Cycles Of Maintenance Therapy Research Articles

Anlotinib for patients with newly diagnosed glioblastoma with unmethylated MGMT promoter: An open-label, single-center, phase 2 clinical trial.

e14039 Background: Glioblastoma (GBM) is the most common primary malignant brain tumor and one of the most deadly forms of cancer in humans. Given the temozolomide’s minimal benefit in O6-methylguanine-DNA Methyltransferase (MGMT) unmethylated GBM, new and effective therapies are urgently needed. In this study, we aimed to assess the safety and efficacy of anlotinib, a novel multitarget tyrosine kinase inhibitor for VEGFR, PDGFR, and c-Kit, in patients with MGMT unmethylated GBM. Methods: This was an open-label, single -center, single-arm, phase 2 trial. Eligible patients included those aged 18 to 70 years who had newly diagnosed histologically confirmed GBM with unmethylated MGMT promoter region. The cutoff value ≥ 10% was used to classify MGMT methylated vs. unmethylated cases. After initial surgical resection, patients with GBM received concurrent radiotherapy (2.0 grays [Gy]/day; total dose, 60 Gy) and anlotinib (beginning on day 43 after surgery, at a dose of 12 mg orally once daily on days 1-14 of a 21-day cycle), followed by 6 cycles of maintenance therapy with anlotinib (at a dose of 12 mg orally once daily on days 1-14 of a 21-day cycle). Patients were re-evaluated every six weeks. The primary endpoint was progression-free survival (PFS), which is defined as the interval from the initiation of anlotinib treatment until the date of disease progression or death. The secondary endpoints were overall survival (OS) and safety. Standard Response Assessment in Neuro-Oncology (RANO) criteria were used to determine tumor response and progression. Adverse events were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. This trial was registered with chictr.org.cn, ChiCTR2000040116. Results: A total of 32 participants were enrolled from September 2020 to June 2022. All patients were with IDH wild-type and MGMT unmethylated status. The median age was 50 years (range, 27-65), and 19 (59.4%) were male. The median follow-up duration was 14.8 months (range, 5.5-23.7). The median PFS was 10.5 months (95%CI: 8.5-12.5), and the median OS was not reached. Treatment-related adverse events (TRAEs) occurred in 13 (40.6%) patients of patients and grade 3 adverse events were observed in 4 (12.5%) patients. The most common toxicities were hypertension (13 [41%]), hand-foot syndrome (12 [38%]), hematuresis (9 [28%]) and liver dysfunction (5 [16%]). Grade 3 therapy-related adverse events included liver dysfunction (2 [6.3%]), hypertension (1 [3.1%]), hand-foot syndrome (1 [3.1%]). No grade 4-5 or unexpected adverse events were observed. Conclusions: This preliminary analysis suggested that anlotinib had promising efficacy and favorable tolerance as treatment of newly diagnosed GBM with unmethylated MGMT promoter. Clinical trial information: ChiCTR2000040116 .

Pulmonary tumor thrombotic microangiopathy during good response to immuno-chemotherapy for advanced non-small cell lung cancer: a case report

BackgroundPulmonary tumor thrombotic microangiopathy is a rapidly progressive and fatal disease in which tumor cells embolize to the pulmonary microvasculature. This condition is characterized by severe dyspnea and right heart failure. Although pulmonary tumor thrombotic microangiopathy typically occurs in patients with untreated and/or advanced cancer, its occurrence in patients who are responding well to medical therapy is poorly documented.Case presentationA 68-year-old Japanese woman who had received four cycles of immuno-chemotherapy (pembrolizumab, carboplatin, and pemetrexed) followed by three cycles of maintenance therapy (pembrolizumab and pemetrexed) for advanced non-small cell lung cancer and had achieved a partial response with a stable clinical course was admitted to the emergency ward because of worsening breathlessness and general fatigue for 1 week. Chest computed tomography showed no evidence of tumor progression or any new lung lesion. Two-dimensional transthoracic echocardiography demonstrated right atrial and ventricular dilatation, tricuspid regurgitation, and a high trans-tricuspid pressure gradient of 65 mmHg. Despite her percutaneous oxygen saturation being 96% on room air at the time of admission, it worsened rapidly; the patient requiring 8 L/min of oxygen within 4 h. Repeat computed tomography with contrast medium revealed no evidence of pulmonary embolism. The patient developed progressive respiratory failure that was unresponsive to optimal cardio-pulmonary supportive therapy. An autopsy revealed tumorous clusters in pre-capillary lung vessels, whereas the primary lesion had shrunk to the point of almost complete resolution.ConclusionPulmonary tumor thrombotic microangiopathy occurs not only in patients with advanced and/or uncontrolled cancer but also in those whose primary lesion seems to have been well controlled by medical treatment.

Clinical case of a successful treatment of stage IV esophagal adenocarcinoma

Background. Esophageal adenocarcinoma is often diagnosed at an advanced stage. The overall five-year survival rate of metastatic esophageal adenocarcinoma is less than 15 %. The main treatment strategy is drug therapy. The search for new drugs is still ongoing. Therefore, the assessment of the effectiveness of currently existing options is of great significance.Description of the clinical case. A 45-year-old patient with advanced esophageal cancer with omental, mediastinal and subclavian lymph node metastases received 4 cycles of CF chemotherapy and 3 cycles of DCF + trastuzumab chemotherapy. After 25 cycles of maintenance therapy with trastuzumab, stable disease was observed. There were no significant adverse events associated with the use of trastuzumab. Currently, the patient has no any symptoms of disease.Conclusion. Trastuzumab for the treatment of HER2- overexpressing esophageal cancer was shown to be very effective. The presented clinical case demonstrates not only the feasibility of controlling metastatic disease using targeted therapy, but also maintaining a high level of quality of life.

Complete remission of an early-stage laryngeal cancer under combined pembrolizumab and chemotherapy treatment of a synchronous lung adenocarcinoma

BackgroundAnti-PD1-Checkpoint inhibition (CI) is an established treatment of recurrent and/or metastatic head and neck cancer. A potential benefit from CI in early-stage disease that is usually treated by radiation or surgery has not been investigated so far and is currently not addressed in clinical trials.Case presentationA 58-year-old man was diagnosed with a cT2 supraglottic laryngeal cancer and a synchronous metastasized adenocarcinoma of the lung. As the patient refused any treatment of his laryngeal cancer, he received combined immune-chemotherapy according to the KEYNOTE-189 protocol. After 4 cycles of pembrolizumab/carboplatin/pemetrexed, the patient showed a complete remission of his laryngeal cancer with a clear shrinkage of the mediastinal and hilar lung cancer metastases. After 21 cycles of maintenance therapy, the lung adenocarcinoma shows a stable disease status with no signs of any residual or recurrent laryngeal cancer.ConclusionsAnti-PD1-CI may be a treatment option also for early-stage HNSCC with excellent functional outcome when established therapies are not available.Graphical

Impact of maintenance therapy following induction immunochemotherapy for untreated advanced non-small cell lung cancer patients

The primary objective of this study was to identify the potential predictors to assess the impact of maintenance therapy after induction immunochemotherapy in the real-world setting of patients with advanced non-small cell lung cancer (NSCLC). We retrospectively identified 152 patients with advanced NSCLC who received immunochemotherapy at 8 hospitals in Japan between January 2019 and December 2019. Patients who received at least four cycles of induction immunochemotherapy and one cycle of maintenance therapy with immune checkpoint inhibitors were included. We investigated the biomarkers for progression-free survival (PFS) for maintenance therapy after induction immunochemotherapy. Out of the 92 patients with advanced NSCLC included in the study, 42 received maintenance therapy with cytotoxic agents, whereas 50 received maintenance therapy without cytotoxic agents. Among those who received maintenance therapy without cytotoxic agents, responders to prior immunochemotherapy had significantly longer PFS than non-responders (p = 0.004), except those with maintenance therapy with cytotoxic agents. In non-responders to prior immunochemotherapy, patients with maintenance therapy with cytotoxic agents had significantly longer PFS than those with maintenance therapy without cytotoxic agents (log-rank p = 0.007), whereas, among responders to prior immunochemotherapy, there was no significant difference in PFS for different maintenance regimens (log-rank p = 0.31). This retrospective study showed that response to prior immunochemotherapy was associated with clinical outcomes among patients with advanced NSCLC who received maintenance therapy.

Abstract 1471: Incorporation of SKI-G-801, novel AXL inhibitor, with anti-PD-1 inhibitor plus chemotherapy improved anti-tumor activity and survival outcome via enhancing anti-tumor T cell immunity

Abstract Background: AXL has been identified to play multiple roles in the tumor microenvironment including the promotion of epithelial-mesenchymal transition and immune evasion. SKI-G-801, a small molecule inhibitor targeting phosphorylation of AXL, presented strong inhibition of cancer migration and invasion. Anti-PD-1(αPD-1) combined with paclitaxel(Pac)/carboplatin(Carbo) and pemetrexed(Pem)/cisplatin(Cis) are standard therapy in non-squamous and squamous lung cancer patients, respectively. Herein, we present that adding AXL inhibition with SKI-G-801 on αPD-1 plus chemotherapy suppressed tumor growth and improved overall survival and also enhanced anti-tumor T cell immunity in both non-squamous and squamous lung cancer models. Methods: C3PQ squamous and TC-1 non-squamous lung cancer bearing mouse models were established. In C3PQ squamous model, mice were treated with 2 cycles of induction Carbo + Pac + αPD-1 and 13 cycles of maintenance with αPD-1. In TC-1 non-squamous model, mice were treated with 3 cycles of induction with Cis + Pem + αPD-1 and 14 cycles of maintenance therapy. Both models included the groups of SKI-G-801 treatment from induction therapy and/or maintenance therapy. The tumor growth and survival were monitored for 60 days in both models. The tumor infiltrated lymphocytes were analyzed by flow cytometry. Results: In TC-1 non-squamous model, upfront addition of SKI-G-801 on αPD-1 plus Pem/Cis chemotherapy followed by αPD-1 and Pem maintenance showed the superior overall survival to the others (vs. αPD-1+ Pem/Cis and αPD-1 + Pem maintenance; p<0.001, vs. αPD-1 + Pem/Cis and αPD-1 + Pem + SKI-G-801 maintenance; p<0.01, vs. αPD-1 + Pem/Cis and SKI-G-801 maintenance; p<0.01). In C3PQ squamous model, upfront addition of SKI-G-801 on αPD-1 plus Pac/Carbo followed by αPD-1 prolonged the overall survival compared the others (vs. αPD-1+Pac/Carbo and αPD-1 maintenance; p<0.05, vs. αPD-1 + Pac/Carbo and αPD-1+ SKI-G-801 maintenance; p<0.05, vs. αPD-1 + Pac/Carbo + SKI-G-801 maintenance; n.s.). In line with survival outcomes, upfront SKI-G-801 on αPD-1 combined with chemotherapy showed the strong tumor growth inhibition compared to the others. Especially, effector memory T cells (CD3+CD4+CD44+CD107-) and IFN-γ secretion level of CD8+ T cells were significantly increased in SKI-G-801 treated groups in C3PQ model (p<0.05). Conclusion: Incorporation of SKI-G-801, a novel AXL inhibitor, with αPD-1 combined with chemotherapy significantly improved overall survival and anti-tumor activity in both non-squamous and squamous lung cancer model through enhancing cytotoxicity of CD8+ T cells and memory CD4+ T cells. These findings provide mechanistic insight into the activity of SKI-G-801 combined with standard therapy and support its clinical development in metastatic NSCLC as first line therapy. Citation Format: Kyoung-Ho Pyo, Wongeun Lee, Hee Kyu Lee, Dong Kwon Kim, Ha Ni Jo, Chun-Bong Synn, Jae Hwan Kim, Yeongseon Byeon, Young Seob Kim, Beung-Chul Ahn, Min Hee Hong, Sun Min Lim, Byoung Chul Cho, Hye Ryun Kim. Incorporation of SKI-G-801, novel AXL inhibitor, with anti-PD-1 inhibitor plus chemotherapy improved anti-tumor activity and survival outcome via enhancing anti-tumor T cell immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1471.

Pneumocystis Jiroveci Pneunomia Prophylaxis during Maintenance Therapy with Hyper-CVAD Regimens for Adult Acute Lymphoblastic Leukemia

BACKGROUNDPneumocystis jiroveci pneumonia (PCP) can be a deadly opportunistic infection in immunocompromised patients. Patients with acute lymphoblastic leukemia (ALL) are at risk for PCP due to their underlying disease, use of high doses of corticosteroids and receipt of lymphocyte-depleting chemotherapy. It is recommended that patients receive PCP prophylaxis during treatment for ALL. Trimethoprim/sulfamethoxazole (TMP/SMZ) is a common agent utilized but some practitioners are concerned about myelosuppression induced by TMP/SMZ. HyperCVAD regimens are the standard treatment strategy for ALL patients at our institution. Historically, PCP prophylaxis with TMP/SMZ was delayed until the beginning of maintenance therapy. This retrospective analysis evaluated PCP prophylaxis and incidence in ALL patients receiving maintenance therapy on a HyperCVAD regimen. Any influence of PCP prophylaxis on clinical outcomes was also evaluated. METHODSNewly diagnosed adult (≥ 18 yo) patients with ALL or lymphoblastic lymphoma who received at least one cycle of maintenance therapy on a HyperCVAD regimen between April 2000 to December 2016 were reviewed. Interim chart reviews were performed to identify the use of PCP prophylaxis and definite or suspected cases of PCP, as well as to document maintenance therapy doses or change in patient status, until the completion of maintenance therapy. Suspected PCP cases (missing microbiological documentation of Pneumocystis) were defined as those patients receiving PCP active therapy based on clinical presentation and imaging. RESULTSDuring the study period, 363 frontline ALL patients received at least one cycle of HyperCVAD maintenance therapy. 346 (198 males and 148 females) patients had sufficient documentation. Of these 346 patients, 145 never received PCP prophylaxis, 67 received i ntermittent PCP prophylaxis, and 134 received uninterrupted PCP prophylaxis throughout maintenance therapy. Only 3 cases of PCP (0.9%) were identified, one confirmed and 2 suspected. All cases occurred within the first 6 months of maintenance therapy and in patients never receiving PCP prophylaxis. The majority of patients receiving prophylaxis were on TMP/SMZ (97%); the most common regimen was 160 mg of the TMP component (1 DS tablet) twice daily two days per week. PCP prophylaxis rates have decreased over time - 55% of patients received uninterrupted PCP prophylaxis if initiated ALL maintenance therapy in 2000-2005 versus 10% of patients received uninterrupted maintenance if initiated ALL maintenance therapy in 2010-2016 (p=<0.001). Philadelphia-positive patients (106/346, 31%) received TKI-based maintenance therapy (TKI, corticosteroid, vincristine). Philadelphia-positive patients were less likely to receive uninterrupted PCP prophylaxis (p<0.0001). Doses of TKI were not statistically different between PCP prophylaxis groups. Philadelphia-negative patients received maintenance therapy containing mercaptopurine and methotrexate (plus corticosteroid, vincristine). Doses of mercaptopurine and methotrexate were not statistically different between PCP prophylaxis groups (p=0.75, p=0.4 respectively). ANC values were analyzed over time and were not significantly different between PCP prophylaxis groups (p=0.36 for never versus uninterrupted PCP prophylaxis). ALC values were also evaluated and were significantly lower in the uninterrupted PCP prophylaxis group at baseline, maintenance year 1 and maintenance year 2 (p=0.0464, p=0.0002, p=0.0001 respectively). Relapse rate, PFS and OS did not differ between the never, intermittent and uninterrupted PCP prophylaxis groups. CONCLUSIONSThe rate of PCP was low in this group of adult patients with newly diagnosed ALL undergoing maintenance therapy as part of a HyperCVAD regimen. All PCP cases occurred in patients not receiving PCP prophylaxis. TMP/SMZ prophylaxis had no significant effect on doses of ALL maintenance therapy provided as well as PFS and OS. TMP/SMZ remains a safe, effective choice for PCP prophylaxis in adult ALL patients. Given the low incidence of PCP in this population, future studies are warranted to identify risk factors that allow selection of patients who would benefit the most from PCP prophylaxis. DisclosuresJabbour:Bristol-Myers Squibb: Consultancy.

The Addition of Midostaurin to Standard Chemotherapy Decreases Cumulative Incidence of Relapse (CIR) in the International Prospective Randomized, Placebo-Controlled, Double-Blind Trial (CALGB 10603 / RATIFY [Alliance]) for Newly Diagnosed Acute Myeloid Leukemia (AML) Patients with FLT3 Mutations

The Addition of Midostaurin to Standard Chemotherapy Decreases Cumulative Incidence of Relapse (CIR) in the International Prospective Randomized, Placebo-Controlled, Double-Blind Trial (CALGB 10603 / RATIFY [Alliance]) for Newly Diagnosed Acute Myeloid Leukemia (AML) Patients with FLT3 Mutations

Duration of pemetrexed maintenance therapy with or without pembrolizumab is associated with risk of renal toxicity in patients with metastatic nonsquamous NSCLC.

e21205 Background: Use of maintenance pemetrexed with pembrolizumab is the standard of care among patients with metastatic nonsquamous NSCLC without EGFR or ALK alterations treated with the KEYNOTE-189 regimen. Whether the addition of pembrolizumab to pemetrexed maintenance alters the risk of renal toxicity is not well characterized. Methods: A single center retrospective study was performed. The frequency of acute kidney injury as well as the rates of discontinuation due to renal injury was assessed. Acute renal injury was defined as ≥ 0.3 increase in serum creatinine (sCr) above the upper limit of normal or a rise in sCr ≥ 1.5 times baseline per KDIGO criteria. A Fisher exact test was conducted to compare the rate of renal injury between the two groups. Logistic regression adjusting for performance status, prior lines of treatment, and number of maintenance cycles was performed. Results: We identified 114 patients who received either maintenance pemetrexed or pemetrexed + pembrolizumab. The median number of cycles for the maintenance pemetrexed and pemetrexed + pembrolizumab groups was 5 and 7 cycles respectively. Of these, 41% (47/114) patients developed acute renal injury during their treatment course. Renal injury was seen in 14.3% (5/35) patients who received single agent pemetrexed maintenance and 25% (3/12) who received maintenance pemetrexed + pembrolizumab with no significant difference in the rates of renal injury between both arms (p = 0.403). Among patients who developed acute renal injury, 9% (4/47) permanently discontinued maintenance due to nephrotoxicity. All patients who permanently discontinued therapy received maintenance pemetrexed alone. When adjusting for covariates, ECOG performance status and number of prior lines of therapy did not increase the risk of renal toxicity. Logistic regression analysis identified that the rate of renal injury was significantly associated with the number of maintenance cycles received (p-value = 0.017, OR = 1.14, 95% CI 1.03 - 1.29). The odds of developing renal injury were 1.14 times higher with each additional cycle of maintenance therapy received. Conclusions: Renal injury is common among patients treated with patients receiving maintenance therapy. The addition of pembrolizumab to maintenance pemetrexed did not significantly increase the rate of renal injury. The risk of renal injury appears to correlate with the total number of maintenance cycles received suggesting a cumulative risk of nephrotoxicity over time.

Experience of pemetrexed in maintenance therapy for metastatic lung adenocarcinoma

Lung cancer is among the most common malignant diseases in Russia. In 80–90%, its morphological type is nonsmall cell lung cancer. Stage IV primary advanced lung cancer is diagnosed in 41% of patients. Median overall survival in stage IV patients receiving chemotherapy is 7–12 months. Treatment for stage IV lung adenocarcinoma is based on predictive and prognostic factors. Chemotherapy, chemoimmunotherapy or immunotherapy is recommended in the absence of driver mutations in the EGFR (exons 19 and 21) and BRAF genes, ALK and ROS1 translocations.Platinum- based regimens are preferred as the fi rst-line chemotherapy. Stabilization, partial or complete response after 4–6 chemotherapy cycles allow for maintenance therapy with pemetrexed to increase progression-free survival and overall survival.Purpose of the study. Using a real clinical case, to confirm the efficacy of pemetrexed in the treatment for stage IV lung adenocarcinoma in the second-line therapy in combination with platinum- based agents and in a maintenance therapy.A clinical case of a patient with central cancer of the lower lobe of the right lung St IV (cT3N2M1) is presented; the first treatment stage involved 3 cycles of the fi rst-line polychemotherapy (paclitaxel 175 mg/m² intravenously on day 1, carboplatin AUC 5 intravenously on day 1, every 3 weeks), and 6 cycles of the second-line polychemotherapy (pemetrexed 500 mg/m2 intravenously on day 1, cisplatin 75 mg/m² intravenously on day 1 of the 21-day cycle). Stabilization of the disease was achieves, and 20 cycles of maintenance therapy with pemetrexed followed; the achieved effect persisted and was confirmed by spiral X-ray computed tomography every 3 months. The objective effect of anticancer therapy was assessed according to the RECIST 1.1 criteria. It took 20 months from the beginning of the second-line anticancer medical therapy to progression, and 16 months from the start of maintenance pemetrexed to progression. The safety profile was satisfactory, and the ECOG performance status 0 maintained. Only one adverse effect, degree I general weakness, was noted, which did not have a negative impact on the patient's quality of life.

PF256 RATIFY: PROGNOSTIC IMPACT OF FLT3 TYROSINE KINASE DOMAIN (TKD) AND NPM1 MUTATION STATUS IN PATIENTS WITH NEWLY DIAGNOSED ACUTE MYELOID LEUKEMIA (AML) TREATED WITH MIDOSTAURIN + STANDARD CHEMOTHERAPY

Background:Mutations localized in the tyrosine kinase domain activation loop of FLT3 (FLT3‐TKD), induce constitutive tyrosine phosphorylation, and activation of the receptor tyrosine kinase similarly to FLT3 internal tandem duplication (ITD) mutations. However, the prognostic role of FLT3‐TKD in AML is not well established. In the phase 3 RATIFY trial [CALGB 10603/Alliance; NCT00651261; Stone et al. N Engl J Med. 2017] midostaurin, in combination with standard chemotherapy, improved survival outcomes across all three FLT3 stratification subgroups (ITD high allelic ratio (AR) [≥ 0.7], ITD low AR [&lt; 0.7] and TKD) vs placebo.Aims:Here, a post hoc analysis was used to establish the efficacy of midostaurin in patients (pts) in the RATIFY trial stratified by FLT3‐TKD AR and NPM1 mutational status.Methods:In RATIFY, newly diagnosed pts with AML 18–60 years (y) old were randomly assigned to receive midostaurin or placebo together with standard induction and consolidation therapy followed by twelve 28‐day cycles of maintenance therapy with midostaurin or placebo. FLT3‐TKD mutation was detected by PCR and capillary electrophoresis at nine reference laboratories. The FLT3‐TKD AR was calculated as the ratio between the areas under the curve of mutant to wild‐type allele. Pts were categorized as NPM1 mutated (mut) or NPM1 wild‐type (WT) using PCR. Efficacy outcomes included complete remission (CR), overall survival (OS), event‐free survival (EFS) and disease‐free survival (DFS). EFS and DFS analyses were performed considering CR within a 60‐day window. P values presented were not adjusted for multiplicity.Results:Of 163 FLT3‐TKD pts, 134 with available NPM1 data had consented for exploratory analysis and were included in this study. Overall, 58.9% of pts had NPM1‐mut, 47.8% were male and the median age was 49 y (range: 19.3–59.9 y). The median white blood cell (WBC) count was higher in pts with NPM1‐mut than in pts with NPM1‐WT (34.1 vs 15.5 × 109 /L). The median FLT3‐TKD AR was 0.4 (range: 0–2.7). Overall CR rate (regardless of NPM1 genotype) was 64% for midostaurin and 56% for placebo in FLT3‐TKD pts. Pts with FLT3‐TKD AR ≥ 0.4 treated with midostaurin showed a trend towards improved OS and reduced cumulative incidence of relapse (CIR) (Figure). In FLT3‐TKD AR ≥ 0.4 pts, the presence of a NPM1 mutation had a significant prognostic effect for all endpoints consistently with hazard ratios (HRs) around 0.50 or lower. Regardless of treatment OS, EFS, and DFS estimates at 3 y were 73% vs 52%, 48% vs 25%, and 74% vs 47%, respectively, for the 45 pts with FLT3‐TKD/NPM1‐mut vs the 25 pts with FLT3‐TKD/NPM1‐WT. It should be noted that the number of pts in each subgroup was small. Multivariate analyses in these FLT3‐TKD pts revealed that NPM1 genotype was an independent prognostic factor for OS and EFS (2‐sided P &lt; 0.05), whereas study drug, age, sex, TKD AR, WBC at baseline and stem cell transplantation (SCT) (no/yes) did not reach this level of significance in the Cox model.Summary/Conclusion:This post hoc analysis of the subset of FLT3‐TKD pts in the RATIFY trial showed the high prognostic value of NPM1 mutational status. Midostaurin showed an overall benefit in the FLT3‐TKD pts for OS, EFS, CR and DFS, with the impact of treatment on outcome for NPM1‐mut pts being greatest in those with higher FLT3‐TKD allelic burden. U10CA180821, U10CA180882, U24CA196171, U10CA180861; Novartis; htt∗∗∗ps://acknowledgments.alliancefound.orgimage

The efficacy and safety of CapeOX plus bevacizumab therapy with a planned oxaliplatin stop-and-go strategy in patients with metastatic colorectal cancer: A multi-center, single-arm, phase II study (CCOG-0902 study).

795 Background: The aim of this study was to evaluate the efficacy and safety of CapeOX plus bevacizumab with a planned oxaliplatin stop-and-go strategy in Japanese patients with metastatic colorectal cancer (mCRC). Methods: Patients with untreated mCRC were treated with 4 cycles of CapeOX plus bevacizumab therapy, followed by capecitabine plus bevacizumab maintenance therapy. Reintroduction of oxaliplatin was scheduled after 8 cycles of maintenance therapy or upon tumor progression. The primary endpoint was progression-free survival (PFS), and secondary end points included overall survival (OS), objective response rate to each treatment, reintroduction rate of oxaliplatin, frequency of peripheral sensory neuropathy (PSN), and safety. Results: The 52 patients who received the protocol treatment were included in the evaluation of efficacy and safety. Median PFS and OS were 12.4 months (95% confidence interval [CI], 10.0–14.8) and 30.6 months (95% CI, 27.6–33.5), respectively. The objective response rates were 55.8% for the initial CapeOX plus bevacizumab therapy, 17.8% for capecitabine plus bevacizumab maintenance therapy, and 31.0% for reintroduced CapeOX plus bevacizumab therapy. The frequency of PSN was 63.5%, including 3.8% of patients with grade 3 PSN. No patients required treatment discontinuation because of PSN during the induction or maintenance therapy. Conclusions: CapeOX plus bevacizumab therapy with a planned oxaliplatin stop-and-go strategy is a feasible first-line treatment for Japanese patients with mCRC. Clinical trial information: UMIN000006478.

Mercaptopurine Tolerance In Early Treatment and Correlation With Dose Modifications In Maintenance Therapy For Pediatric ALL Patients

Multiple studies have demonstrated the importance of oral chemotherapy dosing to outcome in the treatment of pediatric acute lymphoblastic leukemia. Dosing of oral mercaptopurine is adjusted by clinical tolerance using dose escalations or reductions depending on the patient's neutrophil and platelet counts. Current regimens use guidelines to attempt to maximize anti-leukemic effect but minimize risk of infection or bleeding from extreme cytopenias. A recent approach to help predict patient tolerance involves testing of drug metabolites or TPMT activity phenotype or genotype, but these tests remain a send-out test for most centers and have not been universally adopted as standard of care. As a potential additional clinical tool, we sought to determine whether tolerance of mercaptopurine during an early consolidation course could help predict tolerance of mercaptopurine during maintenance.We performed a retrospective chart review of all standard risk ALL patients treated at our center in the last 10 years. Patients qualified for the study if they received standard consolidation using treatment regimens based on Children's Oncology Group (COG) studies AALL0331 or AALL0932 which include mercaptopurine for 28 days without other myelosuppressive chemotherapy (only other chemotherapy includes a single vincristine dose on day 1 and intrathecal treatments on days 1, 8, and 15). Patients receiving consolidation including other myelosuppressive chemotherapy (such as arm LRAsp-IV on AALL0331 which included PEG-asparaginase in consolidation or arm IS-IV on AALL0331 with intensified consolidation for slow early responder patients) were excluded from the study. We hypothesized that patients who had delay in the start of their interim maintenance course following standard consolidation due to cytopenias demonstrate a clinical sensitivity to mercaptopurine that could result in increased risk of interruptions in oral chemotherapy early in maintenance therapy. Thus we correlated delays in start of interim maintenance with interruptions in dosing of mercaptopurine due to cytopenias during the first 2 cycles of maintenance. Data was analyzed using JMP® Statistical Discovery software.A total of 55 patients met our eligibility requirements (standard risk ALL, treated with standard consolidation per the regimens noted above, and completed at least 2 cycles of maintenance chemotherapy). Of these 55 patients, 11% (N=6) had a delay in the start of their interim maintenance course due to cytopenias following standard consolidation. The average duration of this delay was 12.5 days with a range of 7-21 days. Among the 6 patients who had delayed interim maintenance, 5 (83%) had mercaptopurine held during the first 2 cycles because of cytopenias. This was higher than the 61% (30 out of 49) of patients requiring dose interruptions for cytopenias in maintenance among those patients who started interim maintenance without delay. (P=0.28) The interval from start of maintenance until time of first dose interruption and number of interruptions in the first two cycles of maintenance therapy were also examined. Patients who had delays in start of interim maintenance had a mean time to first dose interruption of 51 days which was not different than the mean time of 55 days to first interruption in all other patients. (P=0.76) Both groups had a median of 43 days to time of first interruption. The number of dose interruptions ranged from 0-3. There was not a difference in the number of dose interruptions among patients who did and did not have a delay in interim maintenance. (P=0.28)Our analysis demonstrated that 65% of all patients in our cohort required dose interruptions of mercaptopurine in the first 2 cycles of maintenance therapy, suggesting this is a very common complication. A higher proportion of patients with delays in starting interim maintenance experienced such interruptions compared to those without delays. Although this was not statistically significant it should be evaluated in larger cooperative group studies. Our data does suggest that the time period between day 29 and day 57 of maintenance therapy is a high risk period for cytopenias. This data supports close monitoring of counts early in maintenance (every 2 weeks rather than every 4 weeks with vincristine visits) to minimize risks of infection or bleeding associated with prolonged cytopenias. Disclosures:No relevant conflicts of interest to declare.

Evaluation of Immune Suppression in Multiple Myeloma Patients Treated with Lenalidomide Plus Prednisone and Lenalidomide Alone

AbstractAbstract 3969 Introduction:Lenalidomide is one of the immunomodulatory drugs (IMiDs), which function efficiently as immune system modulator and interfere with tumor and its microenvironment via anti-angiogenic, anti-proliferative and anti-inflammatory effects, and also down regulate adhesion molecules in tumor cells. Lenalidomide has significantly improved survival outcome in multiple myeloma (MM) patients. Recently, we and others have shown that lenalidomide in combination with dexamethasone increased the immune suppressor cell numbers in MM patients (Muthu Raja et al, 2012; Minnema et al, 2009). Also, an in vivo study showed that anti-tumor properties of lenalidomide are not compromised by dexamethasone but lenalidomide induced immune modulatory effects are reduced. Here in this study, we aimed to compare the immune suppressor cells and other immune cells in multiple myeloma patients who are treated with lenalidomide plus prednisone (LP) and lenalidomide alone (L). Patients and methods:A total of 18 patients were included during maintenance therapy, these patients were randomized to receive LP or L until progression. Ten patients received LP and 8 patients received L. All patients were in the stage of ISS-1 (International Stage System) before the start of maintenance therapy. Using flow cytometric analysis, we quantified various immune cell subsets in these two cohorts including T regulatory cells (Tregs), myeloid-derived suppressor cells (MDSCs), CD4, CD8 and total lymphocytes. Results:Tregs and MDSCs were phenotypically characterized as CD4+ CD25hi+FoxP3+ and CD33+CD11b+CD14-HLADR-, respectively. We analyzed these immune suppressor cells and other immune cells before and after each cycle of maintenance therapy, for a period of 4 cycles. In head to head analysis, no significant difference was observed between patients in LP arm and L arm for immune suppressors and immune cells before maintenance (Table 1). However, during maintenance, Treg and MDSC numbers were significantly increased in patients treated with LP compared to patients treated with L (P <0.05) (Table 1). When we compared CD4, CD8 and total lymphocyte numbers, no significant changes were seen between patients in LP arm and L arm (Table 1). Interestingly, L treated patients showed a trend of increase in CD4 and total lymphocyte counts compared to pre-L. On contrary, LP treated patients showed reduced or similar counts for CD4, CD8 and total lymphocytes while numbers of Tregs (P=0.033) and MDSCs were increased compared to pre-LP. Then, we compared immune cell subsets between before and after maintenance therapy with irrespective of the treatment arm. Comparative analysis showed that only Tregs were increased significantly after maintenance compared to pre-maintenance (median: 5.2 vs. 6.4; P=0.032) but not the other cells. Conclusions:Our study clearly showed that immune suppressor cells including, Tregs and MDSCs were significantly increased in MM patients treated with lenalidomide plus prednisone compared to patients treated with lenalidomide alone. Increase in immune suppressor cells might be due to inclusion of prednisone with lenalidomide. This finding is also further supported by lenalidomide arm data, where no significant increase in immune suppressor cells was observed. Expanded immune suppressor cells in lenalidomide plus prednisone treated cohort might be more susceptible to infectious complications and progression risk. [Display omitted] Disclosures:Off Label Use: Lenalidomide and Prednisone.

Smoldering Multiple Myeloma (SMM) At High-Risk of Progression to Symptomatic Disease: A Phase III, Randomized, Multicenter Trial Based On Lenalidomide-Dexamethasone (Len-Dex) As Induction Therapy Followed by Maintenance Therapy with Len Alone Vs No Treatment

Abstract 991▪▪This icon denotes a clinically relevant abstractSmoldering Multiple Myeloma (SMM) is an asymptomatic proliferative disorder of plasma cells (PCs) defined by a serum monoclonal component (MC) of 30 g/L or higher and/or 10% or more plasma cells in the bone marrow (BM). There are several risk factors predicting high-risk of progression to symptomatic disease: >10% of PCs in BM, serum MC >30g/L, >95% aberrant PCs by immunophenotyping, or abnormal free-light chains. Standard of care of SMM is no treatment until progression disease.In this phase III trial, SMM patients at high-risk of progression were randomized to receive Len-dex as induction followed by Len alone as maintenance vs no treatment in order to evaluate whether the early treatment prolongs the time to progression (TTP) to symptomatic disease. The high-risk population was defined by the presence of both >PC 10% and MC >30g/L or if only one criterion was present, patients must have a proportion of aberrant PCs within the total PCsBM compartment by immunophenotyping of 95% plus immunoparesis.Len-dex arm received an induction treatment consisting on nine four-weeks cycles of lenalidomide at dose of 25 mg daily on days 1–21 plus dexamethasone at dose of 20 mg daily on days 1–4 and 12–15 (total dose: 160mg), followed by maintenance until progression disease with Lenalidomide at dose of 10 mg on days 1–21 every two months (amended in May 2010 into monthly).The 124 planned patients were already recruited, and 118 were evaluable (six patients didn't meet inclusion criteria).According to baseline characteristics, both groups were well balanced. On an ITT analysis (n=57), based on IMWG criteria, the overall response rate during induction therapy was 81%, including 56% PR, 11% VGPR, 7% CR and 7% sCR. 51 patients have completed the nine induction cycles, and the ORR was 87%, including 12% VGPR, 8% CR and 8% sCR. After a median of 7 cycles of maintenance therapy (1-21), the sCR increased to 12%.After a median follow-up of 22 months (range: 5–42), six patients progressed to symptomatic disease in the Len-dex arm: four of them during maintenance therapy and the other two progressed 3 and 8 months after early discontinuation of the trial due to personal reasons. In addition, twelve patients have developed biological progression during maintenance, and dex was added according to the protocol. In nine of them, the addition of dex was able to control again the disease without CRAB symptoms (median of 11 months). In the therapeutic abstention arm, 28 out of 61 patients (46%) progressed to active MM. The estimated hazard ratio was 6·2 (95%CI= 2·6-15), corresponding to a median TTP from inclusion of 25 months for the not treatment arm vs median not reached in the treatment arm (p<0.0001). It should be noted that 13 out of these 28 patients developed bone lesions as a symptom of active MM. Deaths in the Len-dex and no treatment arms were 1 and 2, respectively (p=0·6). Estimated 3-years overall survival (OS) from the inclusion in the trial was 98% for Len-dex arm and 82% for no treatment arm (p=0·05) and this difference was more evident if we evaluate the OS from the moment of diagnosis (HR: 6.7; 95% IC (0.7–57); p=0.03).As far as toxicity is concerned, during induction therapy, no G4 adverse events (AEs) were reported with Len-dex; 1 pt developed G3 anemia, 4 patients G3 asthenia 2 patients G3 diarrhea and 1 patient G3 skin rash; 3 patients developed G2 DVT. During maintenance, no G4 AEs were reported and only 1 patient developed G3 infection. Two patients in the Len-dex arm developed second primary malignancies (SPM): one developed polycythemia vera JAK2+, but the analysis of a frozen DNA sample obtained at the moment of inclusion in the trial demonstrated that JAK2 was already positive. The second-one was a prostate cancer in a patient with previous history of prostate enlargement plus elevated prostate specific antigen (PSA) who was closely followed by the urologist.In conclusion, this analysis shows that in high-risk SMM patients, delayed treatment resulted in early progression to symptomatic disease (median 25 months), while Len-dex as induction followed by Len as maintenance significantly prolonged the TTP (HR: 6·2), with a trend to improve the overall survival; in addition, tolerability is acceptable and concerning SPM, no safety warnings are at the present time. Moreover, biological progressions occurring under maintenance have remained controlled over a prolonged period of time. Disclosures:Mateos:Celgene: Honoraria; Janssen: Honoraria. Off Label Use: lenalidomide is not approved for smoldering myeloma. Rosiñol:Janssen: Honoraria; Celgene: Honoraria. Baquero:Celgene: Employment. Quintana:Celgene: Employment. García:Celgene: Employment.

Rituximab Maintenance In Patients with Chronic Lymphocytic Leukemia (CLL) After Upfront Treatment with Rituximab Plus Fludarabine, Cyclophosphamide, and Mitoxantrone (R-FCM): Final Results of a Multicenter Phase II Trial On Behalf of the Spanish CLL Study Group (GELLC)

Abstract▪293▪This icon denotes a clinically relevant abstractThe effectiveness of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) followed by rituximab maintenance in the treatment of CLL has been investigated in a phase II clinical trial that includes two treatment parts. First, patients were given induction therapy with R-FCM up to 6 cycles, achieving an overall response (OR) rate of 93% and a CR rate of 82% (46% MRD-negative CR) (Bosch et al. J Clin Oncol 27:4578–4584, 2009). Patients achieving CR or PR with the initial part of the treatment received rituximab maintenance. Here we present the final results of the treatment maintenance part, initiated three months after concluding R-FCM, and consisting of rituximab 375 mg/m2 every three months for two years (up to 8 cycles). Sixty-four patients (median age 60 years, 70% male) receiving > 4 cycles of maintenance therapy were evaluated for response, including bone marrow (BM) examination and MRD assessment by four-color flow cytometry of peripheral blood and BM. Patients in whom rituximab maintenance was prematurely interrupted (≤ 4 cycles) due to toxicity were considered as failures. Median number of cycles of maintenance administered was 8 (range, 1 to 8) and 76% of patients completed the entire planned treatment. Treatment was delayed due to insufficient hematological recovery in 9 cycles (2%) and to non-hematological toxicity in 4 cycles (0.8%). Neutropenia was observed in 31.3% of cycles (grade 3&4 in 8.5%), thrombocytopenia in 4.6%, and anemia in 1.2%. At the end of the maintenance therapy, 45% of patients had low IgA serum levels, 37% low IgG, and 66% low IgM. Sixteen patients experienced grade 3&4 infectious episodes, including 9 pneumonia, 2 febrile neutropenia, 1 appendicitis, 1 myositis, 1 herpes zoster, and 1 cerebral abscess. Two patients died, one due to multifocal leukoencephalopathy and the other due to hemophagocytic syndrome. Infectious episodes grade 3&4 were observed in 19.5% of cycles with neutropenia 3&4, but in only 3% of cycles with neutropenia inferior to grade 3 (p<0.001). In contrast, no relationship was observed between infectious events and the presence of low levels of immunoglobulins or diminished CD4+ T lymphocyte counts. After rituximab maintenance, 40.6% of patients were in MRD-negative CR, 40.6% in CR, 7.9% in PR, and 10.9% failed to treatment. Failures were due to disease progression (two patients), severe neutropenia (three patients), infectious toxicity (one patient) and death (one patient). Among 35 patients in MRD-negative CR after R-FCM induction, 22 maintained the MRD-negative status at the end of maintenance treatment, 9 (25.7%) switched from MRD-negative to MRD-positive, and 4 failed to treatment (Table 1). Median time to conversion from negative to positive MRD was 45.4 months, significantly longer than that observed in patients treated with FCM only (45.4 vs. 16.4 months; p=0.011) (Bosch et al. Clin Can Res 14:155–161,2008) (Figure 1). Moreover, among 21 patients that achieved MRD-positive CR with the initial R-FCM treatment, 2 (9.5%) became MRD-negative upon rituximab maintenance, 17(81%) continued in MRD-positive CR, 2 achieved PR, and 2 failed to maintenance therapy. Among the 8 patients in PR, 4 patients achieved CR (2 MRD-negative and 2 MRD-positive), 3 patients continued in PR, and one patient progressed (Table I). Three-year progression-free survival was 94% (95% CI 88–100%). Compared to the FCM series, maintenance with rituximab significantly prolonged the time to next treatment in patients that after the initial treatment with R-FCM were in MRD-positive CR (44.1 vs. 54.5 months, p=0.049) or PR (6.5 vs. 54.4 months, p=0.001). In conclusion, treatment maintenance with rituximab after R-FCM in patients with CLL is feasible and might improve patients’ outcome, particularly those who do not attain a MRD-negative CR after the initial, upfront therapy. However, its toxicity is not negligible. Further, ongoing studies should help to clarify the role of maintenance therapy with rituximab in the management of patients with CLL.RESPONSE TO RITUXIMAB MAINTENANCECR MRD(−)CR MRD(+)PRFailureRESPONSE TO R-FCM(N = 64)CR MRD (−) (N = 35)229–4CR MRD (+) (N = 21)21522PR (N = 8)2231 [Display omitted] Disclosures:Bosch:Hoffman La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Rituximab is currently not approved as maintenance therapy for patients with chronic lymphocytic leukemia.

5.40 Rituximab Maintenance in Patients with Chronic Lymphocytic Leukemia after First-Line Treatment with Rituximab plus Fludarabine, Cyclophosphamide, and Mitoxantrone: Final Results of a Multicenter Phase II Trial on Behalf of the Spanish CLL Study Group (GELLC)

Abstract 293[][1] The effectiveness of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) followed by rituximab maintenance in the treatment of CLL has been investigated in a phase II clinical trial that includes two treatment parts. First, patients were given induction therapy with R-FCM up to 6 cycles, achieving an overall response (OR) rate of 93% and a CR rate of 82% (46% MRD-negative CR) (Bosch et al. J Clin Oncol 27:4578–4584, 2009). Patients achieving CR or PR with the initial part of the treatment received rituximab maintenance. Here we present the final results of the treatment maintenance part, initiated three months after concluding R-FCM, and consisting of rituximab 375 mg/m2 every three months for two years (up to 8 cycles). Sixty-four patients (median age 60 years, 70% male) receiving > 4 cycles of maintenance therapy were evaluated for response, including bone marrow (BM) examination and MRD assessment by four-color flow cytometry of peripheral blood and BM. Patients in whom rituximab maintenance was prematurely interrupted (≤ 4 cycles) due to toxicity were considered as failures. Median number of cycles of maintenance administered was 8 (range, 1 to 8) and 76% of patients completed the entire planned treatment. Treatment was delayed due to insufficient hematological recovery in 9 cycles (2%) and to non-hematological toxicity in 4 cycles (0.8%). Neutropenia was observed in 31.3% of cycles (grade 3&4 in 8.5%), thrombocytopenia in 4.6%, and anemia in 1.2%. At the end of the maintenance therapy, 45% of patients had low IgA serum levels, 37% low IgG, and 66% low IgM. Sixteen patients experienced grade 3&4 infectious episodes, including 9 pneumonia, 2 febrile neutropenia, 1 appendicitis, 1 myositis, 1 herpes zoster, and 1 cerebral abscess. Two patients died, one due to multifocal leukoencephalopathy and the other due to hemophagocytic syndrome. Infectious episodes grade 3&4 were observed in 19.5% of cycles with neutropenia 3&4, but in only 3% of cycles with neutropenia inferior to grade 3 (p<0.001). In contrast, no relationship was observed between infectious events and the presence of low levels of immunoglobulins or diminished CD4+ T lymphocyte counts. After rituximab maintenance, 40.6% of patients were in MRD-negative CR, 40.6% in CR, 7.9% in PR, and 10.9% failed to treatment. Failures were due to disease progression (two patients), severe neutropenia (three patients), infectious toxicity (one patient) and death (one patient). Among 35 patients in MRD-negative CR after R-FCM induction, 22 maintained the MRD-negative status at the end of maintenance treatment, 9 (25.7%) switched from MRD-negative to MRD-positive, and 4 failed to treatment ([Table 1][2]). Median time to conversion from negative to positive MRD was 45.4 months, significantly longer than that observed in patients treated with FCM only (45.4 vs. 16.4 months; p=0.011) (Bosch et al. Clin Can Res 14:155–161,2008) ([Figure 1][3]). Moreover, among 21 patients that achieved MRD-positive CR with the initial R-FCM treatment, 2 (9.5%) became MRD-negative upon rituximab maintenance, 17(81%) continued in MRD-positive CR, 2 achieved PR, and 2 failed to maintenance therapy. Among the 8 patients in PR, 4 patients achieved CR (2 MRD-negative and 2 MRD-positive), 3 patients continued in PR, and one patient progressed (Table I). Three-year progression-free survival was 94% (95% CI 88–100%). Compared to the FCM series, maintenance with rituximab significantly prolonged the time to next treatment in patients that after the initial treatment with R-FCM were in MRD-positive CR (44.1 vs. 54.5 months, p=0.049) or PR (6.5 vs. 54.4 months, p=0.001). In conclusion, treatment maintenance with rituximab after R-FCM in patients with CLL is feasible and might improve patients' outcome, particularly those who do not attain a MRD-negative CR after the initial, upfront therapy. However, its toxicity is not negligible. Further, ongoing studies should help to clarify the role of maintenance therapy with rituximab in the management of patients with CLL. View this table: ![Figure][4] Disclosures: Bosch: Hoffman La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Rituximab is currently not approved as maintenance therapy for patients with chronic lymphocytic leukemia. [1]: #fn-2 [2]: #T1 [3]: #F1 [4]: pending:yes

Smoldering Multiple Myeloma (SMM) at High-Risk of Progression to Symptomatic Disease: A Phase III, Randomized, Multicenter Trial Based On Lenalidomide-Dexamethasone (Len-Dex) as Induction Therapy Followed by Maintenance Therapy with Len Alone Vs No Treatment

AbstractAbstract 1935Smoldering Multiple Myeloma (SMM) is an asymptomatic proliferative disorder of plasma cells (PCs) defined by a serum monoclonal component (MC) of 30 g/L or higher and/or 10% or more plasma cells in the bone marrow (BM), but no evidence of end-organ damage. There are several risk factors predicting high-risk of progression to symptomatic disease (>50% at 2 years): >10% of PCs in BM, serum MC >30g/L, >95% aberrant PCs by immunophenotyping, or abnormal free-light chains. Standard of care of SMM is close follow-up without treatment until progression disease. Several trials have evaluated the role of early treatment with convencional agents (melphalan), bisphosphonates and novel agents (thalidomide, anti-IL1a), with no clear benefit, but they didn't focus on high-risk patients.In this phase III trial, SMM patients at high-risk of progression were randomized to receive Len-dex as induction followed by Len alone as maintenance vs no treatment in order to evaluate whether the early treatment prolongs the time to progresioÃŒn (TTP) to symptomatic disease. The high risk population was defined by the presence of both >PC 10% and MC >30g/L or if only one criterion was present, patients must have a proportion of aberrants PCs within the total PCsBM compartment by immunophenotyping of 95% plus immunoparesis.Len-dex arm received an induction treatment consisting on nine four-weeks cycles of lenalidomide at dose of 25 mg daily on days 1–21 plus dexamethasone at dose of 20 mg daily on days 1–4 and 12–15 (total dose: 160mg), followed by maintenance until progression disease with Lenalidomide at dose of 10 mg on days 1–21 every two months (ammended in May 2010 into monthly).The 124 planned patients were recruited between October 2006 and June 2010, and 118 were evaluables (three in Len-dex and three in therapeutic abstention arm didn't meet inclusion criteria). This second interim analysis was planned when all patients were recruited.According to baseline characteristics, both groups were well balanced. On an ITT analysis (n=57), based on IMWG criteria, the overall response rate during induction therapy was 75%, including 51% PR, 12% VGPR, 5% CR and 7% sCR. If we select the group of 33 patients who completed the nine induction cycles, the ORR was 91%, including 15% VGPR, 9% CR and 9% sCR. After a median of 8 cycles of maintenance therapy (1-15), the sCR increased to 16%.After a median follow-up of 16 months (range:1-33), four patients progressed to symptomatic disease in the Len-dex arm: two of them during maintenance therapy after 24 and 28 months from inclusion and the other two progressed 3 and 8 months after early discontinuation of the trial due to personal reasons. In addition, nine patients have developed biological progression during maintenance, but in all but one of these, Len has been able to control the disease without CRAB symptoms (median of 9·5 months (1-18)). In the therapeutic abstention arm, 21 out of 61 patients progressed to active MM. The estimated hazard ratio was 6·7 (95%CI= 2·3-19·9), corresponding to a median TTP from inclusion of 25 months for the not treatment arm vs median not reached in the treatment arm (p<0.0001). It should be noted that 10 out of these 21 patients developed bone lesions as a symptom of active MM. Deaths in the Len-dex and no treatment arms were 1 and 2, respectively (p=0·6).As far as toxicity is concerned, during induction therapy, no G4 adverse events (AEs) were reported with Len-dex; 1 pt developed G3 anemia, 4 patients G3 asthenia 2 patients G3 diarrhea and 1 patient G3 skin rash; 3 patients developped G2 DVT. During maintenance, no G4 AEs were reported and only 1 patient developed G3 infection.In conclusion, this second interim analysis shows that in high-risk SMM patients, delayed treatment resulted in early progression to symptomatic disease (median 25 months), while Len-dex as induction followed by Len as maintenance significantly prolonged the TTP (HR: 6·7), with excelent tolerability; moreover, biological progressions occurring under maintenance have remained controlled over a prolonged period of time. Disclosures:Mateos:Celgene: Honoraria. Off Label Use: Lenalidomide is not approved for the treatment of smoldering multiple myeloma. De La Rubia:Celgene: Honoraria. Rosiñol:Celgene: Honoraria. Lahuerta:Celgene: Honoraria. Palomera:Celgene: Honoraria. Oriol:Celgene: Honoraria. Garcia-Laraña:Celgene: Honoraria. Hernández:Celgene: Honoraria. Leal-da-Costa:Celgene: Honoraria. Alegre:Celgene: Honoraria. Quintana:Celgene: Employment. Baquero:Celgene: Employment. García:Celgene: Honoraria. San Miguel:Celgene: Honoraria.

A nonradiation-containing, intermediate-dose methotrexate regimen for elderly patients with primary central nervous system lymphoma

To assess the efficacy, acute toxicity, and delayed neurotoxicity of intermediate-dose methotrexate (MTX)-containing chemotherapy without whole-brain radiotherapy in the treatment of elderly patients with primary central nervous system lymphoma (PCNSL), we conducted a retrospective analysis of elderly patients (N = 17; median age 67) with newly diagnosed PCNSL who were treated with chemotherapy alone at Tsukuba University Hospital from January 2005 to December 2009. Induction therapy consisted of intravenous intermediate-dose MTX (1 g/m²), ranimustine, procarbazine, methylprednisolone, and intrathecal MTX and cytarabine. Patients who achieved complete response (CR) or partial response (PR) received 5 cycles of maintenance therapy every 6 weeks. All patients in this study achieved CR or PR and received maintenance therapy. Overall survival (OS) and progression-free survival (PFS) were 100 and 80% at 1 year, and 61 and 43% at 2 years, respectively. The median OS and PFS were 36 and 20 months, respectively. Delayed neurotoxicity did not develop in any patient before lymphoma progression. In terms of response rate, OS, and PFS, the nonradiation-containing, intermediate-dose MTX-containing protocol used in elderly Japanese patients was comparable to previous protocols that consisted of more intensive chemotherapy. Acute and delayed toxicities were manageable and quality of life was maintained until progression.

Long-Term Follow-Up of Patients With Follicular Lymphoma Receiving Single-Agent Rituximab at Two Different Schedules in Trial SAKK 35/98

We report the long-term results of a randomized clinical trial comparing induction therapy with once per week for 4 weeks single-agent rituximab alone versus induction followed by 4 cycles of maintenance therapy every 2 months in patients with follicular lymphoma. Patients (prior chemotherapy 138; chemotherapy-naive 64) received single-agent rituximab and if nonprogressive, were randomly assigned to no further treatment (observation) or four additional doses of rituximab given at 2-month intervals (prolonged exposure). At a median follow-up of 9.5 years and with all living patients having been observed for at least 5 years, the median event-free survival (EFS) was 13 months for the observation and 24 months for the prolonged exposure arm (P < .001). In the observation arm, patients without events at 8 years were 5%, while in the prolonged exposure arm they were 27%. Of previously untreated patients receiving prolonged treatment after responding to rituximab induction, at 8 years 45% were still without event. The only favorable prognostic factor for EFS in a multivariate Cox regression was the prolonged rituximab schedule (hazard ratio, 0.59; 95% CI, 0.39 to 0.88; P = .009), whereas being chemotherapy naive, presenting with stage lower than IV, and showing a VV phenotype at position 158 of the Fc-gamma RIIIA receptor were not of independent prognostic value. No long-term toxicity potentially due to rituximab was observed. An important proportion of patients experienced long-term remission after prolonged exposure to rituximab, particularly if they had no prior treatment and responded to rituximab induction.