatment should be considered as adequate; and (iii) the response to treatment. Of 536 articles, 48, reporting on 62 patients, met the inclusion criteria. MRI was positive in 92.1% of the cases and it normalized after clinical resolution. There was no evidence of which steroid schedule should be considered as adequate; high-dose steroids are likely to be more effective both to induce resolution and to avoid recurrences. Pain subsided within the time limit required by the ICHD-II criteria, but signs did not. We conclude that THS diagnostic criteria can be improved on the basis of currently available data. MRI should play a pivotal role both to diagnose and to follow-up THS.

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High Dose Chemotherapy (HD CHT) Followed by Autologous PBPC Transplant in Elderly ANLL Patients.

Blood ◽

10.1182/blood.v104.11.881.881 ◽

2004 ◽

Vol 104 (11) ◽

pp. 881-881

Author(s):

Debora Capelli ◽

Emanuela Troiani ◽

Giancarlo Discepoli ◽

Antonella Poloni ◽

Mauro Montanari ◽

...

Keyword(s):

Elderly Patients ◽

Response Rate ◽

Conditioning Regimen ◽

High Dose Chemotherapy ◽

High Dose ◽

Poor Tolerance ◽

Cytoprotective Agent ◽

Grade Iii

Abstract Poor tolerance of aggressive chemotherapy and intrinsic disease resistance of ANLL in Elderly patients strongly impair the achievement of successful responses in this setting. Moreover, even after the achievement of CR, the intensive consolidation with autotransplantation is feasible in very few cases. We used Amifostine as cytoprotective agent in addition to a regimen containing HD Idarubicine (40 mg/sqm) and HD ARA-C (3 g/sqm for 5 days), the so-called “Memorial”. We treated 35 elderly patients (median age: 66, range: 56–78). Amifostine (740 mg/sqm IV) was administered at day 3, followed by Idarubicin. Patients aged more than 70 yrs received 30% reduced schedule. Karyotype was normal in 18 pts, unfavorable in 12 pts, unevaluable in 5 pts. Complete remission was observed in 24 patients (70.6%). The response rate was 78% (14/18) and 41% (5/12) in the intermediate and the poor prognosis cytogenetic groups respectively. Neutrophil (> 1500/ml) and platelet (>50,000/ml) recoveries were achieved at day 16 (range: 12–36) and 17 (range: 11–52) respectively. We observed one toxic induction death due to infection and other 21 grade III infectious episodes which responded to antibiotic treatment. Grade III–IV oral mucositis was observed in 3 patients. Twentyfour patients underwent a consolidation course with FLAG + Daunoxome (80 mg/sm i.v. day 1 and 2); a successful mobilization was achieved in 12 out of the 20 responder patients with a median collection of 6.6 x 106 CD34+/kg (range 4–14). All these patients were successfully autotransplanted with a conditioning regimen including Busulfan 9 mg/m2, Melphalan 120 mg/m2 in combination with Amifostine and Daunoxome 160 mg/m2. Transplant related mortality was 25% (infectious complication in one patient, congestive hearth failure in one case and severe mucositis in the other case). Haematological recovery was complete and fast in all patients. Grade III–IV extrahematological toxicity was mainly due to mucositis (8%), and infections (33%). The sequence HD CHT and autologous transplant determined a final CCR rate of 23% with a median follow-up of 12 months (range 1–31); two relapsed patients are still alive while 25 patients died, 5 for treatment related causes (14%), 20 for disease progression. We observed a 21% 3 years OS with a 27% in patients with intermediate prognosis kariotype versus 16% in the unfavorable group (p=0.03). The prognostic role of kariotype was not confirmed when 3 years DFS was analysed in the 24 responder patients: 25% vs 22% in the intermediate prognosis kariotype group. Induction response rate is surprisingly high for this setting but we still have high relapse incidence, probably due to the low mobilization rate and the consequent moderately low transplant feasibility. Alternative consolidation regimen, possibly not including Fludarabine, should therefore be explored.

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Imatinib Mesylate Dose Escalation Improves Disease Response in Chronic-Phase Chronic Myeloid Leukaemia Patients after Cytogenetic or Molecular Suboptimal Responses to Standard Doses of Imatinib.

Blood ◽

10.1182/blood.v110.11.1052.1052 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1052-1052 ◽

Cited By ~ 6

Author(s):

Delphine Rea ◽

Gabriel Etienne ◽

Selim Corm ◽

Pascale Cony-Makhoul ◽

Martine Gardembas ◽

...

Keyword(s):

Imatinib Mesylate ◽

Median Duration ◽

Dose Escalation ◽

Standard Dose ◽

Chronic Phase ◽

Cytogenetic Response ◽

High Dose ◽

Molecular Response ◽

Dose Increase

Abstract In chronic phase-chronic myeloid leukemia (CP-CML), a complete cytogenetic response (CCR) along with a major molecular response (MMR) on imatinib mesylate (IM) at 400mg/d represents a strong factor predicting survival. Suboptimal cytogenetic responders (minimal or minor CR (mCR) by 6 months or partial CR (pCR) by 12 months, ELN) have a probability of further achievement of CCR of only 50%. Suboptimal molecular responders (CCR without MMR by 18 months, ELN) have a decreased probability of remaining event-free survivors when compared to optimal responders. Since non-randomized trials suggest that high-dose IM at CML diagnosis produces high rates of optimal responses, dose escalation can be recommended for suboptimal responders to standard dose of IM, but this strategy has not been yet evaluated. Here, we present the results from a series of 24 CP-CML patients who experienced IM-dose escalation for cytogenetic or molecular suboptimal response to standard doses of IM. Suboptimal cytogenetic responders (n=10) included 9 males, median age was 51.3 years-old (27.7–64.2), all were in early CP. Sokal scores were low (n=5), int (n=2), high (n=2) and unknown (n=1). All patients were treated with IM frontline at 400mg/d (n=9) or 600mg/d (n=1) and 2 received PEGIFN associated with IM at 400mg/d (withdrawn after 3 months for intolerance in 1). Prior to dose escalation, 7 patients were in pCR at 12 months and 3 in mCR at 6 months. The search for BCR-ABL mutations was negative in 6 patients tested. IM was increased to 600mg/d (n=7) or 800mg/d (n=3) after a median time of 13.7 months (5.6–15.2) on initial IM treatment. Median follow-up from IM at standard and escalated doses were respectively 28 (16.1–79.1) and 14.9 months (2.2–73.5). Of 9 patients with cytogenetic evaluation, 100% obtained CCR after a median duration of high-dose IM of 6.2 months (2.4–12.6). Five patients (50%) achieved a MMR after a median duration of high-dose IM of 9.7 months (2.9–45). Only one patient treated with PEGIFN and IM increased to 600mg/d obtained a complete molecular response (CMR) 19.9 months after high-dose IM. Suboptimal molecular responders (n=14) included 11 males, median age was 38.2 years-old (20.9–63.2), 9 were in early CP and 5 in late CP. Six had previously received IFN for a median of 4 months (4–53). Sokal scores were low (n=5), int (n=5), high (n=3) and unknown (n=1). All patients had received IM at 400mg/d, for a median duration of 27.3 months (16.7–73.3). BCR-ABL mutations were detected in 2/8 patients tested (M244V and Q252R). IM was increased to 600mg/d (n=13) or to 800mg/d (n=1). Median BCR-ABL prior to dose increase was 0.79% (0.15–3.06). Median follow-up from standard and escalated doses of IM were respectively 45.2 (26.9–85.9) and 12.5 months (3.3–38.1). Six patients (43%) obtained a MMR after a median of 6.7 months (2–25.4) of high-dose IM, including 1 with the M244V mutation. None achieved a CMR. To conclude, IM-dose escalation is beneficial to suboptimal cytogenetic responders with a rate of achievement of CCR and MMR of respectively 100 and 50%. Regarding molecular suboptimal responders, the rate of MMR after dose increase in only 43% and other strategies should be considered.

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Salvage Autologous Hematpoeitic Stem Cell Transplants (AHSCT2) for Myeloma: Single Center Experience.

Blood ◽

10.1182/blood.v116.21.4591.4591 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4591-4591

Author(s):

Bishoy Faltas ◽

Jane L. Liesveld ◽

Michael Becker ◽

Jainulabdeen J. Ifthikharuddin ◽

Gordon L. Phillips

Keyword(s):

Overall Survival ◽

Multivariate Analysis ◽

Stem Cell ◽

Median Overall Survival ◽

Progressive Disease ◽

Conflicts Of Interest ◽

High Dose ◽

The Impact

Abstract Abstract 4591 Although the role of AHSCT1 is well established in multiple myeloma therapy, the role of the salvage (not “tandem”) AHSCT2 is less clear. However, most pts. undergo initial stem cell harvests with plans for eventual AHSCT2. To clarify the indications, the prognostic factors and the outcomes of AHSCT2 in relapsed myeloma, we analyzed our experience in 19 pts. (pts.) who underwent salvage AHSCT2 between the 1994–2008. Mean age at AHSCT1/2 was 54.58 (SD 7.96)/57.03 (SD 8.10) respectively; 15 (79.0%) were males. At the time of diagnosis, 7 (36.8%) pts. had ISS stage I, 6 (31.6%) stage II, 3(15.8%) stage III and in 3 (15.8%) the ISS stage could not be determined. Isotypes: IgG 11 (57.9%), IgA 4 (21.1%), 1 (5.3%) pt. had IgM and 3 (15.8%) had light chain myeloma. Cytogenetics were normal in 6 (31.6%), abnormal in 5 (26.3%) and unavailable for 8 (42.1%) pts. The most common therapy received prior to AHSCT1 was Vincristine/Adriamycin/Dexamethasone in 11 (57.9%) pts.; 7 pts. were exposed to novel agents. One pt. achieved complete response (CR), 15 (79.0%) pts. achieved partial response (PR) and 3 (15.8%) pts. had stable or progressive disease after receiving the initial treatment. All pts. proceeded to receive high dose therapy with Melphalan (MEL), 2 pts received fTBI in addition to MEL. Mean MEL dose was 190.00 mg/m2 (SD 23.01); 15 pts. received 200 mg/m2. All pts. received >2×10e6/kg of CD34+ cells in the first and second transplants. At D+100 after AHSCT1, responses were: 4 (21.1%) CR, 1 (5.3%) VGPR, 8 (42.1%) PR and 6 (31.6 %) with lesser responses. Therapy to prolong response or for salvage after AHSCT1 was given in all pts before AHSCT2, including Thalidomide in 6 (31.6%), Bortezomib in 4 (21.1%) and Lenalidomide in 2 (10.5) pts. Median time to progression after AHSCT1 was 318 days [95 % CI 110– 573]. Median interval between AHSCT1 and AHSCT2 was 896.74 days (SD: 698.34 days). At the time of AHSCT2, 4 (21.1%) were in PR, 15 (79.0%) had progressive disease. For AHSCT2, all pts. Received MEL, one pt. received MEL + Cytoxan and one pt. received MEL + Bortezomib. The median MEL dose/m2 was 175.56 (52.04).All pts. survived AHSCT2 to D+100, responses were as follows: 3 (15.8%) VGPR, 9 (47.4%) in PR; 7 (36.9) pts. had lesser responses. After AHSCT2, nine (47.4%) pts. had grade III toxicity and only one pt. had grade IV toxicity (avascular necrosis). Maintenance therapy after AHSCT2 included Bortezomib in 7 (36.8%) pts., Lenalidomide in 5 (26.3%) pts. and Thalidomide in 4 (21.1%) pts. After AHSCT2, the median overall survival (OS) was 658 days [95 % CI 326–1330] and progression free survival (PFS) after AHSCT2 was 237 days [95 % CI 121– 397] (Figure 1). OS probability at 6, 12, 24 months after AHSCT2 was 81.3, 75.0, 39.3 % respectively. For all pts., the median OS time (i.e. time from diagnosis to death or last follow-up) was 2187 days [95% CI 1413– 4126]. At the end of the follow up period, a total of 14 pts. had died. Causes of death were progression in 12 (63.2%) and sepsis in 2 pts. (10.5%). The number of previous lines of chemotherapy, interval between transplants, disease status at the time of AHSCT1/2, type of myeloma and MEL dose were not predictive of OS and PFS. In the multivariate analysis, only age by decade at AHSCT2 and male gender were independent predictors of OS after AHSCT2 (HR 4.037, P= 0.01), (HR 3.74, P=0.07) respectively. Similarly, in the multivariate analysis for PFS after AHSCT2, age at AHSCT2 was an unfavorable independent predictor (HR 3.48, P=0.009) whereas relapse free response more than 18 months after AHSCT1 was an independent favorable predictor (HR 0.198, P=0.007).Our results are consistent with the few studies examining the impact of salvage transplants for myeloma which report a median overall survival ranging from 20.7 to 38.1 months from the time of AHSCT2.We conclude that salvage AHSCT2 can positively impact PFS and OS but efforts to improve outcomes are mandatory.FigureSEQ Figure ≂,* ARABIC 1Figure. SEQ Figure ≂,* ARABIC 1 X-axis represents time from AHSCT2 in days. Y axis represents survival distribution. Blue line = OS, Red = PFS. Disclosures: No relevant conflicts of interest to declare.

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Impact of Postremission Consolidation Chemotherapy On Outcome After Reduced-Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation (allo-SCT) for AML in First Complete Remission (CR1): A Report From the Acute Leukemia Working Party of EBMT.

Blood ◽

10.1182/blood.v120.21.3098.3098 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3098-3098

Author(s):

Moshe Yeshurun ◽

Myriam Labopin ◽

Didier Blaise ◽

Jan Cornelissen ◽

Henrik Sengeloev ◽

...

Keyword(s):

Stem Cell ◽

Median Time ◽

Risk Group ◽

Remission Induction ◽

High Dose ◽

Consolidation Therapy ◽

Donor Type ◽

Reduced Intensity

Abstract Abstract 3098 The role of consolidation therapy after successful remission induction is well established in the treatment paradigm of patients with AML in the non-transplant setting. Most contemporary treatment protocols for young AML patients not transplanted in CR1 include repetitive cycles of high-dose cytarabine. However, in the standard myeloablative allo-SCT setting, consolidation therapy prior to transplant did not prove to have a beneficial impact on overall survival (OS), leukemia free survival (LFS) or relapse incidence (RI) as shown in 2 previous studies from the IBMTR and EBMT. In the context of RIC and non-myeloablative (NMA) allo-SCT, this picture might be different since one may speculate that consolidation therapy prior to transplantation may allow for reducing the incidence of relapse while waiting for the GVL effect. Nevertheless, the value of consolidation prior to RIC and NMA allo-SCT in AML in CR1 has not yet been explored. Thus, this multicenter retrospective analysis aimed to assess the role of consolidation prior to RIC/NMA allo-SCT in a cohort of AML CR1 patients (n=789) who received HLA-identical (n=564) or MUD (n=225) peripheral blood stem cell grafts between 2000 and 2010 and who were reported to the EBMT registry. Patients who required more than 2 cycles of induction to achieve CR were excluded. In this cohort, 591 patients received at least one course of consolidation and 198 patients did not receive any consolidation before SCT. With a median follow-up of 40 months (range, 1–140), the Kaplan-Meier estimates of OS and LFS at 3 years were 55% (95%CI, 52–59%) and 52% (95%CI, 48–55%), respectively. The cumulative incidence of relapse was 33% (95%CI, 29–36%). The median time from CR to allo-SCT was longer among patients who received consolidation compared with patients who received no consolidation (4.7 vs. 2.2 months; p<0.001). Of note, patients who received consolidation and who were transplanted beyond the median time between CR and transplantation, had an improved 3-year LFS compared with patients who received consolidation and transplanted within the median time (58+/−2 vs. 47+/−3, p=0.002). This was due to a lower RI in the group of patients transplanted beyond the median time (28+/−2% vs. 38+/−3%, p=0.009), irrespective of the number of consolidations they received, suggesting a possible selection bias of patients surviving longer without relapse before allo-SCT. With this background, we elected to focus on the group of 373 patients who were transplanted within the median time frame between CR achievement and allo-SCT (3 months for sibling donors and 4 months for MUDs). In this subgroup, 151 did not receive any consolidation and 222 received ≥1 consolidation (1 course, n=164, ≥ 2 courses, n=58).Patients who did not receive any consolidation were older (58 vs. 56 y, p=0.03), had a shorter time from CR to transplantation (56 vs. 71 days, p<0.001), needed more often 2 induction cycles to achieve CR (80% vs. 35%, p<0.001), and received more often TBI based conditioning (57% vs. 23%, p<0.001). Factors such as transplantation year, patient gender, cytogenetics risk group, donor type (MUD vs. sibling), and female donor to male recipient, were not significantly different between groups. With a median follow-up of 40 months (range, 1–140), the 3-year cumulative incidences of relapse were not significantly different between groups: 36±4% for patients with no consolidation and 38±3% for patients with consolidation (p=0.89). In addition, LFS was similar between groups, 45±4% and 47±3%, respectively (p=0.41). Doses of cytarabine given as consolidation had no influence on RI. By multivariate analysis adjusting for patient age, cytogenetics risk group, number of induction cycles, time from CR to transplantation, donor type, and conditioning regimen category, performing pre-transplant consolidation (0 vs. ≥1 cycle) had no significant impact on RI (HR=1.12, 95%CI, 0.74–1.70, p=0.58), or LFS (HR= 0.90; 95%CI, 0.64–1.27, p=0.90). In all, this retrospective study did not find any impact of postremission consolidation on outcome of patients with AML in CR1 who underwent allo-SCT with reduced-intensity or NMA conditioning. However, further investigation of high-risk subpopulations and well designed prospective controlled studies are warranted. Disclosures: No relevant conflicts of interest to declare.

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Nilotinib Or High-Dose Imatinib Compared With Standard-Dose Imatinib In Early Chronic Phase CML Patients Who Have Suboptimal Molecular Responses To Standard-Dose Imatinib: Including Updated Data From RE-Nice Study

Blood ◽

10.1182/blood.v122.21.1499.1499 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1499-1499

Author(s):

Soo-Young Choi ◽

Sung-Eun Lee ◽

Yun Jeong Oh ◽

Soo-Hyun Kim ◽

Richard C. Woodman ◽

...

Keyword(s):

Dose Escalation ◽

Advanced Disease ◽

Residual Disease ◽

Standard Dose ◽

Chronic Phase ◽

Cytogenetic Response ◽

High Dose ◽

Molecular Response ◽

First Line

Abstract Background In chronic myeloid leukemia (CML), achievement of optimal responses by time point has improved long-term outcomes. In IRIS study, patients who achieved major molecular response (MMR) at 18 months had event-free survival (EFS) benefit, compared to those who achieved complete cytogenetic response (CCyR) without MMR. However, the best treatment for these patients is still not confirmed. By the previous studies, sustaining standard-dose of imatinib (IM) is expected to yield less than 20 percent of additive MMR. In this study, we investigated the efficacy of switching to nilotinib (NIL) versus high-dose IM versus standard-dose IM for patients with suboptimal molecular response to IM as first-line therapy. Methods Early chronic phase (CP) CML patients who have achieved CCyR but no MMR after at least 18 months and up to 24 months ( 18 to 24 months) on first-line IM therapy at a daily dose of 400 mg were enrolled in RE-NICE study, and informed consents were obtained from all patients. In NIL arm, patients received 400 mg BID (800 mg/day) and in high-dose IM arm, patients received 800 mg/day administrated as 400 mg BID. Primary endpoint is to evaluate the cumulative MMR rates by 12 months, and secondary endpoints are to evaluate the cumulative MMR, MR4.0 and undetectable molecular residual disease (UMRD) rates during further 24 month follow-up. The efficacy of switching to NIL or high-dose IM were compared with that of the patients who maintained standard-dose of IM. Patients with standard-dose IM were selected with the same inclusion criteria and maintained standard-dose IM after enrollment period. To compare the efficacy among three groups, MMR rate, MR4.0 and undetectable molecular residual disease (UMRD) rates by 12 months were analyzed. Safety profiles also be assessed. Patients showing lack of response (lack of complete hematologic response (CHR) at 6 months, increasing WBC, no major cytogenetic response (MCyR) at 24 months), loss of response (loss of CHR or MCyR) or severe intolerance to treatment were allowed to crossover to the alternative treatment. Results With a data cut-off date of 15 Jul 2013, a total of 52 patients were randomized into NIL arm (n = 26) or high-dose IM arm (n = 26) and 16 patients were included in standard-dose IM group. With a median follow-up of 21 months (range, 1-36) in NIL arm and high-dose IM arm, all patients have maintained CCyR without progression to advanced disease, and progressive decrease in BCR-ABL1 transcript levels was observed in all patients. With a median follow-up of 12 months (range, 1-60), all patients in standard-dose IM group have maintained CCyR without progression to advanced disease. Cumulative incidence (CI) of MMR by 12 months showed no significant difference between NIL arm and high-dose IM arm (41.1% vs 28.8, P = 0.334). Only in NIL arm, 2 in 26 (8%) achieved confirmed MR4.0 and UMRD. By 12 months, 10 in 26 (39%), 7 in 26 (27%) and 3 in 16 (19%) patients achieved MMR, in NIL arm, high-dose IM arm and standard-dose IM group respectively. Overall, the patients treated with high-dose IM showed toxicities more frequently, such as leucopenia, anemia, Thrombocytopenia, edema, fatigue, dyspnea and decreased phosphate. In addition, 14 patients in high-dose IM arm have cross-over to NIL treatment due to lack of response (n=11) and intolerance (n=3), and the median duration of NIL treatment was 23 months (range, 2-36 months). Among them, 6 (43%) patients have achieved MMR with a median NIL treatment duration of 12 months (range, 0-18). Conclusions These results demonstrate that early switching to NIL or dose escalation of IM could be recommended, considering the results of standard dose of IM in suboptimal molecular responders. When the tolerability of treatment was considered for switching to NIL or high-dose IM, NIL may be preferred. Through further clinical investigation on a large patient population and longer period observation, the efficacy and safety of early intervention of suboptimal molecular response using NIL or dose escalation of IM will be needed. Updated data with longer follow-up duration will be presented in the meeting. Disclosures: No relevant conflicts of interest to declare.

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Role of prognostic factors in patients with metastatic renal cell carcinoma (MRCC) eligible for treatment with interleukin (IL2)

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.14514 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 14514-14514

Author(s):

H. Muniswamy ◽

J. P. Dutcher ◽

P. Mannam ◽

S. Malik ◽

V. Rusciano ◽

...

Keyword(s):

Risk Factors ◽

Prognostic Factors ◽

Historical Data ◽

High Dose ◽

Poor Survival ◽

Kaplan Meier ◽

Prognostic Groups ◽

Lower Limit Of Normal

14514 Background: Motzer (JCO1999) defined 5 factors that predict for poor survival of patients with MRCC: low Karnofsky scale (<80%), high LDH (>1.5 times upper limit), low Hb (<lower limit of normal), elevated corrected calcium (10 mg/dl) and absence of nephrectomy. Method: We retrospectively evaluated 124 patients with MRCC (81 male/43 female, median age 54 years, range (R) 27 to 79 years) treated in our center from 10/98–12/05 with IL2 based therapy. Patients eligible for IL2 study were included. Patients were categorized into favorable (F - 0 risk factors), intermediate (I - 1–2 risk factors) and poor (P - 3 or more risk factors) groups. 89 patients had high dose (HD) IL2 (600,000 u/kg/dose every 8 hours up to 14 doses), and 35 patients had moderate dose (MD) IL2 (5 mu/m2/day for 5 days continuous infusion or 72,000 u/kg every 8h up to 14 doses). 26 patients had prior treatment. Prognostic factors were identified at the start of IL2 therapy. Primary endpoint was survival time defined as the time from initiation of IL2 treatment to time of death or December 2005 as the last follow up for all patients. Results: Analyzed using Kaplan-Meier method. Conclusions: 1. These prognostic factors apply to IL2 treated patients and separate them into prognostic groups. 2. HD IL2 treated patients have ≥ 6 months greater survival compared to MD IL2 treated patients or historical data. [Table: see text] No significant financial relationships to disclose.

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