Additional Courses Of Chemotherapy Research Articles

Final Results of the AIEOP (Associazione Italiana Ematologia/Oncologia Pediatrica) AML 2013 Prospective Randomized Trial in Childhood Acute Myeloid Leukemia (AML)

Background: Treatment of children with newly diagnosed AML is based on induction therapy, followed by consolidation approaches which differ according to the group of risk patients (pts) are allocated to. In this respect, most treatment protocols stratify pts into 3 risk groups, namely standard (SR), intermediate (IR) and high-risk (HR), mainly based on the molecular/cytogenetic characterization and values of measurable residual disease (MRD) at the end of induction therapy. We report the outcomes of 371 pts with de novo AML other than acute promyelocytic leukemia (aged 0-18) enrolled in the randomized trial AIEOP AML 2013 (EudraCT:2014-000652-28). Patients and methods: pts were diagnosed and enrolled in the trial from 06/2015 to 06/2022 at 33 Centers affiliated to the AIEOP group. Main pt characteristics and criteria used for stratification are shown in Table 1. A marker of recurrent molecular lesions was detected at diagnosis for 247 cases out of the 371 enrolled (67%). Monitoring of flow-cytometry MRD at the end of the 1 st and 2 nd induction course was centrally performed in all pts but 7. The 1 st induction course was common for all pts (ICE scheme), while, then, SR pts were treated with 4 additional chemotherapy courses, all including high-dose cytarabine (HD-Ara-C). IR and HR pts were randomized to receive either a 2 nd ICE or the FLA-Liposomal Doxorubicin (L-Doxo) scheme as 2 nd induction course. IR pts were given 3 additional consolidation courses including HD-Ara-C with other agents or, in the presence of an HLA-compatible sibling, 1 consolidation course followed by allogeneic hematopoietic stem cell transplantation (HSCT). Pts of the HR group were consolidated with 2 courses of HD-Ara-C combined with other cytotoxic agents and, then, had an indication to receive HSCT from either a donor compatible for > 9/10 HLA loci or from an HLA-partially matched relative. Data cut-off for the analysis was March 31, 2023. Results: The proportion of pts allocated to the SR, IR and HR groups were 19% (72 pts), 23% (81 pts) and 58% (218 pts), respectively. Overall, 92% of pts obtained morphological complete remission (CR) at the end of the 2 induction courses [as compared to 87% of the previous AIEOP AML 2002 study (Pession et al. Blood 2012), p<0.05]. Twenty-five pts (7%) experienced a primary induction failure. Only 3 pts died during or after the 2 induction courses, while the subsequent cumulative incidence of 3-yr non-relapse mortality in continuous CR was 6.8%. Leukemia recurrence occurred in 63 pts, this leading to a 3-yr cumulative incidence of relapse of 18.9%. With a median follow-up of 4.5 yrs (range 0.8-8), the 3-yr probabilities of overall (OS) and event-free survival (EFS) were 83.9% and 68.5% (Figure 1), respectively, both values being significantly better (p<0.01) than those of the AIEOP AML 2002 study. The 3-yr OS of SR, IR and HR pts were 99.2%, 84.2% and 79.4%, respectively (p=0.01). The 3-yr estimate of disease-free survival (DFS) was 74.3%, with no difference among the 3 risk groups. The EFS did not differ in IR and HR randomized to receive either a 2 nd ICE or the FLA-L-Doxo scheme as second induction course. Levels of flow-cytometry MRD after the 2 nd induction course strongly influenced the probability of EFS which was 76% and 48% in pts with an MRD value < or >0.1%, respectively (p<0.01). Allogeneic HSCT was performed in 160 pts; in these pts, the 3-yr probabilities of OS and DFS were 87.7% and 85.1%, respectively, with no difference according to the type of donor employed. The DFS of the 10 IR pts given HSCT was 100% as compared to 72.1% of the 71 not transplanted (p=0.07). The outcome of infants treated in this study was particularly good, since their 3-yr probability of EFS was 78.3%. The 3-yr EFS of the 35 pts with FLT3-ITD and of the 75 with KMT2-A rearrangements were 57.1% and 64.7%, respectively. Conclusions: These results indicate that in children enrolled in the trial AIEOP AML 2013 the 3-yr OS and EFS overcomes 80% and approaches 70%, respectively, with a significant improvement as compared to the previous AIEOP protocol. Disease recurrence/primary resistance were the main cause of treatment failure, while the probability of DFS did not differ among the 3 different risk groups, this finding indicating that tailoring of consolidation therapy according to the risk profile was successful in improving the outcome of pts with worse prognostic characteristics. The use of FLA-L-Doxodid not offer any advantage over repeating a 2 nd ICE.

Novel Tumor Organoid-Based Mouse Model to Study Image Guided Radiation Therapy of Rectal Cancer After Noninvasive and Precise Endoscopic Implantation

PurposePreoperative (neoadjuvant) radiation therapy (RT) is an essential part of multimodal rectal cancer therapy. Recently, total neoadjuvant therapy (TNT) which combines simultaneous radio-chemotherapy with additional courses of chemotherapy (CTx) has emerged as an effective approach. TNT achieves a pathological complete remission in approximately 30% of resected patients, opening avenues for treatment strategies that avoid radical organ resection. Furthermore, recent studies have demonstrated that anti-PD-1 immunotherapy (IT) can induce clinical complete responses in patients with specific genetic alterations. Overall, there is significant potential to enhance outcomes through intensifying, personalizing, and de-escalating treatment approaches. However, the heterogeneous response rates to RT or TNT and strategies to sensitize patients without specific genetic changes to IT remain poorly understood. Materials and MethodsWe developed a novel orthotopic mouse model of rectal cancer which is based on precisely defined endoscopic injections of tumor organoids that reflect tumor heterogeneity. Subsequently, we employed endoscopic- and computed tomography-guided RT, and validated rectal tumor growth and response rates to therapy using small animal magnetic resonance imaging and endoscopic follow-up. ResultsRectal tumor formation was successfully induced in all mice following two organoid injections. Clinically relevant RT regimens with 5 × 5 Gy significantly delayed clinical signs of tumor progression and significantly improved survival. Consistent with human disease, rectal tumor progression correlated with the development of liver and lung metastases. Notably, longterm survivors after RT showed no evidence of tumor recurrence, as demonstrated by in vivo radiological tumor staging and histopathological examination. ConclusionsOur novel mouse model combines orthotopic tumor growth via non-invasive and precise rectal organoid injection and small animal RT. This model holds significant promise for investigating the impact of tumor cell-intrinsic aspects, genetic alterations of the host, or exogenous factors (e.g., nutrition or microbiota) on RT outcomes. Furthermore, it allows for the exploration of combination therapies involving CTx, IT or novel targeted therapies.

Retrospective Analysis of the Outcomes of Patients with Relapsed/Refractory Acute Myeloid Leukemia Included in a Patient Named Program of Gemtuzumab Ozogamicin

▪Introduction: In 2010 the French Health Agency opened a compassionate patient named program of gemtuzumab ozogamicin (GO, Mylotarg®) in relapsed/refractory (R/R) patients with acute myeloid leukemia (AML). Of note, since 2012, it was recommended to use GO at the dose of 3 or 6 mg/m 2 in addition to chemotherapy. We conducted a retrospective trial (NCT03287128) to evaluate the efficacy and the safety of GO-based regimen in R/R adult AML patients.Patients and methods: We retrospectively collected data of patients older than 18 years treated with GO-based regimen for AML in first relapse or for refractory AML, defined by failure after a prior standard intensive chemotherapy, in 18 French centers between December 15, 2011 and November 10, 2016. The primary objective was to assess the response to GO-based regimen. Patients were considered in response if reaching complete remission (CR), CR without platelet recovery (CRp) or CR with incomplete hematological recovery (CRi). Secondary objectives were the cumulative incidence of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and the safety of the use of GO-based regimen.Results: Three hundred and thirty-five adult patients with R/R AML were included. Median age was 58 years (20 to 80 years). At diagnosis, cytogenetics was favorable in 50 (17%) patients, intermediate in 173 (59%) and adverse in 60 (20%). ELN distribution was favorable: 35%, intermediate: 42% and unfavorable: 23%. NPM1 mutation was present in 29% of patients and FLT3 mutation in 23%. Most patients had de novo AML (84%). Two hundred and thirty-eight patients (79%) were in first relapse and 65 (21%) had a refractory AML. The time between first diagnosis of AML and treatment with GO-based regimen was 4 to 16 months (median 9.4 months). Most patients (88%) received GO in combination with various intensive chemotherapy scheme including “7+3” with anthracycline/cytarabine (n=39 patients), intermediate and high-dose cytarabine (n=68), cytarabine in continuous intravenous infusion (n=78), mitoxantrone/cytarabine (n=49) and fludarabine/cytarabine and/or amsacrine and/or etoposide chemotherapy (n=35). Median follow-up time was 11 months.Among the 305 patients, 191 responded to GO-based regimen: 110 (36%) were in CR, 62 (20%) were in CRp and 19 (6%) in CRi for an overall response rate (CR+CRp+CRi, ORR) of 63%. In multivariate analysis, response was associated with age <50 years, de novo AML and relapse status. Among the 191 responders, 110 received additional courses of chemotherapy, 69 with GO. Main reason to not receive additional course (with or without GO) was allo-HSCT project. In the whole population, median overall survival (OS) after day 1 of treatment with GO was 11.2 months. In the population of responders, median OS after response was 20.4 months. In multivariate analysis, longer survival was associated with age < 50 years, de novo AML and favorable ELN group. Cumulative incidence of relapse at 24 months after response was 46%. One hundred and forty-seven patients received allo-HSCT, including 122 responders after GO-based regimen and 25 patients in treatment failure. Cumulative incidence of allo-HSCT at 18 months was 48%. Four-year OS was 48% in transplanted patients versus 19% in non-transplanted patients (Figure 1).Regarding safety of GO-based regimen, early deaths occurred within <30 days after the first dose of GO in 14 patients, and within <60 days in 35 patients. Myelosuppression was observed in all patients. Mean duration of thrombocytopenia <100 G/L was 35 days in responders. Bleeding grade 3 or more was observed in 22 patients (7%). Infection grade 3 or more was observed in 112 patients (30%). Sinusoidal obstruction syndrome (SOS) after GO treatment was reported in 6 patients, resolving in 4 of them. Four cases of fatal SOS were reported after allo-HSCT. Toxic deaths, i.e., not related to worsening leukemia, were reported in 20 patients after the first course of chemotherapy, 3 after additional courses and 33 after allo-HSCT.Conclusion. Our study is the first to report efficacy data in the real-world setting of R/R AML adult patients treated with GO-based regimen. In our cohort of 305 patients, response rate was 63% and GO-based regimen appears as a valuable bridge-to-transplant option. Safety analysis showed toxicities consistent with the known safety profile of GO and chemotherapy. [Display omitted] DisclosuresLambert: ASTELLAS: Consultancy; CELGENE/BMS: Consultancy. Pautas: PFIZER: Consultancy; ABBVIE: Consultancy. Raffoux: ASTELLAS: Consultancy; PFIZER: Consultancy; ABBVIE: Consultancy; CELGENE/BMS: Consultancy. Legrand: Servier: Consultancy. Gastaud: PFIZER: Consultancy; CELGENE/BMS: Consultancy; ABBVIE: Consultancy; GSK: Consultancy. Pigneux: Amgen: Consultancy; Sunesis: Consultancy, Research Funding; BMS Celgene: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Mathilde: SERVIER: Consultancy; ABBVIE: Consultancy. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Castaigne: PFIZER: Consultancy.

Unresectable thoracic neuroblastic tumors: Changes in image‐defined risk factors after chemotherapy and impact on surgical management

Neuroblastoma management in children is multimodal and depends on multiple factors, including the possibility of complete surgical resection. Image-defined risk factors (IDRFs) are used to assess the feasibility of primary surgery. We studied the changes in IDRFs after neoadjuvant chemotherapy for thoracic neurogenic tumors. We performed a multicenter review of 27 patients presenting with unresectable thoracic neurogenic tumors. Patients received neoadjuvant chemotherapy, according to their risk group. IDRF at diagnosis and before surgery were retrospectively analyzed by a radiologist and a surgeon, blind to the initial assessment. Surgical and oncologic outcomes were reviewed. None of the patients presented MYCN amplification, and 78 IDRFs were identified at diagnosis. Vascular IDRFs were the most frequent, with 28 vascular IDRFs detected in 18 patients, 22 of which disappeared after chemotherapy. Reductions of tumor volume were associated with a regression of IDRFs. Patients undergoing minimally invasive surgery had smaller tumor volumes than those undergoing open surgery, and no vascular IDRF. Two patients received two additional courses of chemotherapy to reduce tumor volume sufficiently for surgery. One patient with ganglioneuroblastoma underwent early surgery due to a lack of response to initial chemotherapy. Tumor volume reduction with neoadjuvant chemotherapy eliminates most IDRF in thoracic neurogenic tumors. Vascular IDRF are rapidly resolved at this site, making surgical resection and minimally invasive surgery possible.

An endoscopic dilation method using the rendezvous approach for the treatment of severe anastomotic stenosis after rectal cancer surgery: a case report

BackgroundPostoperative anastomotic stenosis is a common complication in colorectal cancer patients (3–30%). Complete anastomotic stenosis is rare; however, when it occurs, almost all cases require surgical treatment. We herein report a case in which endoscopic dilation was effective for treating complete anastomotic stenosis after high anterior resection in a rectal cancer patient.Case presentationThe patient was a 67-year-old man who underwent laparoscopic high anterior resection for rectal cancer (RS, T4a, N0, M0, Stage IIB (TNM Classification of Malignant Tumors)) in May 2018. The postoperative course was good and the patient was discharged on the 12th postoperative day. Subsequently adjuvant chemotherapy was initiated with oral uracil and tegafur plus leucovorin (UFT/LV); however, he complained of frequent defecation and melena after completion of the first course of chemotherapy. Thus, colonoscopy was performed, which revealed anastomotic stenosis. Endoscopic dilation was initially attempted, but failed. Thus, low anterior resection was performed with diverting colostomy. Four additional courses of chemotherapy were administered for 1 month after surgery. At 6 months after the second surgery, colonoscopy was performed, and complete anastomotic stenosis was pointed out again. The patient was successfully treated by endoscopic dilation using the rendezvous method. After this treatment, the lumen of the anastomotic site was observed to have narrowed again and endoscopic dilatation to treat anastomotic stenosis was repeated. In addition, he received local injection of steroids in anastomotic stenosis site. The lumen of anastomotic stenosis remained after the local injection of steroids and closure of colostomy was performed 9 months after the second operation.ConclusionsEndoscopic dilation using the rendezvous method was effective for treating anastomotic stenosis after colorectal surgery.

PB1685 RELAPSE OF ACUTE LYMPHOBLASTIC LEUKEMIA MIMICKING MIKULICZ SYNDROME DURING BLINATUMUMAB TREATMENT: A CASE REPORT

Background:Mikulicz syndrome is a rare immune mediated condition characterized by tumor‐like swelling, lymphoplasmacytic infiltrate and fibrosis of salivary and lacrimal glands of poorly understood etiology. Its clinical presentation in the course of treating acute leukemia can be hard to differentiate from progression of the disease. We present a challenging diagnostic case of extramedullary acute lymphoblastic leukemia (ALL) relapse in the course of blinatumumab.Aims:Case report that aims to remember that AAL relapse can mimic any clinical picture.Methods:A 42‐year‐old woman was diagnosed in May 2017 with acute pro‐B lymphoblastic leukemia Ph negative, EGIL B‐II. Treatment with intensive multiagent chemotherapy according to PETHEMA high risk group was started. After induction, patient achieved complete response (CR) with negative minimal residual disease (MRD). Four additional courses of chemotherapy were completed following the PETHEMA high risk schedule. First relapse occurred and salvage therapy with Fludarabine, Ara‐C and Idarubicin was started achieving 2nd CR. Unfortunately, the patient relapsed three months later in the bone marrow and blinatumumab was decided. Two cycles were administered without neurological toxicities achieving CR with MRD of 0.31% and 0.11% after 1st and 2nd cycles, respectively. On 26th day of the 3rd cycle, acute swelling of both submandibular glands, swelling of right parotid gland and right monocular diplopia were observed. Cervical and cranial magnetic resonance was performed (Image 1) showing significant enlargement of the right lacrimal gland and bilateral submandibular glands. Bone marrow aspiration (BMA) showed CR with improved MRD of 0.02%. Cytological and cytometric cerebrospinal fluid analysis did not find ALL infiltration. With no evidence of disease progression and given the characteristics of the clinical and radiological picture, Mikulicz Syndrome was raised as a probable diagnostic possibility. However, a submandibular glandular tru‐cut biopsy showed glandular infiltration by ALL cells. One week later, a body PET/CT found significant metabolic uptake activity in the glands, regional lymph nodes and extensive bone involvement. Then, a new BMA (performed 10 days after de previous one) demonstrated ALL massive medullar relapse.Results:Relapsed/refractory (R/R) ALL is a bad condition with poor survival. Isolated extramedullary ALL relapse occurs in up to 6% of ALL according to literature and is often hard to demonstrate. In our case, the picture started as neck and head glandular swelling and diplopia. In the absence of medullar disease, Mikulicz Syndrome was suspected. Mikulicz Syndrome is a rare immune chronic benign condition characterized of swelling of neck and head glands where diplopia is often the first clinical sign. It has been related with several diseases including sarcoidosis, lymphoma and acute lymphoblastic leukemia. In this scenario, a biopsy of the involved glands is strongly recommended to rule out leukemia progression. In our case, tru‐cut biopsy of one of the involved glands demonstrated AAL extramedullary relapse despite absence of medullar involvement. Unfortunately, massive medullar relapse was confirmed a week later.Summary/Conclusion:Mikulicz syndrome is a diagnostic challenge for clinicians. In the setting of patients with ALL under blinatumumab treatment, clinicians should rule out ALL relapse before confirming this rare condition.image

Ewing Sarcoma in Nepal Treated With Combined Chemotherapy and Definitive Radiotherapy.

PURPOSETo our knowledge, we conducted the first prospective oncologic clinical trial in Nepal aimed at providing state-of-the-art chemotherapy to patients with Ewing sarcoma. The efficacy of external-beam radiotherapy (RT) as the sole local treatment modality was explored and deemed justified as a result of the lack of available advanced tumor-orthopedic services in Nepal.PATIENTS AND METHODSTwenty patients, 11 female and 9 male patients between the ages of 6 and 37 years, with newly diagnosed Ewing sarcoma were enrolled. Neoadjuvant combination chemotherapy, comprising well-established drug combinations, was administered in five courses before external-beam RT, during which one course of etoposide and ifosfamide was given. After RT, six additional chemotherapy courses were scheduled.RESULTSRT was tolerated well, providing rapid symptom relief and local tumor control, with no pathologic fractures observed among the 15 patients who received such treatment. Eleven patients completed the entire treatment protocol; seven patients were under continued follow-up, with no evidence of disease in six patients at a median follow-up time of 2.3 years (range, 1.3 to 3.1 years) and one patient alive but with a regional recurrence. Four patients experienced metastatic relapse and died as a result of their disease. Three treatment-related deaths linked to toxicity from chemotherapy occurred. Four of the six patients who refused to complete the treatment protocol and were lost to follow-up experienced progressive disease and were assumed dead.CONCLUSIONThis study was feasible with RT as the sole local treatment modality in combination with chemotherapy. As a result of the high number of patients lost to follow-up, no firm conclusions can be drawn, but the majority of the patients who completed treatment obtained durable long-term remissions.

Blinatumomab As a Successful Bridge to Hematopoietic Stem Cell Transplant in a Down Syndrome Patient with Relapsed B-Precursor Acute Lymphoblastic Leukemia

Introduction Children with Down syndrome (DS) carry a 20-fold higher risk of developing acute lymphoblastic leukemia (ALL) than other children and have increased rates of treatment-related mortality (TRM) and relapse. The prognosis for relapsed DS-ALL patients is grim with long-term survival rates of 20%. Blinatumomab, a CD19/CD3 bispecific antibody, is FDA approved for relapsed pediatric pre-B ALL, and recently approved for patients with minimal residual disease (MRD). However there are few reports of the use of blinatumomab in DS-ALL patients, and no reports of blinatumomab as a bridge to stem cell transplant (SCT) in this population. Case Description A 19 year old male with DS presented with thrombocytopenia and was diagnosed with pre-B ALL. Upfront therapy included fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, pegaspargase, and rituximab for 8 cycles, and he achieved complete remission (CR). Maintenance therapy included 26 months of 6-mercaptopurine, vincristine, methotrexate, and prednisone. He relapsed 5 months after completion of therapy and was found to have a P2RY8-CRLF2 fusion. IgH gene rearrangement analysis by next generation sequencing (LymphoTrack assay) demonstrated clonal rearrangement. Re-induction therapy included vincristine, pegaspargase, and prednisone. He completed 2 additional courses of chemotherapy but continued to have MRD both by flow cytometry and LymphoTrack. Given persistent MRD with CD19+ lymphoblasts, he was treated with blinatumomab at the FDA recommended dosing; he had no signs of toxicity. He achieved negative MRD by flow cytometry and LymphoTrack after 1 cycle. He then proceeded to a T-cell depleted peripheral blood SCT from a 10/10 matched sibling after conditioning with total body irradiation, thiotepa, and cyclophosphamide. Post-SCT course was uncomplicated and he is now 1 year post-SCT with no evidence of leukemia and 100% donor chimerism. Conclusion Blinatumomab is clinically effective and safe for patients with relapsed/refractory pre-B ALL, yet there is limited information on its use in DS-ALL patients. These patients have been largely excluded from blinatumomab trials given their altered immune system and unknown level of innate T cell dysfunction, potentially altering the efficacy of blinatumomab. We present here the case of a 22 year old male with relapsed DS-ALL who remained MRD positive after several cycles of re-induction chemotherapy, but achieved a CR following 1 cycle of blinatumomab with no toxicities, and safely proceeded to SCT. Although this is a single case, it demonstrates clinical efficacy of blinatumomab in relapsed DS-ALL, suggesting that these patients' T cells can be engaged to recognized CD19-positive leukemic blasts. Furthermore, blinatumomab represents a particularly attractive bridging therapy to SCT for DS-ALL patients who experience high rates of TRM with traditional agents.

Additional Consolidation after Attaining Second Complete Remission Results in Superior Outcomes after Allogeneic Hematopoietic Cell Transplantation in Adults with Acute Lymphoblastic Leukemia

IntroductionTreatment outcomes for adult patients with relapsed ALL are limited. Allogeneic hematopoietic cell transplantation (HCT) is the only curative option in a small subset of patients. We sought to investigate the optimal extent of therapy required prior to proceeding to transplant in second complete remission (CR2).Methods126 consecutive patients with ALL in CR2 underwent HCT at MD Anderson Cancer Center between January 2004 to December 2015. The patient and transplant characteristics are described in table 1. The probabilities of outcomes were calculated with the Kaplan-Meyer method. Variables found to be significant at the p<0.1 level were included in a Cox regression multivariate model. Relative risks (RR) are reported with 95% confidence intervals (CI). All p values are two sided.ResultsMedian follow-up was 38.4 months (range 6-125). The 3-year overall survival (OS), progression-free survival (PFS) and transplant-related mortality (TRM) were 34.6%, 29.5% and 33.2%, respectively. Eighty-three patients received at least one course of chemotherapy after achieving CR2 (median 2, range 1-6). These patients had significantly better OS, PFS and relapse rate than the 34 patients that went to transplant immediately after achieving CR2. Namely, 43.8% vs 7.6% (p=0.002), 39.4% vs. 5.1% (p=0.002) and 37.9% vs. 89.5% (p<0.001), respectively. Both groups had comparable TRM (Table 1). Interestingly, these differences were independent of the patient’s minimal residual disease (MRD) status prior to transplant (Figure 1). Similar results were found when we limited the analysis to the 96 patients who achieved CR2 with the first line of salvage therapy. OS in this group was 46.0% vs. 9.4% (p=0.009) for patients who required additional lines of salvage chemotherapy to achieve CR2.Patient’s age, performance status, comorbidity index and graft source were also predictive for outcome. In multivariate analysis receiving at least one additional course of chemotherapy after achieving CR2 (RR=0.53, CI=0.31-0.91, p=0.02), age>45 (RR=2.06, CI=1.20-3.53, p=0.009), alternative graft sources (RR=1.81, CI=1.09-2.97, p=0.02) and Karnofsky <90% (RR=1.68, CI=1.01-2.79, p=0.04) were independent predictors for OS. Receiving at least one additional course of chemotherapy after achieving CR2 (RR=0.52, CI=0.31-0.87, p=0.01), age>45 (RR=1.92, CI=1.15-3.20, p=0.01) and Karnofsky <90% (RR=1.86, CI=1.14-3.03, p=0.01) were independent predictors for PFS.Conclusion:The outcome of patients with relapsed ALL who proceed to HCT immediately after achieving CR2 is dismal. Our data supports the notion that patients should receive at least one additional course of treatment after achieving CR2 prior to transplantation, regardless of MRD status. However, our observations must be interpreted with caution as this was not an intent to treat analysis so we could not adjust for loss of patients prior transplantation. Further analysis on an intent to treat basis is underway. [Display omitted] [Display omitted] DisclosuresCiurea:Spectrum Pharmaceuticals: Other: Advisory Board; Cyto-Sen Therapeutics: Equity Ownership. Jabbour:Pfizer: Research Funding; BMS: Consultancy; ARIAD: Research Funding; Pfizer: Consultancy; Novartis: Research Funding; ARIAD: Consultancy. Kantarjian:BMS, Pfizer, Amgen, Novartis: Research Funding. Champlin:Intrexon: Equity Ownership, Patents & Royalties; Ziopharm Oncology: Equity Ownership, Patents & Royalties.

The Addition of Bortezomib to Standard Chemotherapy for Pediatric Acute Myeloid Leukemia Has Increased Toxicity without Therapeutic Benefit: A Report from the Children's Oncology Group

▪Introduction:Despite the very high intensity of current chemotherapy regimens for children with acute myeloid leukemia (AML), approximately 50% of patients will experience disease relapse. New therapeutic strategies to improve clinical outcomes have centered on improving the efficacy of standard chemotherapy with novel agents such as gemtuzumab and other agents designed to augment standard chemotherapy. Bortezomib, a proteasome inhibitor, is one such agent. The Children's Oncology Group (COG) Phase III clinical trial AAML1031 tested the hypothesis that the addition of bortezomib to standard chemotherapy would improve treatment outcomes in pediatric patients with newly diagnosed AML.Methods:The COG AAML1031 trial randomized patients younger than 30 years of age with de novo AML to either standard chemotherapy (Arm A) or standard chemotherapy with bortezomib (Arm B). Patients with high allelic ratio FLT3 ITD were offered enrollment on a standard chemotherapy plus sorafenib (Arm C, n = 102) and are excluded from this efficacy analysis. All patients received induction chemotherapy with cytarabine, daunorubicin, and etoposide (ADE). Risk stratification occurred at the end of ADE induction and was based on the presence of high risk cytogenetic/molecular markers and/or minimal residual disease (MRD) >0.1% determined by multidimensional flow cytometry. Low risk patients received three additional courses of chemotherapy consisting of a second course of ADE, a third course of cytarabine/etoposide and a fourth course of cytarabine/mitoxantrone. High risk patients received a second course of cytarabine/mitoxantrone, a third course of cytarabine/etoposide, and then allogeneic stem cell transplant (SCT) from the best available donor. Bortezomib 1.3 mg/m2 was given on days 1, 4 and 8 of each cycle with one dose de-escalation to 1 mg/m2 allowed for dose limiting toxicity.Results:A total of 1097 patients were randomized to either standard therapy (Arm A, n = 542) or standard chemotherapy with bortezomib (Arm B, n = 555). No statistically significant differences in sex, age, race, ethnicity, WHO classification, initial blast count, or initial CNS status was observed between arms. Remission induction rate did not differ between treatment arms 89% vs 91%, p = 0.457. MRD was negative in 75% of patients on both treatment arms at the end of Induction I and mean MRD measures did not differ significantly: 2.8% vs 1.9%, p = 0.247. For all patients, event free survival (EFS) and overall survival (OS) at 3 years were 44.4% ± 3.8% and 60.6% ± 4.4%. EFS was not significantly different between Arms A and B (44.0% ± 5.2% vs 44.6% ± 5.6%, p = 0.285) (Figure 1). Likewise, OS was similar between arms (59.0 ± 6.7 vs 62.2 ± 6.0, p = 0.732) (Figure 1). One year cumulative treatment related mortality (TRM) was 14.6 ± 9.3 and 10.8 ± 7.5, p = 0.49 for Arms A and B, respectively. No significant differences were seen in OS, disease-free survival, and TRM from the end of Induction I in low and high risk groups. Cox proportional hazards analysis demonstrated that initial WBC count at diagnosis was the only consistently identified risk factor for OS, DFS, and TRM. Targeted toxicity monitoring identified increased toxicity risks in Arm B for peripheral neuropathy (Induction I/II), dose reductions (all chemotherapy courses), and PICU admissions (Induction I/II) and Intensification I). Serial monitoring of cardiac ejection fraction/shortening fraction in all patients did not demonstrate a clinically meaningful difference in drop in ejection fraction/shortening fraction by treatment arm. No other consistent differences in targeted toxicity rates were identified.Conclusions:The addition of bortezomib to standard chemotherapy increased toxicity but did not improve EFS or OS in children with newly diagnosedAML Consequently, bortezomib should not be used in children with de novo AML in combination with standard chemotherapy. Future work will evaluate the role of intensifying Induction II therapy for patients with high risk AML, further refine risk stratification, and define a more optimal role for allogeneic donor SCT in pediatric AML. [Display omitted] DisclosuresLoken:Hematologics: Employment, Equity Ownership.

Pleuropulmonary blastoma type III extended into the left atrium in a 16-month old boy

Pleuropulmonary blastoma is an uncommon paediatric neoplasm. Approximately 300 cases have been reported. In seven tumours, extension involved the left heart. Type III occurs typically at ages 3 or 4 years. We report this very unusual case of extensive disease in a 16-month old male patient. Chest computerized tomography revealed a mass extending into the right hemithorax from the posterior mediastinum and propagating inside the left atrium through the right pulmonary veins. Echocardiography showed a huge flexible mass occupying almost all of the left atrium cavity and intermittently prolapsing through the mitral valve. Two preoperative chemotherapy courses of ifosfamide, vincristine, actinomycin D and doxorubicin were administered at 3-week intervals. The patient was placed on cardiopulmonary bypass, cardiac arrest and the left atrium was opened. The tumour and orifice of the inferior right pulmonary vein were resected and the normal free borders reconstructed. A large mass occupying the right pleural space was removed. Seven additional courses of chemotherapy were given. In a 'second-look' surgery 6 months later, through a right thoracotomy, the residual mass at the posterior mediastinum was resected. The child received four additional courses of chemotherapy. After 12 months of the initial resection, there is no evidence of recurrence.

Retroperitoneal abscess shortly after chemotherapy for lung cancer: A case report

To the best of our knowledge, the formation of a retroperitoneal abscess due to acute appendicitis shortly after administration of chemotherapy for lung cancer has not been previously reported. This is the case report of a 59-year-old male who was admitted to the Mito Medical Center (Mito, Japan) and diagnosed with lung adenocarcinoma with pleuritis carcinomatosis. Although no distant metastasis was identified, combination chemotherapy with cisplatin and pemetrexed was administered. Nine days after initiating chemotherapy, the patient developed right lower quadrant abdominal pain and high fever. Computed tomography (CT) of the abdomen and pelvis revealed the collection of gas and fluid in the retroperitoneum adjacent to the cecum. The abscess was locally drained; however, the infection continued to spread, with subsequent development of a scrotal abscess. Consequently, appendectomy was performed. The patient recovered well and the lung adenocarcinoma was treated with additional courses of chemotherapy following the remission of the local inflammation. Retroperitoneal abscess due to acute appendicitis is an unusual finding; however, this rare complication should be considered during or shortly after chemotherapy in patients with lung cancer.

Minimal residual disease-directed therapy for childhood acute myeloid leukaemia: results of the AML02 multicentre trial

We sought to improve outcome in patients with childhood acute myeloid leukaemia (AML) by applying risk-directed therapy that was based on genetic abnormalities of the leukaemic cells and measurements of minimal residual disease (MRD) done by flow cytometry during treatment. From Oct 13, 2002, to June 19, 2008, 232 patients with de-novo AML (n=206), therapy-related or myelodysplasia-related AML (n=12), or mixed-lineage leukaemia (n=14) were enrolled at eight centres. 230 patients were assigned by block, non-blinded randomisation, stratified by cytogenetic or morphological subtype, to high-dose (18 g/m(2), n=113) or low-dose (2 g/m(2), n=117) cytarabine given with daunorubicin and etoposide (ADE; induction 1). The primary aim of the study was to compare the incidence of MRD positivity of the high-dose group and the low-dose group at day 22 of induction 1. Induction 2 consisted of ADE with or without gemtuzumab ozogamicin (GO anti-CD33 monoclonal antibody); consolidation therapy included three additional courses of chemotherapy or haematopoietic stem-cell transplantation (HSCT). Levels of MRD were used to allocate GO and to determine the timing of induction 2. Both MRD and genetic abnormalities at diagnosis were used to determine the final risk classification. Low-risk patients (n=68) received five courses of chemotherapy, whereas high-risk patients (n=79), and standard-risk patients (n=69) with matched sibling donors, were eligible for HSCT (done for 48 high-risk and eight standard-risk patients). All 230 randomised patients were analysed for the primary endpoint. Other analyses were limited to the 216 patients with AML, excluding those with mixed-lineage leukaemia. This trial is closed to accrual and is registered with ClinicalTrials.gov, number NCT00136084. Complete remission was achieved in 80% (173 of 216 patients) after induction 1 and 94% (203 of 216) after induction 2. Induction failures included two deaths from toxic effects and ten cases of resistant leukaemia. The introduction of high-dose versus low-dose cytarabine did not significantly lower the rate of MRD-positivity after induction 1 (34%vs 42%, p=0.17). The 6-month cumulative incidence of grade 3 or higher infection was 79.3% (SE 4.0) for patients in the high-dose group and 75.5% (4.2) for the low-dose group. 3-year event-free survival and overall survival were 63.0% (SE 4.1) and 71.1% (3.8), respectively. 80% (155 of 193) of patients achieved MRD of less than 0.1% after induction 2, and the cumulative incidence of relapse for this group was 17% (SE 3). MRD of 1% or higher after induction 1 was the only significant independent adverse prognostic factor for both event-free (hazard ratio 2.41, 95% CI 1.36-4.26; p=0.003) and overall survival (2.11, 1.09-4.11; p=0.028). Our findings suggest that the use of targeted chemotherapy and HSCT, in the context of a comprehensive risk-stratification strategy based on genetic features and MRD findings, can improve outcome in patients with childhood AML. National Institutes of Health and American Lebanese Syrian Associated Charities (ALSAC).

Dismal long‐term prognosis for children with refractory acute myeloid leukaemia treated with gemtuzumab ozogamicin and stem cell transplantation: where now?

Dismal long‐term prognosis for children with refractory acute myeloid leukaemia treated with gemtuzumab ozogamicin and stem cell transplantation: where now?

Evaluating Methotrexate Treatment in Patients With Low-Risk Postmolar Gestational Trophoblastic Neoplasia

The response of low-risk persistent gestational trophoblastic neoplasia (GTN) to methotrexate (MTX) monotherapy is close to 100%. With use of various MTX regimens, 48%–92% of patients go into remission. There is limited data on potential clinical risk factors indicating the need for additional courses of MTX or alternative chemotherapy following an initial course of MTX. This retrospective observational study identified possible clinical factors predictive of the requirement for additional MTX or alternative chemotherapy to obtain a remission in patients with postmolar low-risk GTN who had received MTX initially. Data was analyzed for 1801 women diagnosed with molar pregnancies between 1973 and 2003. Of the 150 women in the final study population, 110 had been diagnosed as complete mole and 40 as partial mole, and all had received MTX as initial therapy for GTN. All women had low-risk disease according to the combined International Federation of Obstetrics and Gynecology (FIGO) stage and the World Health Organization prognostic scores. Remission was defined as achievement and maintenance of undetectable serum beta human chorionic gonadotropin (β-hCG) levels for 1 year. All 150 patients ultimately achieved remission. Of the 70 women (47%) requiring additional courses of chemotherapy including MTX, 45 (64%) required alternative chemotherapy. Multivariate analysis showed that independent prognostic factors predicting increased risk of requiring additional MTX or alternative chemotherapy were complete mole histology, presence of metastasis, single day MTX infusion and any increase in β-hCG levels 1 week after MTX therapy. Dilatation and curettage within 1 week after the diagnosis of persistence was not an independent risk factor for additional or alternative chemotherapy. For GTN following complete mole, β-hCG levels ≥2000 mIU/ml at 1 week post-MTX were associated with an 89% risk of requiring additional MTX chemotherapy and a 64% risk of alternative chemotherapy to achieve remission. These data identify several independent risk factors that predispose women with low-risk GTN to require additional MTX cycles and alternative chemotherapy after initial MTX.

化学療法中に脳梗塞をきたした若年精巣腫瘍の１例

A 31-year-oldman presented with a 6-month history of right testicular enlargement. The patient underwent a right inguinal orchiectomy. Histopathological examination showed nonseminomatous germ cell tumor (choriocarcinoma>seminoma) which was confined to the tunica albuginea. The postoperative serum level of alpha-fetoprotein (AFP) and lactate dehydrogenase were normal. Serum level of human chorionic gonadotrophin(HCG), however, was 23,000 mIU/ml (normal, < 0.7 mIU/ml). A thoracic computed tomography (CT) at that time showed bilateral and multiple metastases to the lungs but the abdominal CT was normal. After the surgery, the patient was treated with conventional doses of cisplatin, etoposide, and bleomycin. On day 11 of the second chemotherapy course, the patient developed confusion and right sided weakness. Brain magnetic resonance imaging (MRI) showed an ischemic lesion in the left middle cerebral artery area. An echocardiogram showed normal left ventricular function and no valvular vegetations. Finally, the patient completed one additional course of chemotherapy with considerable measures to prevent side effects. A thoracic CT at the end of the third cycle showed no evidence of tumor. At 3 months followup after chemotherapy, he suffered from partial paralysis of right-sided upper and lower limbs but due to intensive rehabilitation he overcame the paralysis and is able to walk by himself. There was no evidence of tumor recurrence.

Evaluating methotrexate treatment in patients with low-risk postmolar gestational trophoblastic neoplasia

Objective To identify clinical factors associated with requiring more than a single course of Methotrexate (MTX) to achieve remission among women with low-risk postmolar gestational trophoblastic neoplasia (GTN). Methods We studied 150 women with persistent GTN after diagnosis of complete ( n = 110) or partial mole ( n = 40) to identify possible predictors of requiring additional treatment after a single treatment of methotrexate (MTX). All women had low-risk disease using FIGO and WHO scoring systems. Results Seventy women (47%) required additional courses of chemotherapy, of whom 45 (64%) received chemotherapy other than MTX. Multivariate analysis revealed that complete mole histology, presence of metastasis, single day MTX infusion and any increase in serum beta human chorionic gonadotropin (β-hCG) level 1 week after MTX therapy were independent predictors of requiring additional MTX or alternative chemotherapy. Dilatation and curettage (D+C) within 1 week after the diagnosis of persistence did not affect future chemotherapy requirements ( p > 0.64). Following complete mole, β-hCG levels > 2000 mIU/mL at 1 week post MTX were associated with a 89% risk of additional cycles chemotherapy including MTX and a 65% risk of alternative chemotherapy. Conclusions Metastatic disease, MTX infusion protocol and complete mole histology were independently associated with the need for additional chemotherapy after an initial course of MTX for women with low risk GTN. D+C at persistence did not alter the chemotherapy requirement. Elevated β-hCG level at 1 week after the initial course of MTX was also an independent factor predicting the need for additional courses of MTX or alternative chemotherapy.

Management and successful desensitization in methotrexate‐induced anaphylaxis

Anaphylactic/anaphylactoid reactions to methotrexate are rare. In patients with methotrexate-induced anaphylaxis, discontinuation of treatment may increase the risk of death due to cancer progression. In such patients, desensitization may enable the patient to continue treatment with methotrexate. We report the case of a child with metastatic osteosarcoma, who experienced an anaphylactic/anaphylactoid reaction to methotrexate. Skin tests with methotrexate were not performed because their diagnostic value is controversial. Desensitization with methotrexate was successful and allowed the patient to complete 12 additional courses of chemotherapy. Thus, we confirm that desensitization may be a safe procedure in patients with cancer who experience methotrexate-induced anaphylaxis.

Changes and Predictive and Prognostic Value of the Mitotic Index, Ki-67, Cyclin D1, and Cyclo-oxygenase-2 in 710 Operable Breast Cancer Patients Treated with Neoadjuvant Chemotherapy

The current study expands upon previous work using a database of 710 patients treated with neoadjuvant chemotherapy. First, we studied phenotypic characteristics of tumors before and after chemotherapy using the following factors: the mitotic index of the Scarff-Bloom-Richardson grade, Ki-67, cyclin D1, and cyclo-oxygenase-2. Second, the predictive value of these factors on response was assessed. Third, we measured the prognostic impact of these markers post-therapy in comparison with clinical and pathological responses according to the Chevallier and Sataloff classifications. Patients were treated using different neoadjuvant chemotherapy combinations, mainly in successive prospective phase II trials. They received a median number of six cycles (range, 1-9). After neoadjuvant chemotherapy, patients underwent surgery and radiotherapy. In cases of important residual disease, some received additional courses of chemotherapy. In addition, menopausal patients with hormone receptor-positive tumors received tamoxifen for 5 years. According to our analysis, we found significant variations before and after neoadjuvant chemotherapy only for cyclin D1 and the mitotic index. Concerning the predictive value of biomarkers for response, Ki-67 and the mitotic index were predictive on univariate analysis, both for objective clinical and pathological complete responses. Because these two factors were correlated, no multivariate analyses were conducted. We then assessed the prognostic impact of the biopathological factors. When the factors were measured before chemotherapy, all were prognostic. When evaluated after chemotherapy, the mitotic index, objective clinical response, and pathological complete response were prognostic. Because these factors were correlated, no multivariate model was done. The main clinical fact is that there were significant correlations between clinical and pathological responses and variations in the biological factors studied.

Excellent prognosis and prevalence of HCV infection of primary hepatic and splenic non‐Hodgkin’s lymphoma

Primary Hepatic (PHL) and Primary Splenic (PSL) non-Hodgkin's Lymphoma are rare entities. Small series of PHL and PSL have been reported, suggesting a non-fortuitous association with Hepatitis C Virus (HCV) infection. The prognosis is believed to be dismal, with early recurrence and short survival. We retrospectively reviewed all PHL and PSL patients diagnosed at our institution between 1990 and 2005. Twenty-five adult patients were identified, six with PHL and 19 with PSL. Twenty-four patients had a B-cell lymphoma, defined as Diffuse Large B-cell lymphoma in 18. The prevalence of HCV infection was 68% among PSL and 66% among PHL. Combination chemotherapy was the mainstay of treatment for PHL and PSL; all but one patient with PSL underwent splenectomy before chemotherapy. Complete remission was achieved in all the cases after frontline therapy; only four patients relapsed but responded to additional chemotherapy courses. Most patients presented with aggressive histological subtypes; 92% were alive at a median follow up of 79 months. HCV infection did not appear to influence the results of therapy. Our study confirms the rarity of PHL and PSL, shows a high prevalence of HCV infection, and demonstrates that the outcome of patients with PHL and PSL may be favourable.