Sustained Complete Response Research Articles

Chimeric Antigen Receptor T-Cell Therapy for the Community Oncologist.

: The field of cancer immunotherapy has rapidly progressed in the past decade as several therapeutic modalities have entered into the clinic. One such immunotherapy that has shown promise in the treatment of cancer is the use of chimeric antigen receptor (CAR)-modified T lymphocytes. CARs are engineered receptors constructed from antigen recognition regions of antibodies fused to T-cell signaling and costimulatory domains that can be used to reprogram a patient's T cells to specifically target tumor cells. CAR T-cell therapy has demonstrated sustained complete responses for some patients with advanced leukemia, and a number of CAR therapies are being evaluated in clinical studies. CAR T-cell therapy-associated toxicities, including cytokine release syndrome, macrophage activation syndrome, and tumor lysis syndrome, have been observed and effectively managed in the clinic. In patients with significant clinical responses, sustained B-cell aplasia has also been observed and is a marker of CAR T-cell persistence that might provide long-term disease control. Education on CAR T-cell therapy efficacy and safety management is critical for clinicians and patients who are considering this novel type of treatment. In the present report, the current landscape of CAR T-cell therapy, the effective management of patients undergoing treatment, and which patients are the most suitable candidates for current trials are discussed. The present report describes the current status of chimeric antigen receptor (CAR) T lymphocytes as an immunotherapy for patients with relapsed or refractory B-cell malignancies. CAR T cells targeting CD19, a protein expressed on many B-cell malignancies, typically induce high complete response rates in patients with B-cell leukemia or lymphoma who have very limited therapeutic options. Recent clinical trial results of CD19 CAR T-cell therapies and the management of CAR T-cell-associated adverse events are discussed. The present report will therefore inform physicians regarding the efficacy and safety of CAR T cells as a therapy for B-cell malignancies.

SAT-097 - Targeted Proteomics Predicts Sustained Complete Response after Transarterial Chemoembolization in Patients with Hepatocellular Carcinoma

SAT-097 - Targeted Proteomics Predicts Sustained Complete Response after Transarterial Chemoembolization in Patients with Hepatocellular Carcinoma

Steroid-refractory immune thrombocytopenia in the era of the new thrombomimetic drugs: is there still a role for rituximab?

TO THE EDITOR: Although corticosteroids and splenectomy represents the main therapeutic strategies [1,2] for immune thrombocytopenia (ITP), some steroid-refractory patients may be unsuitable for the surgical procedure and therefore require alternative treatment options currently available, such as rituximab [2,3] and thrombomimetic drugs [4,5]. Although rituximab is usually used in refractory ITP patients who have failed multiple previous treatments [3], its role in the era of thrombomimetic drugs represents an open question. Herein, we would like to provide our perspective on this topic in the light of our clinical experience, reporting indications to rituximab in a small series of consecutive steroid–refractory/relapsed ITP patients treated with rituximab. There were seven patients (4 male) with a median age of 38 (19-43) years. Rituximab (4 wk infusions of 375 mg/m2) was given after 50 (6–84) months from the date of ITP diagnosis. One patient suffered from active bleeding requiring platelet transfusions and was refractory to all measures, including thrombomimetic agents (eltrombopag and then romiplostim); he achieved a complete response (CR) with rituximab and was soon after splenectomized, having taken into account the high risk of recurrence and his severe bleeding tendency. Splenectomy was offered to four other patients who refused; in the remaining two patients, splenectomy as well as thrombomimetic agents were not indicated given suspected underlying autoimmune disorders and thrombophilic states. All patients who received rituximab achieved a fast response; indeed, a significant increase in platelet count was recorded early during the course of treatment: one week after the first rituximab infusion in five and after two weeks in the remaining two patients respectively. All patients maintained a sustained CR; six did not necessitate further therapy whereas one was splenectomized soon after the response to rituximab. In all patients, CR was durable and persisted after a median follow-up of 19 months (range, 6-64). No patients relapsed. Based on these findings, rituximab therapy allowed, in our experience, for long-lasting remission in patients with relapsed or refractory ITP, with a good safety profile. All patients but one, who successfully received rituximab as a bridge to splenectomy, refused or presented contraindications for the surgical procedure. Although thrombopoietin agonists, such as eltrombopag or romiplostim, in light of their high efficacy, have substantially changed the clinical scenario and the management of steroid refractory ITP [4,5], this treatment option requires prolonged administration, namely for the remainder of one's life and without a predictable suspension of therapy. Indeed, the option of a potentially life-long treatment with thrombopoietin agonists was offered to patients who refused splenectomy after a thorough explanation of the expected benefits and possible disadvantages from the therapy. The long-lasting and dependent therapy, virtually to be administered for life, was the main reason patients sought out an alternative treatment; they wanted to induce a prolonged remission of their disease without needing to depend on the therapy for life. This concern, in the setting of patients who refuse or are unsuitable for splenectomy, can allow them to find a therapy the administration of which can be predictable and carried out in limited time. This includes rituximab, the role of which is yet to be defined for selected indications even in the era of the new thrombomimetic medications.

Addition of n-butyl cyanoacrylate to classic transarterial chemoembolization may improve the radiological response in patients with hepatocellular carcinoma

OBJECTIVE:Transarterial chemoembolization is the treatment of choice for intermediate-stage hepatocellular carcinoma. However, there are no clear data supporting transarterial chemoembolization vs. transarterial embolization or regarding the best chemotherapeutic agent, which may suggest a preponderant role of ischemia over chemotherapeutic action. This study sought to evaluate the radiological response and outcome of transarterial chemoembolization modified by n-butyl cyanoacrylate addition compared to conventional transarterial chemoembolization in hepatocellular carcinoma patients.MATERIALS AND METHODS:A retrospective review identified forty-seven patients who underwent modified chemoembolization and thirty-three who underwent conventional chemoembolization between June 2006 and December 2011. The radiological response was reassessed using the modified Response Evaluation Criteria in Solid Tumors. The sustained complete response, time to progression and overall survival rates were also analyzed.RESULTS:Complete response rates were significantly higher in patients who had undergone modified chemoembolization compared to those who had undergone conventional treatment (61.7% and 24.3%, respectively; p<0.001). The rate of sustained complete response was significantly higher in the modified chemoembolization group compared to the conventional chemoembolization group (median of 236 and 37 days, respectively; p<0.001). Time to progression was significantly higher in the modified chemoembolization group compared to the conventional chemoembolization group (median of 424 and 201 days, respectively; p=0.042). Overall survival rates revealed no difference between patients who received modified chemoembolization and conventional chemoembolization (median of 483 and 399 days, respectively; p=0.316).CONCLUSION:Transarterial chemoembolization modified by n-butyl cyanoacrylate addition was superior to conventional transarterial chemoembolization in terms of the radiological response in the first imaging control. Although the sustained complete response and time to progression rates were higher for the modified chemoembolization group, no differences in overall survival rates were observed.

State-of-the-art management of CML in 2015 and future prospects

The ABL tyrosine kinase inhibitor (TKI) imatinib mesylate has dramatically changed the treatment of chronic myeloid leukemia (CML). However, resistance and intolerance have frequently been reported, particularly in patients with advanced-stage disease. There are several mechanisms underlying imatinib resistance. Notably, point mutations within the ABL kinase domain are the most critical cause of imatinib resistance. It has recently been recognized that adherence to ABL TKIs is very important for resistance. Four second-generation ATP competitive ABL TKIs, i.e., dasatinib, nilotinib, bosutinib and bafetinib, have been developed. The three TKIs other than bafetinib have been approved for CML in Japan. Although bosutinib has not been approved as a first line therapy, dasatinib and nilotinib demonstrated higher efficacy than imatinib for previously untreated CML in the chronic phase. Despite promising clinical results, the frequently observed mutant T315I is not effectively targeted by any of the second-generation ABL TKIs. Thus, a third-generation ABL TKI, ponatinib, was developed to inhibit all mutated BCR-ABL and showed clinical efficacy in CML cells harboring T315I. CML treatment is progressing rapidly and further advancements are highly anticipated. Moreover, it was recently reported that some portion of CML patients who achieved a sustained complete molecular response have been able to stop taking TKI agents.

How Should a Multi-disciplinary Team (MDT) Approach the Issue of Non-Operative Management in Rectal Cancer?

A sustained clinical complete response (CCR) after preoperative chemoradiation (CRT) is observed in 10–20 % of patients with locally advanced rectal cancer (LARC). A selective non-operative management with close surveillance is increasingly being advocated for patients achieving a CCR—on the assumption that outcomes compare favourably with patients subjected to radical surgery (usually requiring a permanent stoma). The aim of this present opinion piece was to capture individual views of an MDT and elicit common themes regarding the question “How should a multi-disciplinary team (MDT) approach the issue of non-operative management in rectal cancer?” A vignette of a real patient was discussed, and all members explained their own perspective in the context of the vignette. Several common themes emerged. Long-term prospective observational studies and randomized studies with more uniform inclusion criteria are required to evaluate the risk-benefit of the standard surgical approach compared against a non-operative approach.

Abstract 297: Immunotherapy with a CD40L/4-1BBL double-armed oncolytic adenovirus drives Th1 immunity and control tumor progression in a pancreas cancer model

Abstract We hypothesized that an immunostimulatory oncolytic virus (LOAd703) is a potent inducer of anti-tumor immunity and tested its biological functions in models of pancreas cancer. LOAd703 is a double-armed oncolytic adenovirus that introduces the simultaneous expression of a trimerized membrane-bound CD40L and 4-1BBL locally in the tumor aiming to induce potent Th1-mediated anti-tumor immunity. By utilizing an oncolytic adenovirus serotype 5/35 for gene transfer, virally induced tumor cell oncolysis will provide a broad release of antigens at the site of immune activation. Transgene expression is driven by a separate promoter to allow for efficient expression in both tumor cells and tumor stroma while virus replication is restricted to tumor cells by E1A delta24 deletion. CD40 ligand is a potent stimulator of myeloid cells including dendritic cells (DCs) that in turn induce robust T cell responses. CD40L can also reduce the levels of myeloid suppressor cells and M2 macrophages as well as enhancing T cell infiltration into tumors. Further, CD40-mediated signaling combined with TLR stimuli (such as adenovirus) induces intense Th1 immunity. 4-1BBL is known to provide expansion and survival signaling to pre-activated T- and NK cells. Pancreatic cancer cell lines and healthy exocrine pancreas cells were transduced with LOAd703 and it efficiently killed tumor cells while normal cells remained intact as evaluated by an MTS assay. CD40L and 4-1BBL were highly expressed by the transduced tumor cells as detected by flow cytometry. Cell lysis by LOAd703 was equally efficient as a similar oncolytic virus without transgenes demonstrating that the double transgene expression did not interfere with viral replication. Repeated (6x) peritumoral injections of LOAd703 in a xenograft Nu/Nu/Panc01 model showed efficient tumor cell growth control and sustained complete responses. The effect could be further enhanced by gemcitabine in both xenograft mice and in a syngeneic immunocompetent C57BL/6/Panc02 model. Transduction of human monocyte-derived immature DCs resulted in a strong CD40L and 4-1BBL expression without lysis of the cells. Instead, the transduced DCs matured as shown by high CD83 and IL12 expression. The addition of 4-1BBL significantly enhanced DC maturation compared to a virus containing only CD40L, or no transgenes, by expressing higher levels of CD70, IL12, TNFa, IFNg and IL21. Further, LOAd703-transduced DCs pulsed with pp65 CMV peptides potently expanded antigen-specific T cells as well as NK cells. In conclusion, LOAd703 is a novel, double-armed immunostimulatory oncolytic gene therapy that initiates robust Th1 immunity, and eradicates pancreatic cancer in experimental models. A clinical trial using LOAd703 for pancreatic cancer is underway. Citation Format: Emma Svensson, Ioanna Milenova, Rafael Moreno, Ramon Alemany, Angelica Loskog. Immunotherapy with a CD40L/4-1BBL double-armed oncolytic adenovirus drives Th1 immunity and control tumor progression in a pancreas cancer model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 297. doi:10.1158/1538-7445.AM2015-297

Abstract 1619: The next-generation ALK inhibitor PF-06463922 overcomes primary resistance to crizotinib in neuroblastoma

Abstract Neuroblastomas (NBs) harboring activating point mutations in the kinase domain of anaplastic lymphoma kinase (ALK) are differentially sensitive to ALK inhibition by crizotinib (Bresler et al. 2011). The F1174L and F1245C amino acid substitutions, which comprise 38.5% (mycancergenome.org) of ALK aberrations in NB, also confer intrinsic resistance to crizotinib and present a significant obstacle in the clinic. Therefore, our goal has been to identify a next-generation ALK inhibitor with improved selectivity and potency to target these resistant mutants effectively. We demonstrate here that PF-06463922 (Pfizer), an ATP-competitive, macrocyclic ALK/ROS1 inhibitor, overcomes crizotinib resistance of these ALK variants in NB, and exerts unprecedented activity as a single agent against the F1174L and F1245C ALK-mutated tumors. At a tenfold lower dose (10 mg/kg) than typically used for crizotinib (100 mg/kg), PF-06463922 induces complete tumor regression in patient-derived (COG-N-426x, F1245C ALK-mutated) and cell line-derived (SY5Y, F1174L ALK-mutated) xenograft mouse models. Whereas crizotinib-treated mice in both models experience rapid tumor growth on therapy, PF-06463922-treated mice showed sustained complete responses for several weeks even after treatment was discontinued. Cell-based and biochemical analyses indicate that the superior activity of PF-06463922 is a function of both higher potency and a broader spectrum of effectiveness across mutants. ATP levels were measured in ten NB cell lines upon treatment with PF-06463922 and crizotinib; at 120 hours post-treatment, PF-06463922 is 26-38 times more effective at inducing growth inhibition in cells with primary resistance than crizotinib. These in vitro and in vivo results are corroborated by our biochemical experiments. In comparative kinase inhibition studies of several next-generation ALK inhibitors, PF-06463922 was most effective against frequently observed ALK variants accounting for approximately 75% of neuroblastoma samples, including those with F1174L mutations. In vitro, PF-06463922 showed at least 3-4 fold higher potency than crizotinib in peptide phosphorylation assays, and its superior inhibition was consistently observed in cellular analysis of transforming ability. Further investigation is necessary to elucidate PF-06463922's mechanism of action and reveal how it induces apoptotic signaling networks without abrogating phospho-ALK. Taken together, these results support the argument that a modified ALK inhibitor may improve outcomes for patients with primary resistance to crizotinib and provide the preclinical basis from which to design a clinical trial for PF-06463922 for the treatment of ALK-mutated NBs. Citation Format: Nicole Infarinato, Jin Park, Renata Sano, Kateryna Krytska, Hannah Ryles, Helen Zou, Nathan Lee, Tod Smeal, Mark A. Lemmon, Yael P. Mosse. The next-generation ALK inhibitor PF-06463922 overcomes primary resistance to crizotinib in neuroblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1619. doi:10.1158/1538-7445.AM2015-1619

Sustained Complete Response to Cytotoxic Therapy and the PARP Inhibitor Veliparib in Metastatic Castration-Resistant Prostate Cancer - A Case Report.

Solid tumors harboring BRCA1 or BRCA2 mutations have been shown to respond to PARP inhibitors. These responses are partial and transient. In this case report, we describe an 82-year-old male with poorly differentiated prostate cancer with metastases to the lung, liver, abdomen, and bowel. Molecular testing demonstrated alterations in BRCA2, ERG, and TP53. Based on this result, he was enrolled in a therapeutic trial and received carboplatin, gemcitabine, and veliparib, to which he had a partial response. He continued to respond while on veliparib maintenance alone, and after 38 cycles he had a sustained complete response. A sustained complete response to PARP inhibitor-based therapy has not previously been described for prostate cancer. This case suggests that cytotoxic therapy in combination with PARP inhibitors may yield exceptional responses, and molecular studies may help guide patient selection for these therapies.

Results of laparoscopic radiofrequency ablation for HCC. Could the location of the tumour influence a complete response to treatment? A single European centre experience

IntroductionIn selected patients, radiofrequency ablation (RFA) is a well-established treatment for hepatocellular carcinoma (HCC). However, subcapsular or lesions close to adjacent viscera preclude a percutaneous approach. In this setting laparoscopic-RFA (LRFA) is a potential alternative. The aim of this study was to analyse the safety and feasibility of LRFA in patients with HCC. Patients and MethodsRetrospective study of patients with HCC meeting strict inclusion criteria who underwent LRFA at a single Institution from December 2000 to March 2013. ResultsForty-one patients underwent 42 LRFA of 51 nodules. The median size of the nodule was 2.5 (range 1.2–4.7) cm. Thirty-one tumours were subcapsular and 17 located near the gallbladder. Major complications occurred in 17 patients. The initial complete response (ICR) rate was 94% and was lower among tumours located adjacent to the gallbladder. At the end of the follow-up period, the sustained complete response (SCR) rate was 70% and was lower in tumours adjacent to the gallbladder while increased for subcapsular tumours. The 1-, 3- and 5-year overall survival rate was 92.6%, 64.5% and 43%, respectively. ConclusionLRFA of HCC is safe, feasible and achieves excellent results in selected patients. LRFA should be the first-line technique for subcapsular lesions as it minimizes the risk of tumoural seeding and improves ICR. Proximity to gallbladder interferes in treatment efficacy (lower rate of ICR and lower rate of SCR).

Performance-enhancing drugs: design and production of redirected chimeric antigen receptor (CAR) T cells.

Performance enhancement of the immune system can now be generated through ex vivo gene modification of T cells in order to redirect native specificity to target tumor antigens. This approach combines the specificity of antibody therapy, the expanded response of cellular therapy and the memory activity of vaccine therapy. Recent clinical trials of chimeric antigen receptor (CAR) T cells directed toward CD19 as a stand-alone therapy have shown sustained complete responses in patients with acute lymphoblastic leukemia and chronic lymphocytic leukemia. As these drug products are individually derived from a patient's own cells, a different manufacturing approach is required for this kind of personalized therapy compared with conventional drugs. Key steps in the CAR T-cell manufacturing process include the selection and activation of isolated T cells, transduction of T cells to express CARs, ex vivo expansion of modified T cells and cryopreservation in infusible media. In this review, the steps involved in isolating, genetically modifying and scaling-out the CAR T cells for use in a clinical setting are described in the context of in-process and release testing and regulatory standards.

Single-Fraction Radiotherapy for CD30(+) Lymphoproliferative Disorders.

Objectives. CD30+ lymphoproliferative disorder is a rare variant of cutaneous T-cell lymphoma. Sustained complete response following first-line treatments is rare. This retrospective review evaluates the response of refractory or recurrent lesions to palliative radiation therapy. Methods. The records of 6 patients with 12 lesions, treated with radiation therapy, were reviewed. All patients received previous first-line treatments. Patients with clinical and pathological evidence of symptomatic CD30+ lymphoproliferative disorder, with no history of other cutaneous T-cell lymphoma variants, and with no prior radiation therapy to the index site were included. Results. The median age of patients was 50.5 years (range, 15–83 years). Median size of the treated lesions was 2.5 cm (range, 2–7 cm). Four sites were treated with a single fraction of 750–800 cGy (n = 3) and 8 sites were treated with 4000–4500 cGy in 200–250 cGy fractions (n = 3). Radiation therapy was administered with electrons and bolus. Median follow-up was 113 months (range, 16–147 months). For all sites, there was 100% complete response with acute grade 1-2 dermatitis. Conclusions. For recurrent and symptomatic radiation-naïve CD30+ lymphoproliferative disorder lesions, palliative radiation therapy shows excellent response. A single fraction of 750–800 cGy is as effective as a multifractionated course and more convenient.

MTOR Inhibitors in Cancer: What Can We Learn from Exceptional Responses?

mTOR Inhibitors in Cancer: What Can We Learn from Exceptional Responses?

A retrospective study to evaluate single agent methotrexate treatment in low risk gestational choriocarcinoma in the United Kingdom

ObjectiveTo determine whether single agent chemotherapy with intramuscular methotrexate 50mg administered on days 1, 3, 5, and 7 and oral folinic acid 15mg administered on days 2, 4, 6, and 8 in 2 weekly cycles (IM MTX/FA) is an effective treatment regimen for patients with low risk gestational choriocarcinoma. MethodElectronic databases were searched to identify patients with gestational choriocarcinoma at the Sheffield and Charing Cross supra-regional trophoblastic disease centres from January 2000 to December 2011. Clinical notes of low risk patients with FIGO score 0–6 were retrospectively reviewed to assess treatment outcomes and subsequent relapse. Results65 patients were identified with low risk choriocarcinoma. Serum hCG levels normalised in 24 patients without the requirement of chemotherapy (19 with histological confirmation, 4 highly suspicious histology and 1 clinical diagnosis). Of 23 patients with histologically confirmed choriocarcinoma, 8 (35%) had a sustained complete response to IM MTX/FA and did not relapse. Both patients with FIGO score 6, and 1 patient with FIGO stage III metastatic disease developed resistance to IM MTX/FA and required further treatment. Despite the development of drug resistance or relapse all patients were successfully salvaged by subsequent treatments. ConclusionsNot all patients with low risk choriocarcinoma that have had primary intervention prior to staging, such as surgical resection or uterine evacuation will require chemotherapy, providing hCG levels continue to decline to normal. Low risk (FIGO 0–5) patients should initially receive IM MTX/FA due to its low toxicity, outpatient administration and reasonable efficacy. Patients with FIGO score 6 or FIGO stage III disease should make an informed choice between IM MTX/FA and combination chemotherapy.

First Results of the Multicenter Total Therapy Gimema LAL 1509 Protocol for De Novo Adult Philadelphia Chromosome Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) Patients

▪Introduction: Ph+ ALL management has changed since the introduction of tyrosine kinase inhibitors (TKI). In the GIMEMA LAL 1509 protocol for adult Ph+ ALL, Dasatinib was administered in combination with steroids as induction treatment, and chemotherapy and/or allogeneic transplantation (HSCT) was given if patients did not reach a sustained complete molecular response (CMR) after induction.Methods: Steroids were administered from day -6 to day 31. Dasatinib (140 mg/day) was given between days 1 and 84. Patients reaching a confirmed CMR (i.e. BCR/ABL to ABL ratio=0) at the end of induction (day +85), continued Dasatinib for 6 additional months. Patients in complete hematologic remission (CHR), but not in CMR, were stratified according to HSCT eligibility: those with a promptly available donor underwent directly a HSCT; if the donor was not readily available, a consolidation cycle with clofarabine and cyclophosphamide was administered. HSCT non-eligible patients received two cycles of clofarabine and cyclophosphamide of 5 and 3 days, respectively. Dasatinib was administered until disease progression. Molecular testing was used to identify the presence of a BCR/ABL transcript, define the fusion protein and quantify BCR/ABL levels at baseline and at follow-up. Mutational screening was performed in relapsed cases.Results: Sixty of the 64 enrolled patients were eligible. Median age was 41.9 years (range: 18.7-59.1), 34 were males and 26 females; the median WBC count was 12.5 x 109/l (range 1.4-178.0); the p190 fusion product was detected in 33 patients, p210 in 18 and p190/p210 in 9. Median follow-up is 17.6 months (range 4.1-31.6). After the steroid pre-phase, 38 patients (63%) had a blast reduction ≥75%. At day 85, 58 patients achieved a CHR (97%) and 2 were non-responders (1 hematologic relapse and 1 disease progression): notably, both had a p210 fusion transcript. A CMR was obtained in 11 patients (18.6%): of these, 72% had a p190 fusion transcript. Overall, 24% of p190+ patients and 11% of p210+ or p190/210+ cases obtained a CMR. As previously reported in other GIMEMA trials, no deaths in induction occurred. Among the CMR patients, only 1 experienced a hematologic relapse and harbored a T315I mutation. Among the 46 non-CMR cases, 17/27 eligible patients underwent a HSCT, while 9 did not; 5 relapses occurred in the non-transplanted group, while 1 was observed in the HSCT group. Of the 19 HSCT non-eligible patients, 14 received the planned therapy: in this group, 2 relapses occurred. At 24 months, the overall survival (OS) is 69.1% (95%CI: 55.3-86.3), with a disease-free survival (DFS) at 18 months of 61.6% (95%CI: 47.6.0-79.8). A better DFS was observed in patients who obtained a CMR at day +85. Dasatinib exerted a rapid blast clearance, that was highly significant (p<0.0001) between the onset and day +22, and between day +22 and +45; a significantly more rapid clearance (p=0.0005, p=0.0013 and p=0.001 at days +22, +45 and +57, respectively) was observed in patients who achieved a CMR at day +85, underlining the heterogeneous sensitivity of Ph+ ALL blasts to TKI. Importantly, a significantly greater clearance was observed in p190 (n=33) vs p190/210 and p210 (n=27) cases (p=0.0008, p=0.0032, p=0.0031, p=0.0016, p=0.007 at diagnosis, days +22, +45, +57, and +85, respectively). Mutational screening was performed in 6/12 patients who relapsed and mutations were detected in 5: 3 T315I and 2 V299L, of which 1 with a concomitant F317L. Overall, 12 relapses (5 in the p190 and 7 in the p210 subgroup) and 7 deaths in CR occurred, 5 of which in allografted patients. The median time to relapse was 6.7 months (range 0.3-22.5).Conclusions: We confirm that a chemo-free induction approach for adult Ph+ ALL patients results in a very high CHR rate (97%), with no deaths in induction. In this Dasatinib-based protocol, a sustained CMR is achieved after induction in >18% of cases, suggesting that a subset of patients may be spared further intensive treatment. We witnessed an increase in p190/p210-p210+ cases compared to earlier studies; these patients showed a worse prognosis as underlined by a lower susceptibility to TKI, lower blast clearance and greater incidence of relapses (58%). At this first analysis, OS and DFS are at least comparable to those obtained in previous GIMEMA studies, despite the higher incidence of p210+ patients – which accounted for 45% of cases in this cohort – and which may require an intensified approach. DisclosuresMartinelli:Pfizer: Consultancy; BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; ARIAD: Consultancy.

Persistence of Abnormally-Spliced, Functionally-Dead BCR-ABL Variants Is a Critical Obstacle to Achieve Sustained Complete Molecular Response in CML Patients: Results of a Quantitative, Highly-Sensitive, Deep Sequencing Study

Background: Tyrosine kinase inhibitors (TKI) have dramatically changed the treatment algorithm of chronic myeloid leukemia (CML). Despite improved outcomes in the TKI era, mutations in the BCR-ABL kinase domain are one of the major mechanisms of resistance to TKIs. In addition, recent studies have suggested that abnormally-spliced (AS) BCR-ABL transcript variants, such as retention of 35bp intronic nucleotides at Exon8/9 splice junction (BCR-ABL Ins 35bp) is one of the main obstacles for patients to exhibit "optimal response" to TKI (Gaillard JB, et al. Mol Cancer Ther 2010; T O’Hare, et al. Blood 2011). These BCR-ABL variants have a stop codon in kinase domain residues, resulting in generation of "function dead" BCR-ABL. We hypothesized that emergence of such functionally-dead BCR-ABL variants should render such CML clones insensitive to TKI, contributing to persistence of CML clone, even at molecular remission phases. Here, by combining a long-range nested PCR-amplification method and an analysis by high-throughput next generation sequencer (NGS), we have established a highly-sensitive assay system to track minimal amounts of AS BCR-ABL transcript variants.Methods: We analyzed 294 samples from 62 CML patients. Twenty-six patients were treated with Imatinib and Dasatinib, 13 with Imatinib alone, 9 with Dasatinib alone, 6 with Nilotinib alone, 6 with Imatinib and Nilotinib, and 2 with Dasatinib and Nilotinib. cDNA was synthesized from extracted RNA samples, and BCR-ABL was amplified by long-range nested PCR method. Splicing forms of BCR-ABL were then deep-sequenced by using HiSeq 1500 (illumina). Samples capable of achieving>10,000 read counts on ABL-1 Exon 8 were regarded as reliable to enroll into further statistical analysis.Results: In all 7 patients analyzed at diagnosis, CML cells have wild-type (WT) BCR-ABL but also have extremely small amount of AS BCR-ABL transcript variants. After TKI treatment, mainly two type of splicing variants became evident; the BCR-ABL Ins 35bp and Intron8-retained BCR-ABL that possesses inappropriately spliced Intron8 of ABL-1. In both cases, such transcripts fail to form functional BCR-ABL. As shown in Figure 1, along with TKIs treatment for 6 months, total amount of BCR-ABL quickly decreased, whereas percentages of AS BCR-ABL variants (BCR-ABL Ins 35bp and Intron8-retained BCR-ABL) gradually increased, suggesting that clones possessing AS BCR-ABL variants might become dominant by clonal selection through TKI treatment. In 55 patients with deep molecular response under TKI treatment for >1 year, 29 out of 55 (52%) patients achieved MR4.5, whereas the remaining 26 (48%) patients retained MR3.0, failing to achieve MR4.5. In 29 patients who have reached MR4.5, BCR-ABL variants were detected in 11 (38%) patients in any points during treatment. In contrast, within 26 patients who retained only MR3.0, 22 (85%) patients possessed BCR-ABL variants. Thus, emergence of AS BCR-ABL variants are significantly more frequent in patients retaining only MR3.0 (p<0.05). In these patients, BCR-ABL transcript variants were continually detected at several points of analysis. A representative patient who could not achieved MR4.5 is shown in Figure 2. After switching from Imatinib to Dasatinib, total amount of BCR-ABL gradually decreased, while AS BCR-ABL transcript variants did not, resulting in the poor response to Dasatinib.Discussion: Our highly-sensitive quantitation system for AS BCR-ABL variants revealed that the majority of major molecular responders (≥MR3.0) possess BCR-ABL variants, but these are more frequently found in patients failed to achieve MR4.5 (P<0.05). These data strongly suggest that selective persistence of AS BCR-ABL variants is one of the key mechanisms of TKI resistance in major molecular responders. CML clones with kinase-dead BCR-ABL should not be sensitive to TKI, should not be addicted to ABL kinase activity, and should therefore be difficult to be killed by TKI alone. Thus, quantitation of AS BCR-ABL variants might be critical to predict clinical outcomes of CML patients, for example, whether or not they relapse after TKI cessation. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A randomized study of the efficacy and safety of transdermal granisetron in the control of nausea and vomiting induced by moderately emetogenic chemotherapy in Korean patients.

The granisetron transdermal system (GTS) showed non-inferior efficacy to oral granisetron to control chemotherapy-induced nausea and vomiting (CINV) during multiday chemotherapy. We compared the efficacy and safety of GTS with that of intravenous and oral granisetron in Korean patients receiving moderately emetogenic chemotherapy (MEC). A total of 276 patients were randomized into GTS (n = 139, one patch on days 1-4) or control group (n = 137, intravenous on day 1 and oral on days 2-4). The primary endpoint was the percentage of patients achieving complete response (CR) from chemotherapy initiation until 24 h after the final administration. Out of 234 patients (112 in GTS and 122 in control group) included in the per protocol analysis, 97.9 % had gastrointestinal cancer and 76.9 % received 3-day chemotherapy. The GTS showed non-inferior efficacy achieving CR in 75.0 % of the patients; 74.6 % of the patients in the control group achieved CR (95 % confidence interval -10.73 to 11.55 %). The CR rate did not change after subgroup analyses by sex, age, and chemotherapy naivety and analysis per day and overall days of treatment. The GTS group showed sustained CR from day 1 to day 4. Patients' satisfaction, assessed using Functional Living Index-Emesis (FLI-E), showed no difference. Both treatments were well tolerated and safe. The GTS showed non-inferior efficacy to intravenous and oral granisetron. The safety, tolerability, and FLI-E scores of the GTS were comparable to those of control group. The GTS offers a convenient alternative option for relieving CINV in patients receiving MEC.

P-036 YI Clinical and Serological Factors Associated With Response to Infliximab in Chronic Refractory Pouchitis and Pouch Complications

Pouchitis refractory to first-line therapies and pouch complications remains problematic following colectomy and ileal-pouch anal anastomosis (IPAA) for ulcerative colitis (UC). Evidence for infliximab (IFX) use in this setting and factors predicting its success remain limited. Here, we investigated IFX use in refractory pouchitis and clinical and serological variables associated with treatment response. Patients were identified from the Mount Sinai Hospital IBD and Pelvic Pouch Databases, Toronto, Canada. Clinical, endoscopic and serological data were reviewed from 579 individuals who underwent colectomy and IPAA from 2000 to 2014. Patients with chronic refractory pouchitis and Crohn’s Disease- like outcome treated with IFX were included. Pretreatment parameters were measured within 4 weeks of induction and IFX response at a median of 9 (initial) and 48 weeks (sustained) respectively. Complete response was defined as symptomatic and endoscopic resolution with modified Pouchitis Disease Activity Index (mPDAI) score <5. Partial response was defined as improvement in symptoms with reduction in mPDAI >2. Endoscopic mucosal healing, pouch excision, pouch complications and CRP were recorded. Serum was analyzed for antibodies against Saccharomyces cerevisiae (ASCA), OmpC, CBir1 and perinuclear neutrophil cytoplasm (pANCA). Fisher’s exact testing and Kruskal-Wallis detected differences in clinical and serological variables between subgroups. Logistic regression models were applied to estimate odds ratio (OR) and 95% confidence interval (CI) of clinical and serological factors with initial and sustained clinical response as dependent variables. Results were deemed significant if P-value was ≤0.05. Thirty-one patients were included (33% male; age 32.6 ± 2.6 [mean ± SE]). 26% were on combined therapy with immune-modulator. Seventy-four present achieved post-induction response at median 9 weeks (IQR [6.5–13]) (48% complete, with concomitant mucosal healing). At median 48 weeks (IQR [25–71.5]), 62.6% retained response (29.6% complete). There were significant reductions in mPDAI in the entire cohort from a pre-induction score of 8.5 ± 0.3 to 2 ± 3.4 at final follow-up (mean, SE; P < 0.002) and in CRP from 29.48 ± 6.2 mg/L to 5.76 ± 1.6 mg/L (P < 0.001). Age, gender, smoking, pre-pouch disease extent and CRP did not affect response to IFX. Pretreatment mPDAI score did not significantly affect sustained IFX response but higher pretreatment mPDAI scores were negatively associated with early mucosal healing (P = 0.056; OR = 0.5, 95% CI, [0.2–1.010]). Patients with pretreatment mPDAI >10 were less likely to have initial mucosal healing (P = 0.03). Initial mucosal healing was associated with sustained complete response (P < 0.05; [OR] = 13.2; 95% confidence interval [CI], 1.0–165). Presence of ASCA was associated with higher initial mPDAI (P = 0.016), but no difference in treatment response. IFX responders had a lower number of positive antibody titers (2 positive titers versus 3, mean; P < 0.05). Having >2 positive titers was associated with longer term non-response to IFX though not significantly. IFX was effective in the short- and longer term in patients with chronic refractory pouchitis and pouch complications. Mucosal healing after induction is the strongest clinical association with a complete sustained response to IFX in this group and pretreatment mPDAI may help predict this.

Ever-advancing chronic myeloid leukemia treatment

Treatment of chronic myeloid leukemia (CML) has been drastically changed by the emergence of the ABL tyrosine kinase inhibitor (TKI), imatinib mesylate. However, resistance and intolerance have frequently been reported, particularly in patients with advanced-stage disease. Point mutations within the ABL kinase domain that interfere with imatinib binding are the most critical cause of imatinib resistance. To overcome this resistance, four second-generation ATP competitive ABL TKIs, dasatinib, nilotinib, bosutinib and bafetinib, have been developed. Dasatinib and nilotinib also demonstrated higher efficacy than imatinib in previously untreated CML patients in chronic phase. Despite promising clinical results, the frequently observed mutant T315I is not effectively targeted by any of the second-generation ABL TKIs. Thus, a third-generation ABL TKI, ponatinib, was developed to inhibit all mutated BCR-ABL and showed clinical efficacy in CML cells harbouring T315I. CML treatment is rapidly progressing and further evolution is surely expected. Moreover, it was recently reported that some CML patients who achieved sustained complete molecular response could stop TKI. CML may become the first human cancer to be conquered solely with oral medicines.

Allogeneic Hematopoietic Cell Transplantation For Patients With Mycosis Fungoides and Sezary Syndrome: The Experience Of The EBMT Lymphoma Working Party With An Extended Five-Year Follow Up

PurposeIn 2010 the EBMT Lymphoma Working Party reported our experience on allogeneic HCT in patients with mycosis fungoides and SŽzary syndrome (MF/SS) in what remains the largest series on this topic published to date [JCO 2010; 28: 4492-4499]. Despite the encouraging results, the main shortcoming of our initial report was a limited follow up of 36 months; in particular, for a series in which 73% of the cases received a reduced-intensity conditioning prior to HCT. The purpose of this study is to analyze our experience in this setting with an extended follow up, including standard outcomes of non-relapse mortality (NRM), incidence of relapse/progression (R/P), progression-free survival (PFS) and overall survival (OS), as well as to identify factors associated with patient outcome 5 years after allogeneic HCT. Patients and MethodsSixty patients with MF (n=36) and SS (n=24) who received a first allogeneic HCT from matched related (mRD, n=45) or unrelated (mUD, n=15) donors between 1997 and 2007, included in our original series were analyzed: 37 men and 23 women, median age 46.5 years (22-66). Forty-four patients (73%) had TNM stage IV, and 40 (67%) were at advanced disease phase at transplantation, defined as either those on third or later complete response (CR), partial response (PR) or relapse/progression, or those primary refractory to systemic therapy. Forty-four patients (73%) received reduced-intensity (RIC) and only 16 (27%) myeloablative (MAC) conditioning regimens, with 25 (42%) undergoing T-cell depletion (TCD). Extended follow up data was collected from the EBMT Registry and closed in July 2013. ResultsWith an extended median follow up in survivors of 60 months (4–117), allogeneic HCT continues to offer patients with MF/SS an advantageous estimated OS of 66% at 1 year, 54% at 3 years and 48% at 5 years (95% CI: 36% - 64%), and a first PFS of 41% at 1 year, 35% at 3 years and 33% at 5 years (95% CI: 23% - 48%). Disease R/P remains the main complication, with a total of 26 cases (43%) at a median of 3.8 months (1-37) after HCT. While 16 of them died from disease R/P, it is worth noting that at present 10 of these patients (38%) remain alive at last follow up, suggesting that after R/P, patients can be successfully rescued with donor lymphocyte infusions and other lines of therapy. Indeed, at last follow up, a total of 31 patients remain alive, and of these only 2 have active disease, while 29 of them are also in sustained or re-attained CR from their MF/SS. NRM has remained stable at 22% (13 cases; median 52 days from HCT, 8-403) in this analysis. As described in Table 1, the outcome of MF/SS patients 5 years after allogeneic HCT is primarily driven by the type of donor, the intensity of conditioning, and the status of the disease at the time of transplant. In addition, patients with a poor performance status (Karnofsky <70) have a higher risk of NRM, and patients receiving TCD, a higher incidence of disease R/P, none of which translate into a significant impact on OS. ConclusionsOur data with a prolonged patient follow up provides a clearer picture of the value of allogeneic HCT as a therapeutic strategy for high-risk patients with advanced-stage MF/SS. They further suggest the existence of a clinically relevant graft-versus-MF/SS effect that provides prolonged survival with no evidence of disease to patients with advance phase at the time of transplant and even to many of those who relapse/progress after allogeneic HCT. This study identifies as well factors that may influence the overall outcome of these patients at a longer 5-year term after transplant. Disclosures:Dreger:Riemser Pharma : Consultancy, Honoraria, Research Funding.