Effective re-induction regimen for children with recurrent medulloblastoma.

Background: There is no standard treatment for the recurrence of medulloblastoma, the most common malignant childhood brain tumor, and prognosis remains dismal. In this study, we introduce a regimen that is well-tolerated and effective at inducing remission. Methods: The primary objectives of this study were to assess tolerability of the regimen and overall response rate (ORR). A retrospective chart review of patients with recurrent medulloblastoma, treated at two institutions with a re-induction regimen of intravenous irinotecan and cyclophosphamide with oral temozolomide and etoposide, was performed. Demographic, clinicopathologic, toxicity, and response data were collected and analyzed. Results: Nine patients were identified. Median age was 5.75 years. Therapy was well-tolerated with no therapy-limiting toxicities and no toxic deaths. Successful stem cell collection was achieved in all 5 patients in whom it was attempted. ORR after 2 cycles was 78%. Three patients had a complete response, 4 patients had a partial response, 1 patient had stable disease, and 1 patient had progressive disease. Four patients are alive with no evidence of disease (NED), 2 patients are alive with disease, 2 patients have died of disease, and 1 patient died of toxicity related to additional therapy (NED at time of death). Conclusions: This regimen is well-tolerated and effective. Tumor response was noted in the majority of cases, allowing patients to proceed to additional treatment with no or minimal disease. Further study of this regimen in a clinical trial setting is an important next step.

Single or continuous multiple intravenous re-induction in Crohn's disease patients who lost response to ustekinumab: Evidence from real-world data.

BACKGROUND AND AIMS: Re-induction optimization of ustekinumab is effective in Crohn's disease (CD) patients who experienced a loss of response (LOR) to ustekinumab. However, whether continuous multiple intravenous optimization is better than single dose re-induction remains unknown. We aimed to compare effectiveness of two strategies in CD patients with LOR to ustekinumab. METHODS: We retrospectively included CD patients who had LOR to standardized ustekinumab therapy. They were divided into three groups according to different times (one to three) for re-induction. RESULTS: This study included 50, 26 and 22 of 98 eligible patients in one intravenous re-induction subgroup, double intravenous re-induction subgroup and three intravenous re-induction subgroup, respectively. At week 24, 67.3%, 75.5%, 56.6%, 69.8% and 61.2% of all achieved steriod free clinical remission, clinical response, endoscopic remission, endoscopic response and C-reactive protein normalization, respectively. No differences were found in all endpoints between three groups. Ustekinumab trough level at week 24 but not times of re-induction showed a tendency to predict clinical remission. No serious adverse events were found in this cohort. CONCLUSION: Intravenous re-induction was safe and effective in CD patients who experienced LOR to ustekinumab. Trough level of ustekinumab but not times of intravenous re-induction may associated with clinical efficacy.

Efficacy of Immune Checkpoint Inhibitor (ICI) Rechallenge in Advanced Melanoma Patients' Responders to a First Course of ICI: A Multicenter National Retrospective Study of the French Group of Skin Cancers (Groupe de Cancérologie Cutanée, GCC).

BACKGROUND: The long-term effectiveness of immune checkpoint inhibitor (ICI) rechallenge for progressive or recurrent advanced melanoma following previous disease control induced by ICI has not been thoroughly described in the literature. PATIENTS AND METHODS: In this retrospective multicenter national real-life study, we enrolled patients who had been rechallenged with an ICI after achieving disease control with a first course of ICI, which was subsequently interrupted. The primary objective was to evaluate tumor response, while the secondary objectives included assessing the safety profile, identifying factors associated with tumor response, and evaluating survival outcomes. RESULTS: A total of 85 patients from 12 centers were included in the study. These patients had advanced (unresectable stage III or stage IV) melanoma that had been previously treated and controlled with a first course of ICI before undergoing rechallenge with ICI. The rechallenge treatments consisted of pembrolizumab (n = 44, 52%), nivolumab (n = 35, 41%), ipilimumab (n = 2, 2%), or ipilimumab plus nivolumab (n = 4, 5%). The best overall response rate was 54%. The best response was a complete response in 30 patients (35%), a partial response in 16 patients (19%), stable disease in 18 patients (21%) and progressive disease in 21 patients (25%). Twenty-eight adverse events (AEs) were reported in 23 patients (27%), including 18 grade 1-2 AEs in 14 patients (16%) and 10 grade 3-4 AEs in nine patients (11%). The median progression-free survival (PFS) was 21 months, and the median overall survival (OS) was not reached at the time of analysis. Patients who received another systemic treatment (chemotherapy, targeted therapy or clinical trial) between the two courses of ICI had a lower response to rechallenge (p = 0.035) and shorter PFS (p = 0.016). CONCLUSION: Rechallenging advanced melanoma patients with ICI after previous disease control induced by these inhibitors resulted in high response rates (54%) and disease control (75%). Therefore, ICI rechallenge should be considered as a relevant therapeutic option.

Re-induction therapy in patients with acute myeloid leukemia not in complete remission after the first course of treatment.

A standard salvage regimen for patients with acute myeloid leukemia (AML) who are not in complete remission (CR) after initial induction therapy does not exist. We retrospectively investigated re-induction therapy for 151 patients with AML who did not achieve CR after the initial course between January 2014 and March 2021. The re-induction regimen did not correlate with the CR rate after the second course, whereas patients had similar 5-year overall survival (OS) and event-free survival (EFS) based on different re-induction regimens. Multivariable analysis revealed that International European Leukaemia Net (ELN) risk stratification independently predicted both OS and EFS among patients not in CR after the first course, although the re-induction regimen did not predict prognosis. Urgent salvage alloHSCT may improve the prognosis of patients with refractory AML. In summary, our study showed that the re-induction regimen did not significantly predict the prognosis of patients with AML not in CR after the first course of treatment. The development and selection of an efficient treatment algorithm for the treatment of AML remains a pressing research challenge.

Multicenter comparison of first salvage chemotherapy versus novel therapy regimens in adult relapsed/refractory acute lymphoblastic leukemia.

Patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) represent a heterogeneous population and therefore there is no standard of care first salvage regimen. We conducted a multicenter, retrospective analysis to compare chemotherapy (e.g. HyperCVAD, MOAD, Larson/CALGB-9511, etc.) to novel agents (blinatumomab or inotuzumab) in first salvage. The primary endpoint, overall survival (OS), was not significantly different among treatment arms, with a median OS of 10.6 months with chemotherapy and 10.1 months with novel therapy (p = .799). Similarly, there was no difference in the CR/CRi rate, with a CR/CRi in 18 patients (41.9%) versus 16 patients (47.1%) treated with salvage chemotherapy and novel therapy, respectively (p = .817). Age significantly impacted the probability of achieving CR/CRi with novel therapy versus chemotherapy. This analysis suggests the use of chemotherapy in first salvage still represents an appropriate treatment option, particularly for young fit patients, as the median OS was roughly 10 months regardless of whether patients received novel therapy or chemotherapy in first salvage. For the reported outcomes, 100% of patients in the novel therapy arm received a novel therapy (per design), whereas only 60.5% of patients in the chemotherapy arm required a novel therapy. Thus, 40% of patients did not require a novel therapy for similar OS. This analysis demonstrates that first-line chemotherapy can achieve similar results to novel therapies, especially now that novel therapies are available for subsequent relapses. However, this study has several limitations including younger age, increased CNS involvement, and higher blast percentage in the chemotherapy arm and potential confounders, including selection of treatment sequence as 43 patients (55.8%) ultimately received both chemotherapy and novel therapy. Therefore, a larger, prospective, randomized study with adequate chemotherapy comparators and availability of novel agents upon relapse is warranted to confirm these results.

Immune Checkpoint Blockade for Metastatic Uveal Melanoma: Re-Induction following Resistance or Toxicity.

Re-induction with immune checkpoint blockade (ICB) needs to be considered in many patients with uveal melanoma (UM) due to limited systemic treatment options. Here, we provide hitherto the first analysis of ICB re-induction in UM. A total of 177 patients with metastatic UM treated with ICB were included from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of ICB re-induction, two cohorts were compared: patients who received at least one ICB re-induction (cohort A, n = 52) versus those who received only one treatment line of ICB (cohort B, n = 125). In cohort A, a transient benefit of overall survival (OS) was observed at 6 and 12 months after the treatment start of ICB. There was no significant difference in OS between both groups (p = 0.1) with a median OS of 16.2 months (cohort A, 95% CI: 11.1-23.8) versus 9.4 months (cohort B, 95% CI: 6.1-14.9). Patients receiving re-induction of ICB (cohort A) had similar response rates compared to those receiving ICB once. Re-induction of ICB may yield a clinical benefit for a small subgroup of patients even after resistance or development of toxicities.

Re-induction With Intravenous Ustekinumab in Patients With Crohn's Disease and a Loss of Response to This Therapy.

BACKGROUND: A significant percentage of patients treated with ustekinumab may lose response. Our aim was to evaluate the short-term efficacy and safety of intravenous re-induction with ustekinumab in patients with Crohn's disease who have lost the response to the treatment. METHODS: This is a retrospective, observational, multicenter study. Treatment efficacy was measured at week 8 and 16; clinical remission was defined when the Harvey-Bradshaw Index was ≤4 points, and clinical response was defined as a decrease of ≥3 points in the index compared with the baseline. Adverse events and treatment decisions after re-induction were also collected. RESULTS: Fifty-three patients from 13 centers were included. Forty-nine percent had previously failed to respond to 2 biological treatments, and 24.5% had failed to respond to 3. The average exposure time to ustekinumab before re-induction was 17.7 ± 12.8 months. In 56.6% of patients, the administration interval had been shortened to every 4 to 6 weeks before re-induction. At week 8 and 16 after re-induction, 49.0% (n = 26) and 43.3% (n = 23), respectively, were in remission, whereas 64.1% (n = 34) and 52.8% (n = 28) had a clinical response. Patients who achieved remission at week 16 had lower C-reactive protein levels than those who did not respond (2.8 ± 1.6 vs 12.5 ± 9.5 mg/dL; P = 0.001). No serious adverse events related to re-induction were observed. CONCLUSION: Intravenous re-induction with ustekinumab is an effective and safe strategy that recovers the response in approximately half of the patients with refractory Crohn's disease who experience a loss of response. Re-induction can be attempted before switching out of the therapy class.

Management of suboptimal response to induction chemotherapy in locoregionally advanced nasopharyngeal carcinoma: Re-induction therapy or direct to Radiotherapy?

BACKGROUND: Unsatisfactory tumor response to induction chemotherapy (IC) is an adverse prognostic factor of locoregionally advanced nasopharyngeal carcinoma (LANPC). A re-induction strategy which applies additional cycles of an alternative IC regimen prior to radiotherapy (RT) has been adopted. METHODS: A total of 419 LANPC patients who attained suboptimal response (stable disease or disease progression) according to the Response Evaluation in Solid Tumors (RECIST) guideline after initial IC were retrospectively included. They were divided into those who received additional cycles of re-induction regimen prior to RT (re-induction group, n = 87) and those who had no additional chemotherapy (direct to RT group, n = 332). Propensity score matching (PSM) was used to adjust for potential confounders. Tumor response and long-term survival were compared between two groups. RESULTS: After receiving a second IC regimen, 39.1% of the patients in re-induction group attained partial response; however, the tumor control of subsequent RT was not significantly improved when compared with direct to RT group (patients attaining complete response after RT 55.2% vs. 52.5%, P = 0.757). Patients who received re-induction therapy showed worse locoregional relapse-free survival (LRFS) and progression-free survival (PFS) than those proceeded directly to RT (3-year LRFS 75.7% vs. 83.1%, P = 0.005; 3-year PFS 62.4% vs. 68.3%, P = 0.037). The increased hematological toxicities were observed in re-induction group that included grade 3-4 anemia, thrombocytopenia and liver enzyme increase. CONCLUSION: Re-induction therapy decreased LRFS and PFS and increased toxicities among patients who attain suboptimal response to initial IC regimen, as compared with direct to RT strategy.

Propensity-score Matched Comparison of Salvage Chemotherapy Regimens in Relapsed/Refractory Acute Myeloid Leukemia.

BACKGROUND: Relapsed/refractory acute myeloid leukemia (AML) confers a poor prognosis, and there is no single standard of care first-line salvage regimen. FLAG (fludarabine, cytarabine, and granulocyte colony-stimulating factor) is a common salvage regimen with a favorable toxicity and efficacy profile in poor-risk AML. MATERIALS AND METHODS: We conducted a single-center, retrospective analysis of first relapse/primary refractory patients with AML that received salvage chemotherapy from January 2009 to July 2019. We propensity-score matched patients 1:1 (based on age at diagnosis, cytogenetic risk group, Charlson comorbidity index, de novo vs. secondary AML, and whether or not they received an allogeneic stem cell transplant in first complete remission) into 2 groups, FLAG (Group 1) or non-FLAG (Group 2) as first-line salvage regimen, with 66 patients in each group. The primary endpoint was overall response rate (complete response and complete response with incomplete hematologic recovery). RESULTS: The median patient age was 59 years (range, 19-80 years). Patients treated with FLAG had a higher overall response rate (complete response/complete response with incomplete hematologic recovery) (71.2% vs. 50.0%; odds ratio, 2.47; 95% confidence interval [CI], 1.21-5.08; P = .013), longer event-free survival (8.9 vs. 2.1 months; hazard ratio [HR], 0.58; 95% CI, 0.39-0.86; P = .005), and longer overall survival (14.2 vs. 5.9 months; HR, 0.62; 95% CI, 0.41-0.93; P = .019). Patients who received FLAG had a shorter median duration of neutropenia (22 vs. 34 days; HR, 0.43; 95% CI, 0.29-0.64; P < .001). CONCLUSION: This analysis supports the FLAG regimen as an effective and well-tolerated salvage therapy for patients with relapsed/refractory AML.

Comparison of efficacy of HCAG and CAG re-induction chemotherapy in elderly low- and intermediate-risk group patients diagnosed with acute myeloid leukemia.

PURPOSE: The present study aimed to investigate the efficacy and severity of adverse effects of HCAG and CAG re-induction chemotherapy in elderly low- and intermediate-risk group patients diagnosed with acute myeloid leukemia (AML) following induction failure. METHODS: A total of 94 AML patients were enrolled in the study, of whom 46 were treated with HCAG chemotherapy, while 48 were treated with CAG chemotherapy. RESULT: The complete remission (CR) was 39.6% in the patients with HCAG, while the CR was 33.3% in the CAG group. The overall remission (ORR) was 63.0% and 43.5% in patients of the HCAG and CAG groups, respectively (P = 0.038). The median survival time of progression free survival (PFS) was 8.0 (95% CI 3.843-10.157) months in the HCAG group and 7.0 (95% CI 2.682-13.318) months in the CAG group (P = 0.032). A total of 31 patients in the HCAG group suffered from grade 4 hematological toxicity, whereas 29 patients were treated with CAG (P = 0.622). A total of 27 (58.7%) cases indicated apparent pulmonary infection in the HCAG group, while 25 (52.1%) were noted with this complication in the CAG group (P = 0.519). Oral cavity toxicity was evident for 13 (28.3%) and 11 (23.0%) cases in the HCAG and CAG groups, respectively (P = 0.216). CONCLUSION: The HCAG regimen was more effective than the CAG regimen in elderly low- and intermediate-risk group patients diagnosed with acute myeloid leukemia although the HCAG regimen exhibited similar toxicity with that of the CAG group.

Efficacy of high-dose cytarabine and aclarubicin in combination with G-CSF regimen compared to intermediate/high-dose cytarabine and standard-dose cytarabine induction regimen for non-remission acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) patients with non-remission (NR) after the first cycle of standard induction chemotherapy remain a challenge owing to poor response and tolerance to re-induction regimen. We retrospectively evaluated the efficacy and safety of three regimens in AML patients refractory to the first course of standard induction regimen. MATERIALS AND METHODS: The three regimens consisted of (1) High-dose cytarabine, aclarubicin and granulocyte colony-stimulating factor (HD-CAG) regimen (n = 44); (2) intermediate/high-dose cytarabine (I/HDAC) regimen (n = 30); and (3) standard-dose cytarabine (SDAC) combination regimen that was identical to the first course of standard induction regimen (n = 27). RESULTS: Results indicated that after the second course, the overall response (OR), i.e., complete remission [CR]+partial remission [PR]) rates in HD-CAG was higher than in the I/HDAC group (84.1% vs. 56.7%, P = 0.009), whereas the CR rates among 3 groups were not statistically different (P = 0.541). Meanwhile, the proportion of subjects reporting certain adverse effects in the HD-CAG group was lower than the I/HDAC or SDAC groups. There were no significant differences in overall survival (OS) and disease-free survival (DFS) rates among the 3 groups (P = 0.881 and P = 0.872, respectively). CONCLUSION: Our preliminary results indicate that HD-CAG regimen may represent a better alternative option for AML patients with NR after the first course of standard induction chemotherapy.

A systematic review of re-induction chemotherapy for children with relapsed high-risk neuroblastoma.

BACKGROUND: Despite aggressive multimodal therapy, >50% of children with high-risk neuroblastoma (HRNB) relapse. Survival after relapse is rare, and no consensus currently exists on the most effective therapy. OBJECTIVE: To conduct a systematic review of the literature on effectiveness of re-induction chemotherapy in children with relapsed HRNB. METHODS: Database searches were performed to identify studies looking at response to 1st line chemotherapy for children >12 months at diagnosis with first relapse of HRNB. Studies not reporting separate outcomes for HRNB patients or of refractory patients only were excluded. Two independent reviewers extracted the data and assessed study quality using a modified Newcastle-Ottawa tool. RESULTS: Nine studies were identified fitting the inclusion criteria. All except one were single arm cohorts, and two were retrospective database reviews from single centres. One was a multicentre randomised controlled trial. All used a version of the validated International Neuroblastoma Response Criteria with 8 recording best ever response and 1 at a specified time, and 5 had central review. The proportion of relapsed patients varied from 24 to 100% with 30-93% receiving upfront myeloablative therapy. The response rate varied from 6 to 64%; however, because of heterogeneity, studies were not directly comparable, and no single treatment emerged as the most effective re-induction therapy. CONCLUSIONS: To date, there is no clear superior re-induction therapy for 1st relapse of HRNB. Randomised controlled trials with separate arms for relapsed versus refractory disease are needed to determine optimal re-induction chemotherapy to act as a backbone for testing newer targeted agents.

Comparison of efficacy of HCAG and FLAG re-induction chemotherapy in acute myeloid leukemia patients of low- and intermediate-risk groups.

PURPOSE: The aim of the present study was to investigate the efficacy and adverse effects of HCAG and FLAG re-induction chemotherapy in acute myeloid leukemia (AML) patients of low- and intermediate-risk groups following induction failure. METHODS: A total of 98 AML patients were enrolled. Among these subjects, 47 patients were treated with HCAG chemotherapy, while 51 patients were treated with FLAG chemotherapy. RESULT: The complete remission (CR) and overall remission (OFF) were 24% and 38%, respectively in patients with HCAG induction chemotherapy, while the corresponding percentages were 28% and 42% in subject receiving FLAG chemotherapy. The median survival time of progress-free survival (PFS) was 29.8 (95% CI 23.749-35.851) months in the HCAG group and 30.8 (95% CI 21.728-39.872) months in the FLAG group (P = 0.620). A total of 42 patients in the HCAG group suffered from grade 4 hematological toxicity, while this adverse reaction was noted for all patients who were treated with FLAG chemotherapy (P = 0.023). A total of 19 cases indicated apparent nonhematological toxicity in the HCAG group, while only 40 (78.4%) were noted with these adverse reactions in the FLAG group (P = 0.000). CONCLUSION: The HCAG regimen exhibited a similar effect compared with the FLAG regimen in low- and intermediate-risk groups, although the HCAG regimen significantly decreased the toxicity compared with that noted in the FLAG regimen group.

Re-induction using whole cell melanoma vaccine genetically modified to melanoma stem cells-like beyond recurrence extends long term survival of high risk resected patients - updated results.

BACKGROUND: AGI-101H is an allogeneic gene modified whole cell therapeutic melanoma vaccine, evaluated in over 400 melanoma patients in the adjuvant and therapeutic settings. We present updated long-term survival results from two single-arm, phase II adjuvant trials (Trial 3 and Trial 5) with the focus on treatment beyond recurrence of the disease. METHODS: Patients with resected high-risk melanoma (stage IIIB-IV) were enrolled to Trial 3 (n = 99) and Trial 5 (n = 97). The primary endpoint was disease-free survival (DFS), and the secondary was overall survival (OS). In the induction phase, the vaccine was administered every 2 weeks (eight times), followed by the maintenance phase every month until progression. At progression, maintenance was continued or re-induction was applied with or without surgery. RESULTS: In Trial 3, the 10-year DFS was equal to 33.0% overall and to 52.4, 25.0, and 8.7% for stage IIIB, IIIC, and stage IV patients, respectively. In Trial 5, the overall 10-year DFS was equal to 24.2%, and to 37.5, 18.0, and 17.6% for stage IIIB, IIIC, and stage IV patients, respectively. In Trial 3, the 10-year OS was equal to 42.3% overall, and to 59.5, 37.5, and 17.4% for stage IIIB, IIIC, and stage IV patients, respectively. In Trial 5, the 10-year OS was equal to 34.3% overall and to 46.9, 28.0, and 29.4% for stage IIIB, IIIC, and stage IV patients, respectively. Among the 65 patients of Trial 3 who developed progression, 43 received re-induction with (n = 22) or without (n = 21) surgery. Two patients received surgery without re-induction. All the 22 progressing patients, who did not receive re-induction, died. Among the 75 patients of Trial 5 who experienced progression, 39 received re-induction with (n = 21) or without (n = 18) surgery. Among the 36 progressing patients who did not receive the re-induction, 35 died. Surgery and re-induction reduced (independently) the increase of mortality after progression in both trials, with the effect of re-induction reaching statistical significance in Trial 5. CONCLUSIONS: Vaccination beyond recurrence of the disease with additional re-induction combined with surgery or alone increased long term survival of melanoma patients. However, further studies on larger patient cohorts are required. TRIAL REGISTRATION: Central Evidence of Clinical Trials (EudraCT Number 2008-003373-40 ).

Outcomes of fludarabine, high dose cytarabine and granulocyte-colony stimulating factor (FLAG) as re-induction for residual acute myeloid leukemia on day 14 bone marrow.

BACKGROUND: Patients with acute myeloid leukemia (AML) treated with intensive chemotherapy may require re-induction based on the evaluation of day 14 bone marrow biopsy. METHODS: A retrospective chart review was performed to evaluate adult patients with AML who received re-induction with fludarabine, high dose cytarabine and granulocyte colony stimulating factor (FLAG) regimen for residual disease (≥ 5% blasts by morphology) on day 14 bone marrow examination between September 2012 and July 2017 at our institution. RESULTS: We identified 27 patients who received FLAG therapy for treatment of residual disease on day 14 marrow examination following initial induction. The median age at diagnosis was 61 years and the majority of patients had poor risk AML. The overall response rate was 78% and 15 patients proceeded to allogeneic hematopoietic stem cell transplantation. CONCLUSION: The regimen was well tolerated and is a viable re-induction option for patients with residual disease on a day 14 bone marrow.

Re-induction chemotherapy regimens in patients with recurrent central nervous system mixed malignant germ cell tumors.

BACKGROUND: The lack of a standard treatment approach has contributed to poor outcomes of patients with recurrent central nervous system (CNS) mixed malignant germ cell tumors (MMGCT). There are no data in the literature supporting optimal re-induction chemotherapy regimens that should be used for patients with recurrent CNS MMGCT. METHODS: We conducted a literature review to explore the response rate of patients with recurrent CNS MMGCT to different re-induction chemotherapy regimens by searching PubMed from 1985 through November 2017. Tumors were classified according to Japanese, European, and North American prognostic group classifications determined at initial presentation. RESULTS: Forty-two responses to various re-induction chemotherapy regimens reported in 38 patients were included. Two patients were inevaluable and their responses to re-induction chemotherapy were excluded. Thirty-five responses to various re-induction chemotherapy regimens were evaluable in 33 patients following a first relapse. Six (17%) responses were reported as complete or continuous complete responses, seven (20%) partial responses, two (6%) were stable disease, two (6%) were mixed responses, and 18 (51%) were progressive disease. Five of ten patients treated without platinum-based chemotherapy experienced tumor progression. There was a trend towards a higher rate of tumor progression among histological poor prognostic group patients, and among patients relapsing within 24 months of initial diagnosis; however, it was not statistically significant. CONCLUSIONS: The histological prognostic group and time to relapse may affect the response to re-induction chemotherapy. However, further studies with larger sample size are needed to examine these associations and determine the optimal re-induction chemotherapy regimens for patients with recurrent MMGCT.

Re-induction chemotherapy using FLAG-mitoxantrone for adult patients with relapsed acute leukemia: a single-center experience from United Arab Emirates.

We studied the outcome of 47 adult patients with relapsed acute leukaemia (AML = 25 and ALL = 22) treated with FLAG-mitoxantrone regimen. Median time to relapse was 10.7 months (range 1.9-27.7). Complete remission (CR2) was 60.1% which was significantly more frequent in ALL compared to AML (P = 0.049). WBC count < 100 × 109/L at initial diagnosis and time to relapse > 1 year were significantly predictor for CR2 in AML (P = 0.005 for both). Induction death was significantly higher in ALL compared to AML (P = 0.039). Median follow-up was 4.0 months (0.9-119.8) for AML and 2.1 months (range 0.6-118.1) for ALL. Nine patients underwent allogeneic stem-cell transplantation (allo-SCT). Estimated overall survival (OS) at 12 and 18 months was 60.5 and 34.6%, respectively, for AML, and 39.9 and 29.9%, respectively, for ALL. For AML patients failure to achieve CR, WBC count at initial diagnosis > 5 × 109/L and poor cytogenetic risk group was significant predictors of poor OS (P = 0.010, P = 0.025, and P = 0.015, respectively). For ALL patients failure to achieve of CR, WBC count at relapse < 5 × 109/L (CR patients) and lack of any type of consolidation therapy were significant predictor of poor OS (P < 0.001, P = 0.008, P = 0.008, respectively).

Extracellular vesicles in leukemia.

Extracellular vesicles (EV) are nano-sized membrane enclosed vehicles that are involved in cell-to-cell communication and carry cargo that is representative of the parent cell. Recent studies have highlighted the significant roles leukemia EVs play in tumor progression, and ways in which they can lead to treatment evasion, thus meriting further investigation. Leukemia EVs are involved in crosstalk between the leukemia cell and its surroundings, transforming it into a cancer favorable microenvironment. Due to the diverse biological content found in leukemia EVs, they have an assortment of effects on the cells they interact with and can be harnessed as candidates for diagnostic and therapeutic treatments. This review focuses on EVs in the context of leukemia and the means by which they modulate their microenvironment, hematopoiesis, and the immune system to facilitate malignancy. We will also address current and prospective EV-based therapeutics.

Efficacy and safety of re-induction therapy with bevacizumab and paclitaxel for metastatic breast cancer.

BACKGROUND: In many trials (including E2100), bevacizumab (Bmab) monotherapy has been continued if toxicity of paclitaxel (PTX) becomes unacceptable during combined treatment with Bmab and PTX. When progression occurs on Bmab monotherapy, one possible option is re-induction with the combination of Bmab and PTX (rBP therapy), because PTX was previously stopped due to toxicity rather than progression. However, we have no data about rBP therapy. Therefore, we investigated the efficacy and safety of rBP therapy in this study. METHODS: We retrospectively investigated 46 patients who started Bmab and PTX between October 2011 and April 2013 at our institution. RESULTS: After induction with Bmab and PTX, 19 patients subsequently received Bmab monotherapy and 12 patients received rBP therapy. The overall response rate and clinical benefit rate of rBP therapy was 25 % (3/12) and 58 % (7/12), respectively, while the median time to failure of rBP therapy was 174 days (95 % CI 49-273). The median overall survival time of the 46 patients was 777 days (95 % CI 543-NA). Adverse events of grade 3 or worse associated with rBP therapy were neutropenia (25 %), fatigue (8 %), and gastrointestinal bleeding (8 %). CONCLUSIONS: This is the first report about rBP therapy, which was found to be both safe and effective. The OS of all 46 patients in this study (including 12 patients given rBP therapy) was better than in past reports. Selecting rBP therapy for patients with progression on Bmab monotherapy might have contributed to better overall survival, but a randomized controlled trial will be needed to confirm these findings.

Hematopoietic stem cell transplantation following unsuccessful salvage treatment for relapsed acute lymphoblastic leukemia in children.

BACKGROUND: For children who experience a re-induction failure or multiple recurrences following the first relapse of acute lymphoblastic leukemia (ALL), it is uncertain whether additional intensive chemotherapy aimed at hematopoietic stem cell transplantation (SCT) in complete remission (CR) or immediate SCT even in non-CR should be performed. This study aimed to investigate the impact of disease status at SCT on the outcomes of SCT for these children, whose prognosis is considered unquestionably poor even with SCT. PROCEDURE: The medical records of 55 children with ALL who underwent SCT following the experience of re-induction failure (n = 25) or multiple relapses (n = 30) were retrospectively analyzed. RESULTS: Twenty-one patients underwent SCT in CR (delayed CR2, CR3, and CR4) and 34 in non-CR (first or subsequent relapse). The probability of overall survival of patients with CR and with non-CR at SCT was 42.9% and 23.5% (P = 0.15), leukemia-free survival was 38.1% and 20.6% (P = 0.18), and the cumulative incidence of relapse at 2 years was 23.8% and 50%, respectively (P = 0.05). In multivariate analysis, non-CR at SCT was a significant risk factor for higher relapse incidence and male sex was a significant risk factor for lower survival. CONCLUSIONS: Our results indicated that in case of tolerable patient condition, further re-induction chemotherapy might be reasonable so that SCT could be performed in CR, which might result in a low incidence of relapse after SCT. Novel approaches are required to induce CR for the treatment of children with relapsed/refractory ALL.