1. Citation: J Clin Oncol 32, 2014 (suppl; abstr e20008)
The experience of administration of high-dose recombinant interleukin-2 in combination with chemotherapy in the management of disseminated skin melanoma.
Background: Interleukin-2 (Biotech, Russia) is a complete structural and functional analogue of human endogenous interleukin-2 produced from nonpathogenic Saccharomyces cerevisiae. Our retrospective study evaluated the results of the first-line chemoimmunotherapy of 71 patients with disseminated skin melanoma treated with interleukin-2 from 2004 till 2012.
Methods: We retrospectively evaluated efficacy and safety of chemotherapy dacarbazine 800 mg/m2, d 1 and cisplatin 20 mg/m2, d 1–4 (control arm, n=31). In the treatment arm chemotherapy was supplement of one of the following immunotherapy regiments: high-dose IL-2 (9 mg/m2, d 1–5) or gradual dose reduction IL-2 (18 mg/m2, d 1; 9 mg/m2, d 2; 4 mg/m2, d 3–4) (n=71). The median follow –up was 10, 0 months.
Results: The objective response rate was 33.8 % and 19.4% in the treatment and control arms respectively. Four complete responses were registered in the treatment arm only (5.6%). The median PFS was 5.3 and 3.2 (p=0.04), the median overall survival was 12.4 and 8.4 months (p=0.1) among the patients treated with chemoimmunotherapy and with chemotherapy alone respectively. The blood serum level of lactate dehydrogenase (LDH) exceeding more than 1.5 fold the upper reference value was an unfavourable prognostic factor with no impact of the treatment type (chemotherapy or chemoimmunotherapy) on its efficacy. At the same time, chemoimmunotherapy for disseminated skin melanoma patients with the LDH level not exceeding more than 1.5-fold the upper reference value increased the median PFS up to 6.3 months and the median overall survival up to 14.7 months. All adverse effects were overcome with conventional medications and had not caused cancels of immunotherapy.
Conclusions: Our experience confirmed that immunochemotherapy with high-dose interleukin-2 is an effective treatment of disseminated skin melanoma, is satisfactily tolerated and may be beneficial in patients with the LDH level not exceeding more than 1.5-fold the upper reference value.
治疗方案：对2004年至2012年收治的71位散播性皮肤黑色素瘤患者行一线化学免疫疗法。对照组31例，仅接受化疗，第1天予达卡巴嗪800 mg/m2，第1-4天予顺铂20 mg/m2。治疗组71例，在化疗的同时接受IL-2治疗，IL-2用药方案二者择其一：第1-5天予高剂量IL-2，每天9 mg/m2；或IL-2剂量递减，第1天18 mg/m2，第2天9 mg/m2，第3-4天4 mg/m2。中位随访期是100个月。
2. Citation: J Clin Oncol 32:5s, 2014 (suppl; abstr 4523)
carcinoma (mRCC) in the targeted therapy era: Extension of
OS benefits beyond complete response (CR) and partial response (PR).
Background: HD IL-2 has been reported to have a overall response rate (ORR) for mRCC of 15% and a median OS of 19 months (Fyfe,1995), however, the studies that led to its regulatory approval are >15 years old and were performed in an era preceding targeted therapies.
Methods: The PROCLAIM registry (www.proclaimregistry.com), a HD IL-2 observational database currently with over 30 participating sites, consists of a retrospective cohort (treated between 2007 and 2012) informing an ongoing prospective cohort (~ 600 patients). We report on the retrospective mRCC subjects (n=97, 13 sites) with survival status determined as of November 2013 and a median follow-up of 32 months. Sites were encouraged to enroll patients sequentially. Inclusion criteria required that patients have received at least one dose of HD IL-2.
Results: The ORR was 22% (8% CR and 14% PR). Of 97 subjects, 36 were confirmed deceased and 61 were known to be alive, none were lost to follow-up. The median OS was 51 months, compared to a median OS range of 5-35 months for FDA-approved targeted agents (Harrison, 2013). There was significant clinical benefit in patients with CR, PR, and stable disease (SD), none of which reached median OS compared to 37.9 months in patients with progressive disease (PD). There is a significant advantage in PROCLAIM for those patients treated 1st vs. 2ndline HD IL-2; the median OS was 61.8 months (n=82) vs 15.3 months (n=15), respectively. The clinical benefit of HD IL-2 therapy as front line is consistent with published data (Birkhauser, 2013). No deaths due to IL-2 related toxicity were reported in the retrospective cohort.
Conclusions: The PROCLAIM registry documents a vastly improved OS for HD IL-2 compared to historical results during a time interval marked by the advent of targeted therapy for advanced RCC. Response to IL-2 (CR or PR) is associated with prolonged survival, however, stable disease as well as front line use also appears to positively impact survival. Issues including patient selection characteristics and treatment sequencing are hypotheses currently being explored in the prospective database.
结果：总缓解率(ORR)是22%(8% CR，14% PR)。97例患者中，36例确认死亡，61例确认存活，无一例失访。中位总生存期(OS)是51个月，而FDA批准的靶向药物治疗的中位OS是5-35个月。对CR、PR、SD的患者明显更有利，其OS均达到了中位OS，而PD患者的OS是37.9个月。未发生因IL-2不良反应引起的死亡。
3. Citation: J Clin Oncol 32, 2014 (suppl; abstr e15550)
improve the outcome of sunitinib (Su) treatment (tx) in
patients (pts) with metastatic renal cell carcinoma (mRCC).
Background: Targeted txs are the tx of choice in most mRCC pts. However, HDIL2 which may produce durable responses in a small percentage of cases, is still an option in carefully selected pts. While the effect of prior HDIL2 on the outcome of targeted txs in mRCC pts is poorly defined, a recent single center report (Birkhäuser FD, Cancer J 2013) revealed an improved disease-specific survival in pts treated with prior HDIL2. We aimed to study the effect of prior HDIL2 tx on outcome of mRCC pts treated with sunitinib.
Methods: Records from 302 mRCC pts treated with Su from 2004 to 2013 in 9 centers across 2 countries were retrospectively reviewed. We compared the response rate, progression free survival (PFS), and overall survival (OS), between post HDIL2 pts (n=27) and individually matched tx naïve pts (n=27). Progression free survival and overall survival were determined by Cox regression.
Results: All pts had prior nephrectomy and clear cell histology. The groups were matched by age (median 61), gender (male 74%), Heng risk (favorable 37%, intermediate 59%, poor 4%), sunitinib induced hypertension (67%), sunitinib dose reduction/treatment interruption (41%), smoking status (active 7%), use of angiotensin system inhibitors (41%), the presence of more than one metastases site (96%), and pre-tx neutrophil to lymphocyte ratio (> 3 in 22%). Furthermore, they were balanced regarding the presence of lung (68%), liver (31%), and bone (43%) metastases, and the use of bisphosphonates (32%). In prior HDIL2 versus tx naïve pts, objective response was partial response/stable disease 89% (n=24) versus 74% (n=20), and progressive disease at first imaging evaluation within the first 3 months (mos) 11% (n=3) versus 26% (n=7) (p=0.29, OR 2.4). Median progression free survival was 21 versus 12 mos (HR 2.3, p=0.005), and median overall survival 25 versus 20 mos (HR 2.2, p=0.013).
Conclusions: In metastatic renal cell carcinoma patients treated with sunitinib, prior high dose IL-2 therapy may improve the outcome.
结果：研究组和对照组的客观缓解率分别是89%(n=24)和74%(n=20)；根据第一次影像学评价，前3个月疾病进展的患者分别占11%(n=3)和26%(n=7) (p=0.29, OR 2.4)；中位无进展生存期分别是21个月和12个月(HR 2.3, p=0.005)；中位总生存期分别是25个月和20个月(HR 2.2, p=0.013)。
4. Citation: J Clin Oncol 32:5s, 2014 (suppl; abstr 10028)
Immune activation and clinical responses following
combination with interleukin-2 in high-risk neuroblastoma patients.
Background: A less toxic treatment using long-term infusion (LTI) of anti-GD2antibody ch14.18/CHO and subcutaneous interleukin-2 (IL-2) may improve outcome in high risk neuroblastoma (NB).
Methods: 53 NB patients received 5/6 cycles of 6×106 IU/m2 s.c. IL-2 (d1-5; 8-12), LTI of 100 mg/m2 ch14.18/CHO (d8-17) and 160 mg/m2 oral 13-cis-RA (d19-32) in a single center program. Usage of i.v.-morphine and scores established for pediatric pain assessment were documented. Effector cells (NK- and T-cell subsets), ch14.18/CHO levels and GD2 specific killing of neuroblastoma cells by ADCC, CDC, and whole blood were analyzed. KIR/KIRL mismatch and Fcγ-receptor polymorphisms were determined with a validated PCR-based method for KIR, HLA, FCGR2A (H131R), -3A (V158F) and -3B (NA1/NA2). Clinical response was assessed following INRG criteria by mIBG, MRI/CT, BM and catecholamines.
Results: LTI of ch14.18/CHO translated into a decreasing degree of i.v. morphine usage allowing for treatment in the outpatient setting. The expansion of effector NK- (3x) and T-cells (2x) was combined with a pro-inflammatory cytokine response (IL-2, IL-6, IL-8, IFNγ). Effective levels of ch14.18/CHO (12.48 ± 0.93 μg/ml) at the end of antibody infusion translated into GD2specific activity against NB cells in functional assays (CDC, ADCC, WBT). Interestingly, ch14.18/CHO levels and functional parameters before subsequent treatment cycles indicate persistent anti-NB activity measurable for the entire treatment period of 6-7 months. Response rates were 41.7 % in mIBG (15/36), 31.8 % MRI/CT (7/22), 28.6 % bone marrow- (6/21) and 38.1 % in catecholamines (8/21). An overall response of 30% (12/40), EFS of 32.4 % (observation 3.2 years, mean: 1.6 years) and an OS of 66.8% (observation 3.9 years, mean: 3.1 years) was observed. Patients with KIR/KIRL mismatch and high affinity FCGR alleles are associated with a longer event-free survival (P = 0.025), which supports NK-cell mediated ADCC as the mechanism of action.
Conclusions: LTI of ch14.18/CHO shows anti-NB activity over the entire treatment period and objective clinical responses.