First-line Salvage Therapy Research Articles

Salvage therapies including retreatment with BCMA-directed approaches after BCMA CAR-T relapses for multiple myeloma

AbstractFor patients with relapsed/refractory multiple myeloma with a relapse after B-cell maturation antigen (BCMA)–directed chimeric antigen receptor T-cell therapy (CAR-T), optimal salvage treatment strategies remain unclear. BCMA-directed CAR-T and bispecific antibodies (BsAbs) are now commercially available, and the outcomes for retreatment with BCMA-directed approaches are not well studied. We performed a retrospective analysis of 68 patients with relapsed disease after BCMA-directed CAR-T to evaluate outcomes and responses to salvage therapies. With a median follow-up of 13.5 months, median overall survival from time of relapse until death was 18 months (95% confidence interval [CI], 13.2 to not reached [NR]). Fifty-eight patients received subsequent myeloma-directed therapies, with a total of 265 lines of therapy (LOTs). The overall response rate for firstline salvage therapy was 41% (95% CI, 28-55). Among all LOTs, high response rates were observed among those receiving another BCMA-directed CAR-T (89%), BCMA-directed BsAbs (60%), CD38-directed combinations (80% when combined with BsAb; 50% when combined with immunomodulatory drugs and/or proteasome inhibitors), and alkylator-combinations (50% overall; 69% with high-dose alkylators). Thirty-four patients received at least 1 line of salvage BCMA-directed therapy; median progression-free survival was 8.3 months (95% CI, 7.9 to NR), 3.6 months (95% CI, 1.4 to NR), and 1 month (95% CI, 0.9 to NR) with median duration of response (DOR) of 8 months, 4.4 months, and 2.8 months for subsequent BCMA-directed CAR-T, BsAb, and belantamab mafadotin, respectively. Retreatment with BCMA-directed CAR-T and BsAbs can be effective salvage options after BCMA-directed CAR-T relapse; however, DORs appear limited, and further studies with new combinations and alternative targets are warranted.

Acute Vertebrobasilar Artery Occlusion with Underlying Atherosclerosis: Balloon Angioplasty Combined with Tirofiban as Initial Salvage Therapy

The optimal rescue endovascular treatment for patients with intracranial atherosclerotic stenosis in acute vertebrobasilar artery occlusion is not well established. We investigated the safety and efficacy of balloon angioplasty combined with tirofiban as the initial rescue strategy in these patients. We retrospectively analyzed the records of 41 patients admitted between January 2014 and September 2022, with vertebrobasilar artery atherosclerotic occlusion. Balloon angioplasty in combination with tirofiban was used as the first-line salvage therapy after the failure of mechanical thrombectomy. The technical success rate, recanalization outcome, procedure-related complications, symptomatic intracranial hemorrhage, and functional outcome at 90days were reviewed. Recanalization with a modified Thrombolysis in Cerebral Infarction grade of 2b-3 was achieved in 38 of the 41 patients (92.7%). Acute stents were deployed in 5 patients who did not achieve successful reperfusion after balloon angioplasty. Six patients (14.6%, 6/41) underwent stent angioplasty in the stable stage for severe residual stenosis detected on follow-up imaging. There was no procedure-related complication. Hemorrhagic transformation was detected on follow-up imaging in 11 patients (26.8%), while no symptomatic intracranial hemorrhage was recorded. Good functional outcome rate was 31.7% (13/41). Balloon angioplasty combined with intravenous tirofiban administration is a safe and effective salvage therapy in patients with acute atherosclerotic occlusion of the vertebrobasilar artery.

Balloon Angioplasty Combined with Tirofiban as a First-Line Rescue Treatment After Failed Mechanical Thrombectomy for Middle Cerebral Artery Occlusion with Underlying Atherosclerosis

The standard rescue modality for patients with intracranial atherosclerotic stenosis after failed mechanical thrombectomy (MT) is not well established. We evaluated the safety and efficacy of balloon dilation in combination with tirofiban as the first-line salvage therapy when MT failed in these patients. We retrospectively analyzed the records of 47 patients admitted between January 2018 and June 2021, with middle cerebral artery atherosclerotic occlusion, who underwent balloon angioplasty in combination with tirofiban as the first-line salvage therapy after the failure of MT. The recanalization outcome, procedure-related complications, symptomatic intracranial hemorrhage, and functional outcome at 90days were reviewed. Recanalization with a modified Thrombolysis in Cerebral Infarction grade of 2b-3 was achieved in 41 (87.2%) of the 47 patients. Acute stents were deployed in another 6 patients who did not achieve successful re-perfusion after balloon angioplasty. Successful recanalization was achieved in 3 of them. One patient (2.1%, 1/47) experienced re-occlusion several days later due to the withdrawal of antiplatelet therapy for parenchymal hematoma. Seven patients (14.9%, 7/47) underwent stent angioplasty in the stable stage (range: 1-2months) because severe residual stenosis was detected on follow-up imaging. There was only one event of periprocedural complication, namely ectopic migration of emboli. The good functional outcome rate was 55.3% (26/47), without the events of symptomatic intracranial hemorrhage and mortality. Balloon angioplasty in combination with tirofiban is safe and effective for middle cerebral artery atherosclerotic occlusion after the failure of MT.

Venetoclax Plus Hypomethylating Agent for the Salvage Treatment of Myeloid Malignancies Relapsing after Hematopoietic Stem Cell Transplantation: A Multicenter Retrospective Study on Behalf of the Zhejiang Cooperative Group for Blood and Marrow Transplantation

ObjectiveHematopoietic stem cell transplantation (HSCT) is one of the most efficient treatments for hematologic malignancies. However, relapse remains the main cause of transplant failure. In myeloid neoplasia, the long-term survival for patients who relapsed after HSCT ranges from 10% to 20%. Conventional chemotherapy and donor lymphocyte infusion (DLI) exhibit limited effect and are accompanied by high risks of infection and graft versus host disease (GVHD). New, less toxic, and more efficient treatment options are urgently needed. Venetoclax (VEN), a selective inhibitor of anti-apoptotic protein Bcl-2, combined with hypomethylating agents (HMAs) was well-tolerated and showed an impressive response rate in elderly patients with AML, both as frontline therapy and for relapse. While in post-transplant relapsed patients, the efficacy of the combination of VEN and HMA (VEN-HMA) still needs to be explored.MethodsBetween July 2018 and May 2021, forty-two patients who experienced post-transplant relapse were retrospectively analyzed in this study. All these patients received at least one cycle of VEN-HMA. The salvage therapy consisted of VEN for 28 consecutive days (100 mg of VEN for the first day and 200 mg for the second day, then increased to the final dose of 400 mg daily or equivalent with azole co-administration). Thirty-nine patients received azacytidine (100mg/m2, d1-7) while the other 3 patients were given decitabine (10mg/m2, d1-5) in combination with VEN.Disease types included acute myeloid leukemia (AML, n=32), myelodysplastic syndrome (MDS, n=7), chronic myelomonocytic leukemia (CMML, n=2) and chronic myeloid leukemia (CML, n=1). 28 (66.7%) patients achieved complete remission before transplantation and 14 (33.3%) patients were transplanted in a non-remission status. Haploidentical-related donor (HID, n=31) was the most common donor type, followed by matched sibling donor (MSD, n=6) and unrelated donor (URD, n=5). Each patient was analyzed for chromosomal and genetic abnormalities either at diagnosis and at post-transplant relapse. Complex/monosomal karyotype was seen in 10 (23.8%) patients. 9 (21.4%) patients had TP53 mutation or deletion and 7 (17.9%) had IDH1/2 mutation. The median time from transplantation to relapse was 329 (range, 30-1584) days, 27 (64.3%) patients had an early relapse (within 1-year post-HSCT). 16 (38.1%) patients developed acute GVHD and 15 (35.7%) developed chronic GVHD before relapse.24 (57.1%) patients received VEN-HMA as first-line salvage therapy, while the other 18 (42.9%) patients received this combination therapy after failure with chemotherapy or DLI. 22 (52.4%) patients had a higher tumor burden (bone marrow blasts >20%) at the initiation of VEN-HMA. In total, 20 (47.6%) patients responded to the VEN-HMA therapy with a reduction in bone marrow blasts. 14 (33.3%) patients fulfilled the criteria of CR/CRi and all of them achieved the best response in the first cycle of VEN-HMA. However, 4 (9.5%) patients even experienced disease progression after VEN-HMA. After a median follow-up time of 84 (18-535) days, patients who achieved CR/CRi experienced a significantly higher overall survival (OS) than those who did not (85.7% vs 14.3%, p <0.0001). In univariate and multivariate analysis, we found that early relapse (HR=4.000, p=0.046) was the only independent risk factor that influenced the CR/CRi rate.ConclusionVEN-HMA is safe and efficacious for patients with myeloid malignancies relapsing after transplantation. Patients relapsing within 1-year post-transplantation may be more likely to benefit from this combination therapy. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Response to blinatumomab or inotuzumab ozogamicin for isolated extramedullary relapse of adult acute lymphoblastic leukemia after allogeneic hematopoietic cell transplantation: a case study.

Isolated extramedullary relapse (EMR) without bone marrow relapse (BMR) after allogeneic hematopoietic cell transplantation (allo-HCT) is a rare condition in patients with acute lymphoblastic leukemia (ALL), and the role of immunotherapeutic agents for these patients remains unclear. We analyzed treatment outcomes of blinatumomab or inotuzumab ozogamicin (INO) as first- or second-line salvage therapy in nine patients with Philadelphia chromosome-negative B-cell precursor ALL presenting with isolated EMR after previous allo-HCT. In seven patients receiving blinatumomab as first-line salvage therapy, 4 (57.1%) achieved complete remission (CR). Among the three patients without remission after blinatumomab, two switched to INO and subsequently showed responses {one CR and one partial response [PR]}, and one switched to multiagent chemotherapy that led to CR. In the two patients receiving first-line salvage therapy with INO, one showed PR and the other achieved CR. Overall, 6 (66.7%) of nine patients achieved CR, and five of them proceeded to allo-HCT in CR. The median overall survival after relapse was 27.8months. In conclusion, both blinatumomab and INO showed good response rates and a safe bridging role to second allo-HCT in patients with isolated EMR. However, clinical differences between isolated EMR and EMR with BMR remain to be elucidated.

Efficacy and Safety of Neostigmine and Decompressive Colonoscopy for Acute Colonic Pseudo-Obstruction: A Single-Center Analysis.

BackgroundAcute colonic pseudo-obstruction (ACPO) is characterized by acute colonic dilation in the absence of anatomical obstruction. Neostigmine is an acetylcholinesterase inhibitor recommended as first-line salvage therapy for uncomplicated ACPO. Decompressive colonoscopy is recommended if neostigmine is contraindicated or unsuccessful. There is a need to better characterize relative efficacy and factors impacting treatment choice. The aim of the study was to examine the use, efficacy, and safety of neostigmine and decompressive colonoscopy in the management of ACPO at a single academic center.MethodsPatients ≥ 18 years of age meeting established criteria for uncomplicated ACPO and with cecal diameter ≥ 10 cm on imaging between 1999 and 2019 were identified. Individuals were categorized as having received supportive care alone or subsequent trials of neostigmine or decompressive colonoscopy. Demographics and pre- and post-intervention data were collected, including indication and contraindication to intervention used, time to intervention, initial response, and adverse events.ResultsIn 46 cases of ACPO (N = 42 patients), all but one individual received initial supportive care. Seven responded to conservative measures alone. Of the patients failing supportive care, 15 cases were initially treated with neostigmine (response rate 86.7%) and 24 initially underwent decompressive colonoscopy (response rate 95.8%) (P = 0.390). One episode of transient bradycardia, resolved with atropine, occurred in the neostigmine group. One patient experienced respiratory instability during colonoscopy.ConclusionsBoth neostigmine and decompressive colonoscopy appear effective for treating uncomplicated ACPO in individuals failing conservative therapy. Adverse events were infrequent in both cohorts. Future prospective studies examining treatment for ACPO should focus on whether either intervention is superior to the other.

Early radiotherapy preserves vision in sporadic optic pathway glioma.

Sporadic optic pathway/hypothalamic gliomas represent a unique entity within pediatric low-grade glioma. Despite favorable survival, location makes treatment difficult and local progression debilitating. This study is a longitudinal assessment of visual acuity (VA) among children treated within the last 2 decades. Clinical characteristics were abstracted for patients treated from 2000 to 2018 at Texas Children's Cancer Center in Houston. Ophthalmologic data taken at 3- to 6-month intervals were examined with age-appropriate VA metrics converted to the LogMAR (logarithm of the minimum angle of resolution) scale. Kaplan-Meier blindness-free survival (BFS) curves, calculated as time-to-bilateral functional blindness (LogMAR ≥0.8 in both eyes), were calculated for patients receiving early radiation therapy (RT; upfront or as first-line salvage treatment) or chemotherapy (CT) and evaluated using the log-rank test. Thirty-eight patients with a median follow-up of 8.5 years (range, 2-17 years) were identified. Median age at diagnosis was 3 years (interquartile range, <1-6 years). Early RT was administered in 11 patients (29%). Twenty-seven patients (71%) were treated primarily with CT, initiated at a median age of 3.5 years (range, <1-11 years). Eight patients in the CT group did eventually require RT secondary to VA loss and following multiple lines of CT. Median age at RT for all patients was 11 years (range, 3-17 years). BFS rates were 81% at 5 years and 60% at 8 years for CT and 100% at 5 and 8 years for early RT (P = .017). In a contemporary cohort, early RT, defined as initial or first-line salvage therapy, was found to have superior BFS for appropriately selected patients with sporadic optic pathway/hypothalamic gliomas. Children with low-grade brain tumors of the optic pathway generally have excellent long-term survival; however, given the location of these tumors, there can commonly be threatened vision if the tumor grows. Although radiation is generally deferred in children on the basis of legitimate concerns regarding the effects on the developing brain, it may represent a vision-preserving therapy for well-selected older patients.

Brentuximab Vedotin Plus Bendamustine for Pediatric Patients with Relapsed/Refractory Hodgkin Lymphoma: A Multi-Institution Retrospective Analysis

Background: Pediatric patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL) are often curable through a combination of salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplant (ASCT). Complete response (CR) to salvage treatment prior to HSCT is associated with superior outcomes, therefore optimal salvage treatments need to be identified. Brentuximab vedotin (BV), an antibody-drug conjugate combining an anti-CD30 murine/human chimeric monoclonal antibody covalently linked by an enzyme cleavable peptide to monomethyl auristatin E, and bendamustine, a fusion hybrid molecule containing the purine analogue fludarabine and the alkylating nitrogen mustard, are novel agents that have demonstrated potency as single-agent therapies for patients with R/R HL. Recently, the combination of BV and bendamustine proved to be highly active in adults with R/R HL. However, safety and efficacy data for pediatric patients are lacking. Patients and Methods: We performed a multi-institution retrospective review of pediatric patients with R/R HL &amp;lt;21 years of age treated with BV/bendamustine. Patients received BV (1.8mg/kg) on Day 1 with bendamustine (90mg/m2) on Days 1 and 2 of 3-week cycles. Response was assessed utilizing Lugano criteria. Twenty-nine patients with a median age of 16 years (range 10 to 20 years) were identified across 3 institutions. Ten patients were classified as having refractory disease and 19 with relapsed disease, with 14/19 patients having relapsed less than a year from the completion of initial therapy. Twenty-one patients received BV/bendamustine as first line salvage therapy. Eight patients (28%) previously received radiation therapy (RT), 4 patients (14%) received prior BV and 4 patients (14%) had ASCT as part of prior therapy. Results: Patients received a median of 3 cycles of BV/bendamustine (range 2-7). Overall, 18 (62%) patients achieved a CR (95%CI: 42 to 79%). An objective response (OR) was observed in 23 patients (ORR 79%) (95%CI: 60 to 92%). Notably, response rates were comparable among patients with relapsed (CR/ORR: 63/79%) or refractory (CR/ORR: 60/80%) disease. Among responders, 15 (65%) achieved best response within 2 cycles. CR and OR rates in patients receiving BV/bendamustine as first-line salvage therapy versus second-line salvage or greater was 67/81% and 50/75%, respectively. The most common grade 3 or 4 toxicities were hematologic (neutropenia (n=13), anemia (n=4), thrombocytopenia (n=4)). Three patients experienced grade 3 infusion reactions. Two patients proceeded with BV/bendamustine following desensitization protocols and 1 patient continued therapy with single-agent bendamustine. Sixteen patients received a consolidative transplant following BV/bendamustine (13 autologous, 3 allogeneic), 5 patients received consolidative RT, and 10 patients received post-transplant consolidation with BV. For the entire cohort, the 3-year post-BV/bendamustine event-free and overall survival was 65% (95%CI: 46 to 85%) and 89% (95%CI: 74 to 100), respectively. Conclusions: Combination therapy with BV/bendamustine for pediatric patients with R/R HL compares favorably with currently accepted salvage regimens in terms of response and tolerability. These results support evaluation of this regimen in a multi-center prospective clinical trial. Disclosures Absalon: Jazz Pharmaceuticals: Research Funding. Shukla:Syndax Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees.

Evaluating Blinatumomab for the Treatment of Relapsed/Refractory ALL: Design, Development, and Place in Therapy.

Although adults with B-cell acute lymphoblastic leukemia (B-ALL) achieve high complete remission (CR) rates following treatment with intensive multi-agent chemotherapy regimens, up to two-thirds of these patients eventually relapse. Unfortunately, adults with relapsed or refractory (R/R) B-ALL have a poor prognosis, with variable responses to salvage chemotherapy regimens and allogeneic stem cell transplant. As such, the need to develop effective and well-tolerated treatments for this patient population has been of paramount importance over the past decade. In this regard, treatment options for R/R B-ALL patients have expanded considerably over a relatively short period of time, with the approvals of blinatumomab, inotuzumab ozogamicin and tisagenlecleucel occurring within only the past six years. Blinatumomab, a CD19 x CD3 bispecific T-cell engager (BiTE) was the first of these immune therapies to receive approval, and for many patients, is used as first-line salvage therapy. A number of large clinical trials have demonstrated improved progression-free survival and overall survival for R/R B-ALL patients receiving blinatumomab as compared to those receiving conventional salvage chemotherapy. In addition to being approved for both Philadelphia chromosome-negative and Philadelphia chromosome-positive R/R B-ALL, blinatumomab is also the only ALL therapy that carries approval for the treatment of measurable residual disease (MRD). Although blinatumomab has changed the therapeutic landscape for adults with R/R B-ALL, a number of important clinical considerations and questions remain, including the potential role of blinatumomab in the frontline setting, mechanisms of resistance, optimal goal MRD level, the role of transplant following MRD clearance, the optimal place for blinatumomab in the context of other recently approved immune-mediated therapies, and real world outcomes for patients treated outside the context of clinical trials. These issues are the focus of ongoing studies, which will hopefully inform future clinical practice regarding the utility of blinatumomab in the treatment of B-ALL patients.

The value of bendamustine dose and cycles, sIL-2R, and LDH in follicular lymphoma patients treated with bendamustine plus rituximab.

e20055 Background: Bendamustine plus rituximab therapy (BR) is one of the mainstays of therapy for follicular lymphoma (FL) patients (pts). Adverse events such as lymphopenia, neutropenia, and skin lesions sometimes prevent the completion of six cycles of BR. Till date, the bendamustine dose, treatment cycle of BR, and prognostic markers of FL response to BR have not been analyzed sufficiently. Methods: We retrospectively evaluated 56 FL pts treated with BR from January 2011toJanuary 2019 at our hospital; 19 pts and 37 pts received BR as first-line therapy and salvage therapy, respectively. Results: There was no statistical difference in the response rate, OS, and PFS between the first-line group and the salvage group. The table summarizes the survival analyses. Comparing the OS and PFS according to FL grades 1, 2, and 3 in all pts, there were significant differences in both OS (P = 0.0028) and PFS (P = 0.0058). Patients were divided into two groups based on a cutoff sIL-2R value of 682 U/mL; survival benefits were observed in the sIL-2R-low group in OS (P = 0.0226) and PFS (P = 0.0265). Similarly, on dividing the pts into two groups based on a cutoff LDH value of 225 U/L, survival benefits were observed in the LDH-low group in OS (P = 0.0375) and PFS (P = 0.0453). The LDH value was significantly high in pts with progression of disease within 24 months (POD24) compared to pts without POD24 (P = 0.0134). However, there was no statistical relationship between sIL-2R and POD24.The rate of treatment cycles ≧4 was 69%, and the mean number of treatment cycles was 4.3. Survival benefits were observed in pts who were treated for more than 3 cycles in OS (P = 0.0094) and PFS (P = 0.0103). The mean bendamustine dose was 78.5 mg/m2. Conclusions: Approximately 30% pts could not receive more than 3 cycles of BR, probably because of adverse events and preexisting bone marrow suppression with previous chemotherapy, suggesting that 90 mg/m2of bendamustine in BR may be excessive, especially in pts requiring salvage therapy. Our data suggest that 75−80 mg/m2of bendamustine may be appropriate. Our survival data also suggest that new treatment strategies may be needed for FL pts with high levels of sIL-2 ( &gt;682 U/mL) and LDH ( &gt;225 U/L) and grade 3 disease. [Table: see text]

ElectroMotive drug administration (EMDA) of Mitomycin C as first-line salvage therapy in high risk \u201cBCG failure\u201d non muscle invasive bladder cancer: 3\u2009years follow-up outcomes

BackgroundIn case of high grade non-muscle invasive bladder cancer (HG-NMIBC), intravesical BCG represents the first-line treatment; despite the “gold” standard therapy, up to 50% of patients relapse, needing radical cystectomy. Hence, alternative therapeutic strategies have been developed. The aim of the study was to evaluate a first-line salvage treatment with EMDA®-MMC in patients with HGNMIBC unresponsive to BCG.MethodsWe carried out a prospective, single-center, single-arm Phase II study in order to evaluate the efficacy (in terms of recurrence and progression) and the safety of the EMDA®-MMC treatment in 26 (21 male, 5 female) consecutive patients with “BCG refractory” HGNMIBC on a 3 years follow-up.EMDA®-MMC treatment consisted of 40 mg of MMC diluted in 100 ml of sterile water retained in the bladder for 30 min with 20 mA pulsed electric current.EMDA®-MMC regimen consisted of an induction course of 6 weekly instillations followed by a maintenance course of 6 monthly instillations.Follow-up was performed with systematic mapping biopsies of the bladder (with sampling in the prostatic urethra for men), voiding and washing urinary cytology, radiological study of the upper urinary tract.We performed Survival Kaplan-Meier curves and Log-rank test in order to analyze high grade disease-free survival.ResultsAt the end of follow-up, 16 patients (61.5%) preserved their native bladder; 10 patients (38.4%) underwent radical cystectomy, in 6 patients (23.1%) for recurrent HGNMIBC and in 4 patients (15.4%) for progression to muscle-invasive disease.At the end of follow-up, stratifying patients based on TNM classification (TaG3, T1G3, Cis, TaT1G3 + Cis), disease-free rates were 75, 71.4, 50 and 25%, respectively; survival curves showed statistically significant differences (p value < 0.05).Regarding toxicity, we reported severe adverse systemic event of hypersensitivity to the MMC in 3 patients (11.5%), and local side effects in 6 patients (26.1%).ConclusionsIn the field of alternative strategies to radical cystectomy, the EMDA®-MMC could be considered safe and effective in high-risk NMIBC unresponsive to BCG, as a “bladder sparing” therapy in selected patients. Multicenter studies with a larger number of patients and a longer follow-up might confirm our preliminary results.Trial registrationEudraCT2017-002585-43. 17 June 2017 (retrospectively registered).

Salvage regimens for pediatric patients with relapsed nasopharyngeal carcinoma.

There is no established salvage regimen for pediatric patients with relapsed nasopharyngeal carcinoma (NPC) and outcomes are dismal. We performed a multicenter retrospective review to determine outcomes after first salvage therapy for pediatric patients with relapsed NPC. Fourteen patients were treated with varied regimens. Two of the 14 patients received oxaliplatin-containing regimens and achieved a long-term complete response. Although definitive recommendations cannot be made based on outcomes for 14 patients who received varied regimens, we discuss justification for an oxaliplatin-containing regimen in combination with gemcitabine as a reasonable choice for first-line salvage therapy for pediatric patients with relapsed NPC.

High intensity focused ultrasound as first line salvage therapy in prostate cancer local relapse after radical prostatectomy: 4-year follow-up outcomes.

Prostate cancer (PCa) is the most commonly diagnosed malignancy in men and the second leading cause of cancer death in developed countries. Despite the primary treatments, 20-30% of patients experience a recurrence. The main objective of this study was to evaluate the clinical efficacy of salvage high intensity focused ultrasound (HIF U) after radical prostatectomy in terms of biochemical free survival rate (BFSR) and PSA nadir. Twenty two patients with local recurrence of Pca after radical prostatectomy underwent HIFU as first-line salvage therapy. Considering that in all HIFU experiences, PSA nadir and PSA failure are different and PSA definition of BFSR is unknown, we defined treatment success as a PSA nadir ≤0.4 ng/mL 3 months after treatment. All early and late medical and surgical complications were recorded. Ten of the 22 patients (45.5%) were classified as "success" three months after HIFU, showing a nadir PSA≤0.4 ng/mL; 12/22 patients (54.5%) were classified as "failure" during follow-up (median follow-up: 48 months). Seventeen of 22 (77%) patients were continent (no-pad) before HIFU. A new diagnosis of stress urinary incontinence was made in 5 cases (early onset) after treatment. A case of vesicoureteral anastomotic stenosis was treated, endoscopically through cold urethrotomy. We did not observe cases of recto-urinary fistula or persistent lower urinary tract symptoms. Two sevenths of the patients complained about de novo erectile dysfunction after HIFU. The positive oncologic outcomes in the short term anyway obtained in selected patients, associated with documented mild side effects, represent the basis to start more organic, prospective, randomized and multicenter study protocols, that with a long term follow-up could confirm these promising preliminary results.

Relapsed/refractory pediatric B-cell non-Hodgkin lymphoma treated with rituximab combination therapy: A report from the Japanese Pediatric Leukemia/Lymphoma Study Group.

Pediatric relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) has been reported to be extremely difficult to cure, but rituximab is expected to be effective in improving the prognosis of pediatric R/R B-NHL patients. Here, we assessed the treatment and prognosis of pediatric R/R B-NHL in the rituximab era in Japan. We collected information on patients with R/R B-NHL who were registered with the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) B-NHL03 protocol, a nationwide multicenter trial for newly diagnosed patients. We assessed the treatment and outcome of 33 pediatric R/R B-NHL cases. Twenty-eight patients received rituximab combination therapy as salvage treatment. R-ICE (rituximab, ifosfamide, carboplatin, and etoposide), the most common regimen, was used in 22 patients as first-line salvage therapy. Twenty-three patients received hematopoietic stem cell transplantation (HSCT). Among all 33 patients, 23 (70.0%) achieved partial remission or complete remission. Their 5-year overall survival rate was 48.5%, which was far superior to that in both our previous study and in another study on pediatric R/R B-NHL. Four toxic deaths associated with viral infection occurred after allogeneic HSCT following on rituximab combined salvage therapy. Risk factor multivariate analysis for survival in patients receiving rituximab combination therapy showed central nervous system combined relapse had inferior outcome. The prognosis of pediatric R/R B-NHL in a Japanese cohort remained poor but is showing improvement in the rituximab era. Rituximab combination therapy is effective for R/R B-NHL patients who did not receive rituximab as primary treatment. We need to consider possible viral infections in allogeneic HSCT after rituximab treatment.

Improved Outcome of Relapsed or Refractory Pediatric B-Cell Non-Hodgkin Lymphoma in Japan

IntroductionRelapsed or refractory pediatric B-cell non-Hodgkin lymphoma (B-NHL) has been reported to be extremely difficult to cure. We previously conducted a retrospective study of pediatric relapsed or refractory B-NHL in Japan between 1996 and 2004 and found that the four-year overall survival rate was only 20.5% (Fujita N. e al. PBC. 2008). Rituximab, a chimeric anti-CD20 monoclonal antibody, is expected to be effective in improving the prognosis of pediatric relapsed or refractory B-NHL and was approved for use in 2003 in Japan. Here, we retrospectively assessed the treatment and prognosis of pediatric relapsed or refractory pediatric B-NHL in the rituximab era in Japan.MethodsWe collected relapsed pediatric B-NHL cases from patients enrolled in our current study, JPLSG B-NHL03 study, which was the first nationwide multicenter trial for newly diagnosed pediatric B-NHL. We collected information on treatment and outcome after induction failure or relapse.ResultsIn 33 patients enrolled this study, the median age at diagnosis was 9.7 years and male predominance was observed. Nine cases were pathologically subclassified initially as diffuse large B-cell lymphoma, 11 as Burkitt lymphoma, 11 as Burkitt Leukemia and two as others. According to initial Murphy staging, most cases were in the advanced stage. The most common site of relapse was abdomen (8 cases), followed by bone marrow (8 cases) and central nervous system (7 cases). Twenty-three cases relapsed in one site while 10 did so in multiple sites. Among them, 20 relapsed within six months after initial diagnosis.Among them, 28 patients received some rituximab combined treatment as salvage therapy. R-ICE (rituximab, ifosfamide, carboplatin and etoposide) regimen was the most popular and used in 22 patients as first-line salvage therapy. As a result, 22 patients (66.7%) achieved complete remission (CR) by some salvage therapy. 23 received hematopoietic stem cell transplantation (HSCT). Their 5-year overall survival rate was 48.5%, which was far more superior to both our previous study (Figure 1) and another on relapsed or refractory B-NHL in childhood.In risk factor analysis for survival, rituximab combined treatment and HSCT did not influence the outcome, but achievement of CR after salvage treatment resulted in significantly better survival (68.2% vs 9.1%, p=0.001). These results suggest that the advent of rituximab induced an improvement of CR rate for relapsed paediatric B-NHL, which resulted in an improvement of the survival rate.ConclusionIn conclusion, the prognosis of the pediatric relapsed or refractory B-NHL in a Japanese cohort remained poor but is showing improvement in the rituximab era. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Cyclophosphamide and Topotecan as First-line Salvage Therapy in Patients With Relapsed Ewing Sarcoma at a Single Institution

The combination of cyclophosphamide and topotecan (cyclo/topo) has shown objective responses in relapsed Ewing sarcoma, but the response duration is not well documented. We reviewed characteristics and outcome of 14 patients with Ewing sarcoma, treated uniformly at a single institution and offered cyclo/topo at first relapse. Six patients (43%) had relapse at distant sites. All patients received first-line salvage therapy with cyclophosphamide 250 mg/m and topotecan 0.75 mg/m, daily for 5 days repeated every 21 days. The median number of cycles was 4 (range 1 to 10). All toxicities were manageable, the most common being transient cytopenias. There were also 4 episodes of febrile neutropenia, and 3 episodes of gross hematuria. Response was assessable in 13 patients and showed progressive disease in 6 (46%), stable disease in 4 (31%), and partial response in 3 (23%). Nine patients had local control, consisting of radical surgery in 2, radiation in 3, and a combination in 4 patients. Response, when it occurred, was maintained for a median of 8 months (range, 4 to 28 mo). Four patients (29%) are alive at 3, 7, 9, and 110 months after relapse; 1 is receiving cyclo/topo, 1 is on third-line therapy, and 2 are in second and fourth remission. The low toxicity of this combination, and the lack of sustained responses, warrant its investigation in combination with targeted or novel therapeutic agents in relapsed disease.

Salvage chemotherapy for metastatic germ cell tumours: The known unknowns.

Salvage chemotherapy for metastatic germ cell tumours: The known unknowns.

Brentuximab Vedotin As First Line Salvage Therapy in Relapsed/Refractory HL

AbstractAbstract 3699 Background:A defining feature of HL is CD30 expression by Reed-Sternberg cells. Brentuximab vedotin, an antibody drug conjugate (ADC), selectively induces apoptotic death of CD30+ cells by binding, internalizing, and releasing monomethyl auristatin E, a microtubule agent. A pivotal phase II trial of brentuximab vedotin in heavily pretreated patients with HL demonstrated an overall objective response rate of 75% (CR, PR) and CR of 34% with manageable toxicities. This novel ADC compares favorably with historical first-line salvage regimens such as ICE and DHAP (CR 17–21%) To examine the outcomes (e.g., toxicity, response) of brentuximab vedotin when given as first-line salvage therapy for HL, we retrospectively analyzed data from a consecutive case-series of patients who received brentuximab vedotin as first -line salvage therapy at COH. Patients and Methods:Three patients received brentuximab vedotin as salvage therapy on IRB 10089 (expanded access protocol) and 8 patients received brentuximab vedotin as salvage therapy on IRB 11051 (prospective phase II trial). All patients had relapsed/refractory HL post induction therapy with ABVD, BEACOPP or a combination +/− consolidative XRT. Patients were treated with 1.8 mg/kg of brentuximab vedotin intravenously every 3 weeks as outpatients for a maximum of 4 cycles. Descriptive statistics were generated for response, toxicity, stem cell mobilization/collection and engraftment (for those patients who went on to autologous HCT). Response rate post brentuximab vedotin treatment was determined with either CT or PET at cycle 2 and CT/PET at cycle 4 as per Cheson 2007 criteria. Results:A total of 11 patients were treated at COH from 8/2011 to 7/2012 (Table 1). The median age was 34 years (22, 64); 7/11 were female. All patients received ABVD or ABVD/BEACOPP combination induction therapy. Three patients had also received consolidative radiation therapy. Six were considered primary refractory and 5 had relapsed HL. Thus far, 8 were evaluable for response and 10 were evaluable for toxicity. The overall response rate was 87.5% (7/8); CR was 50% (4/8) and PR was 37.5% (3/8); one patient achieved SD after 4 cycles. Three out of 4 patients who achieved CR did so after 2 cycles. No one developed progressive disease while on treatment. Overall the regimen is considered well tolerated. No grade 2 neuropathy was reported. The incidence of grade 1 neuropathy was 20% (2/10). There were no grade 3 or 4 adverse events or hospitalizations during brentuximab vedotin treatment. Additionally, the use of growth factors or red blood cell or platelet transfusions was not required.A total of 6/11 patients have undergone stem cell mobilization with cyclophosphamide/G-CSF priming after the 4th dose of brentuximab vedotin. The median cells dose collected was 5.87 × 10⋀6 CD34+ cells (2.78–11.13, minimum acceptable is 2 × 10⋀6 CD 34+ cells). The median time to reach the minimum collection was 1.5 days (1–5). All six patients have undergone ASCT using either BEAM or CBV for conditioning. The median time for neutrophil engraftment (ANC>500) was 10 days (10–11) and platelet engraftment (>20K) was 11 days (10–13). All 6/6 patients achieved CR after stem cell transplantation. The other five patients are undergoing stem cell mobilization or are have not completed brentuximab vedotin treatment. Conclusion:These data show brentuximab vedotin as first-line salvage therapy can produce an adequate ORR of 87.5% and CR of 50%. Brentuximab vedotin also has acceptable toxicity and does not adversely impact stem cell collection or post autologous HCT engraftment.Table 1PatientsAgeStage at diagnosisInduction regimenRelapsed/RefractoryPrior XRTBulky DiseaseBest Response (PET)122IIABVDRelapsedNoNoCR264IIABVDRefractoryNoNoPR344IIBABVDRelapsedNoNoPR451IIBABVD/BEACOPPRefractoryYesYesPR533IIIABVDRefractoryNoNoSD659IIABVDRelapsedNoNoCR732IVBABVDRelapsedNoYesCR834IIABVDRelapsedYesYesCR932IIBABVDRefractoryNoYesN/A1045IIBABVDRefractoryNoYesN/A1127IIABVDRefractoryNoNoN/A Disclosures:Chen:Seattle Genetics, Inc.: Consultancy, Research Funding, Speakers Bureau, Travel Expenses Other. Off Label Use: This clinical trial involves the use of brentuximab vedotin as first line salvage therapy in Hodgkin lymphoma, which is an off-label use. Siddiqi:Seattle Genetics, Inc.: Consultancy, Research Funding.

Lenalidomide plus donor-lymphocytes infusion after allogeneic stem-cell transplantation with reduced-intensity conditioning in patients with high-risk multiple myeloma

Myeloma relapse is the main cause of death after allogeneic stem cell transplantation. The aim of our observational study was to evaluate the anti-myeloma effect of lenalidomide followed by donor-lymphocyte infusion (DLI) as post-transplantation adoptive immunotherapy. Twelve patients with refractory myeloma were analyzed. The median age at transplantation was 56 years (range, 46-64 years). All patients received reduced-intensity conditioning. Patients were included if progressive or residual disease was observed at day +100 and if no signs of graft-vs-host disease were evident. DLIs were administered after two cycles of lenalidomide. Median dose of lenalidomide was 15 mg (range, 10-25 mg). Patients received a median of six cycles (range, 1-10 cycles). Nine patients (60%) received an escalating dose of DLI. The 1 and 2-year probability of progression-free survival was 75% and 50%, and overall survival was 83% and 69%, respectively. Median overall survival was not reached and median progression-free survival was 23 months. Lenalidomide is well tolerated after allogeneic stem cell transplantation; the combination with DLI did not cause a higher risk of graft-vs-host disease; an immunological synergistic effect was probably present with this strategy. This combination should be evaluated further in a larger cohort of patients.

Conventional second‐line salvage chemotherapy regimens are not warranted in patients with malignant lymphomas who have progressive disease after first‐line salvage therapy regimens

This study aimed to determine the outcome of patients with relapsed or refractory lymphoma who have an inadequate response to first-line salvage therapy (1 degrees ST) and who subsequently receive a second-line salvage regimen (2 degrees ST) with the intention of ultimately proceeding to high-dose therapy. The outcome of 57 patients [Hodgkin's Lymphoma 17, histologically-aggressive non-Hodgkin's Lymphoma (NHL) 26, histologically-indolent NHL 14] who received more than one modality of conventional-dose salvage therapy was analysed. Sixteen patients had a partial response (PR) to 1 degrees ST, but subsequently received 2 degrees ST because the PR was judged to be inadequate (iPR) because of persisting disease bulk or marrow infiltration. Of these 16 patients, 10 (63%) continued to respond to 2 degrees ST. Of the 15 patients who had stable disease following 1 degrees ST, 5 (33%) responded to 2 degrees ST. Only one of the 24 (4%) with progressive disease (PD) following 1 degrees ST, responded to 2 degrees ST. 25 of the 57 patients ultimately underwent stem cell transplantation. The 2-year progression-free survival (PFS) and the 3-year overall survival (OS) for all patients was 24% and 31%, respectively. Long-term survival was highly dependent on response to 1 degrees ST (P = 0.0001); in patients with PD following 1 degrees ST, the PFS and OS at 3 years was only 4%. This analysis indicates that patients with malignant lymphomas, who have PD on 1 degrees ST, are not rescued by subsequent salvage regimens. They should either be treated palliatively or novel approaches should be explored.