Sequential High-dose Chemotherapy Research Articles

First-line salvage treatment options for germ cell tumor patients failing stage-adapted primary treatment

PurposeIn this review, we summarize and discuss contemporary treatment standards and possible selection criteria for decision making after failure of adjuvant or first-line cisplatin-based chemotherapy for primarily localized or metastatic germ cell tumors.MethodsThis work is based on a systematic literature search conducted for the elaboration of the first German clinical practice guideline to identify prospective clinical trials and retrospective comparative studies published between Jan 2010 and Feb 2021. Study end points of interest were progression-free (PFS) and overall survival (OS), relapse rate (RR), and/or safety.ResultsRelapses of clinical stage I (CS I) patients irrespective of prior adjuvant treatment after orchiectomy are treated stage adapted in accordance for primary metastatic patients. Surgical approaches for sole retroperitoneal relapses are investigated in ongoing clinical trials. The appropriate salvage chemotherapy for metastatic patients progressing or relapsing after first-line cisplatin-based chemotherapy is still a matter of controversy. Conventional cisplatin-based chemotherapy is the international guideline-endorsed standard of care, but based on retrospective data high-dose chemotherapy and subsequent autologous stem cell transplantation may offer a 10–15% survival benefit for all patients. Secondary complete surgical resection of all visible residual masses irrespective of size is paramount for treatment success.ConclusionsPatients relapsing after definite treatment of locoregional disease are to be treated by stage-adapted first-line standard therapy for metastatic disease. Patients with primary advanced/metastatic disease failing one line of cisplatin-based combination chemotherapy should be referred to GCT expert centers. Dose intensity is a matter of ongoing debate, but sequential high-dose chemotherapy seems to improve patients’ survival.

Sequential High-Dose Chemotherapy Reinduction Followed By Haploidentical Transplantation in Acute Leukemias

Introduction: Outcomes after T-cell replete haploidentical stem cell transplantation (Haplo HSCT) with post- transplant Cyclophosphamide have been encouraging. As previously published (Schmid C. et al, JCO 2005; Ringdén O. et al, Br J Haematol. 2017), the sequential use of intensive chemotherapy and allogeneic transplantation represents a possible approach for the treatment of high-risk / relapsed-refractory Acute Myeloid Leukemia (AML).Patients and Methods: At our Center, 22 high-risk patients were transplanted during chemo-induced neutropenia after high-dose salvage chemotherapy. Median age at transplant was 49 years (range 21-62); 6/22 (27%) had received a previous allograft. All patients but 2, who presented with blast crisis of chronic myeloid leukemia, suffered from refractory (no. 12) or secondary AML (no. 8). All patients had active disease at the time of Sequential Therapy and median marrow blast count before reinduction was 25% (range 6-88%). All patients received high-dose Cytarabine (≥1g/sqm) containing regimens as reinduction therapy. Conditioning, myeloablative, in 14/22 (64%) and non-myeloablative in 8/22 (36%), was started at a median of 9 days (range 4-15) after the last day of chemotherapy. Graft-versus-host disease (GVHD) prophylaxis consisted of post-transplant Cyclophosphamide with calcineurine inhibitors and mycophenolic acid. Bone marrow was used as stem cell source in 18/22 (82%) patients.Results: One/22 patient (4%) experienced primary graft failure and was successfully rescued with a second haploidentical transplant from the same donor. Median day of neutrophil recovery was day +18 (range 14-24). Median follow-up of survivors was 4.1 years (range 5-69 months); 1-year Overall and Event-Free Survivals were 34.5% and 30.3%, while 1-year Relapse Incidence and Non Relapse Mortality were 41.9% and 28%, respectively. Overall cumulative incidences of acute and chronic GVHD were 41% and 33.6% at day +100 and + 400. Among patients who developed GVHD, 3 grade III-IV acute GVHD and 2 moderate-severe chronic GVHD were observed. At 4.1 years post Haplo-HSCT, 5/22 (23%) patients are alive and disease free.Conclusions: To our knowledge, we report the first experience of a sequential approach including Haplo HSCT. Though small the patient cohort, which also includes second transplants, our findings suggest that transplant-related toxicity was acceptable and early relapse was the major treatment-failure. However, long-term survival and disease-free rates in these very poor prognosis patients are rather encouraging. Only the prompt availability of a haploidentical donor allowed to implement this treatment modality. DisclosuresBoccadoro:Sanofi: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; AbbVie: Honoraria; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Mundipharma: Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Vitolo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Takeda: Honoraria; Mundipharma: Honoraria.

Long-term remission in mantle cell lymphoma following high-dose sequential chemotherapy and in vivo rituximab-purged stem cell autografting (R-HDS regimen)

AbstractMantle cell lymphoma (MCL) is rarely cured with standard-dose chemotherapy. From January 1997 to February 2000, 28 previously untreated advanced-stage MCL patients younger than 61 years of age were treated at 9 Italian hematologic departments with 3 cycles of standard-dose debulking chemotherapy followed by a high-dose rituximab-supplemented sequence (R-HDS) including intravenous administration of high-dose cyclophosphamide, high-dose cytarabine, high-dose melphalan, and high-dose mitoxantrone plus melphalan. Study end points included toxicity, clinical and molecular response rates, long-term event-free survival (EFS), and overall survival (OS) rates, as well as the ability to harvest tumor-free peripheral blood stem cells. Optimal amounts of polymerase chain reaction–negative (PCR-negative) CD34+ cells were collected from all 20 informative patients. One patient died of toxicity. All 27 patients assessable for response achieved a complete response (CR), of which 24 remain in continuous complete remission (CCR) after a median follow-up of 35 months. Three patients had transient evidence of PCR-detectable disease in the bone marrow. The OS and EFS rates at 54 months were 89% and 79%, respectively. These results compare with the 42% OS rate and the 18% EFS rate observed in 35 age-matched historic controls treated with standard-dose chemotherapy at the participating centers. The use of rituximab in combination with high-dose chemotherapy represents a very effective in vivo purging method. The R-HDS regimen can be safely applied in a multicenter hematology setting and leads to long-term EFS and OS in the majority of patients with an otherwise incurable disease.

Role of high-dose chemotherapy with autologous stem cell transplantation for primary central nervous system lymphoma: A systematic review.

2562 Background: High dose chemotherapy (HDCT) followed by autologous stem cell transplant (ASCT) has shown to overcome intrinsic chemo-resistance and improve disease control in Primary Central Nervous System Lymphoma (PCNSL). Our study reviews the treatment outcome in PCNSL with sequential HDCT and ASCT. Methods: 8/34 studies were finalized after systematic search of PubMed, Cochrane, and Clinicaltrials.gov for treatment of PCNSL with HDCT followed by ASCT. Results: 251/288 patients were evaluated. Mean age was 55.5 years. 227 underwent HDCT-ASCT. 174 were newly diagnosed (ND) and 77 had relapsed refractory (R/R) PCNSL. ND patients showed superior outcomes in terms of progression free survival and overall survival. Combinations of High dose Rituximab, Busulfan and Cyclophosphamide significantly improved survival outcomes in RR patients. Significant toxicities mainly included pancytopenias and opportunistic. Conclusions: Primary CNS lymphoma treated with HDCT followed by ASCT has shown promising outcomes and has set a benchmark for future studies. [Table: see text]

Randomized trial comparing standard vs sequential high-dose chemotherapy for inducing early CR in adult AML

AbstractHere we evaluated whether sequential high-dose chemotherapy (sHD) increased the early complete remission (CR) rate in acute myelogenous leukemia (AML) compared with standard-intensity idarubicin-cytarabine-etoposide (ICE) chemotherapy. This study enrolled 574 patients (age, 16-73 years; median, 52 years) who were randomly assigned to ICE (n = 286 evaluable) or sHD (2 weekly 3-day blocks with cytarabine 2 g/m2 twice a day for 2 days plus idarubicin; n = 286 evaluable). Responsive patients were risk-stratified for a second randomization. Standard-risk patients received autograft or repetitive blood stem cell-supported high-dose courses. High-risk patients (and standard-risk patients not mobilizing stem cells) underwent allotransplantation. CR rates after 2 induction courses were comparable between ICE (80.8%) and sHD (83.6%; P = .38). sHD yielded a higher single-induction CR rate (69.2% vs 81.5%; P = .0007) with lower resistance risk (P < .0001), comparable mortality (P = .39), and improved 5-year overall survival (39% vs 49%; P = .045) and relapse-free survival (36% vs 48%; P = .028), despite greater hematotoxicity delaying or reducing consolidation blocks. sHD improved the early CR rate in high-risk AML (odds ratio, 0.48; 95% confidence interval [CI], 0.31-0.74; P = .0008) and in patients aged 60 years and less with de novo AML (odds ratio, 0.46; 95% CI, 0.27-0.78; P = .003), and also improved overall/relapse-free survival in the latter group (hazard ratio, 0.70; 95% CI, 0.52-0.94; P = .01), in standard-risk AML, and postallograft (hazard ratio, 0.61; 95% CI, 0.39-0.96; P = .03). sHD was feasible, effectively achieved rapid CR, and improved outcomes in AML subsets. This study is registered at www.clinicaltrials.gov as #NCT00495287.

Updated 13 Yr Follow-Up of the GITMO-IIL Trial Comparing Upfront R-HDS with Autograft vs. CHOP-R in High-Risk Follicular Lymphoma: Prolonged Survival in Both Arms and a High Rate of Long-Term Disease Free Survivors

Background A prospective trial conducted in 2000-2005 showed no survival advantage at a median 4-yr follow-up by high-dose sequential chemotherapy with Rituximab and autograft (R-HDS) compared to conventional cyclophosphamide, doxorubicin, vincristine, prednisone supplemented with Rituximab (CHOP-R) as first-line therapy in high-risk Follicular Lymphoma (FL) patients aged <60 yr. Results have been now updated at 13-yr median follow-up. Methods Between March 2000 and May 2005, 136 patients had been enrolled in the multicenter randomized study, launched in Italy among Centers affiliated to GITMO (Gruppo Italiano Trapianto Midollo Osseo) and/or to the Italian Lymphoma Intergroup known as IIL (now joined into FIL, Fondazione Italiana Linfomi). The trial was registered at www.clinicaltrials.gov as no. NCT00435955. The long-term outcome was assessed by taking information from 28 out of 29 participating Center on the clinical status of each patient entered the prospective trial. Findings As of February 2017, 88 (66%) patients were alive, with Overall Survival (OS) of 66.4% at 13 yrs, without significant difference between R-HDS (64.5%) and CHOP-R (68.5%). So far, 46 patients died, mainly due to disease progression (47.8% of all deaths), secondary malignancies (3 solid tumor, 9 Myelodysplasia/Acute Leukemia, 26.1% of all deaths), other toxicities (23.9% of all deaths). Complete remission (CR) was documented in 98 (73.1%) patients and was associated with OS, with 13-yr estimates of 77.0% and 36.8% for CR vs. no-CR, respectively. Molecular remission (MR) was documented in 39 (65%) out of 60 evaluable patients, also MR achievement was associated with improved OS. In multivariate analysis, CR achievement had the strongest impact on survival, along with younger age and female gender (borderline value). Overall, 50 patients (37.3%) survive in absence of disease recurrence (18 CHOP-R, 32 R-HDS). Interpretation This is the longest follow-up ever reported on FL upfront-treated with Rituximab-chemotherapy and demonstrates an unprecedented improvement in OS compared to the pre-Rituximab era, regardless of the use of intensified or conventional treatment. CR achievement resulted the most important factor for prolonged survival. Unexpectedly, a high proportion of patients had prolonged survival in 1st CR, raising the issue of curability in FL. Funding: This work was supported in part by Ministero Italiano Universita e Ricerca (MIUR), Rome, Italy (grant PRIN 2010-2011, pr. N.: 2010B5B2NL) and by Banca del Piemonte (Torino, Italy): their financial support covered the cost for the present update of the study. The initial clinical trial (March 2000 - May 2005) was made possible by Compagnia di San Paolo (Torino, Italy), Regione Piemonte (Torino, Italy), and by Roche (Milan, Italy), which provided free rituximab for all the patients. We are indebted to GITMO (Gruppo Italiano Trapianto Midollo Osseo) and to IIL, now merged into FIL (Fondazione Italiana Linfomi) for their fundamental participation in the development and completion of the study. Declaration of Interest: M. Ladetto: honoraria from Abbvie, Acerta, Amgen Archigen Celgene ADC therapeutics, Gilead Novartis J&J Roche Roche Diagostics Sandoz Takeda. Francesco Di Raimondo honoraria from Roche Alessandro Rambaldi Travel support, sponsored lectures and advisory board meetings: Roche, Amgen, Pfizer, Novartis, Celgene. Corrado Tarella Travel support from Amgen and Celgene Ethical Approval: The Institutional Review Boards of all the participating centers approved the study.

Pediatric extraspinal sacrococcygeal ependymoma (ESE): an Italian AIEOP experience of six cases and literature review.

Primary pediatric extraspinal sacrococcygeal ependymoma (ESE) is a very rare disease, poorly described in literature, whose diagnostic, therapeutic, and follow-up approach is still controversial. We describe six cases of pediatric ESE treated at Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) centers in Italy since 1983, with a review of the literature. All six patients had primary sacrococcygeal disease (two presacral and four subcutaneous) with median age of 10years. Three patients were males, and two of them are metastatic at diagnosis; 3/6 had myxopapillary ependymoma grade I and 3/6 had classic ependymoma grade II. Five patients underwent surgical resection with complete removal only in one case with coccygectomy. Adjuvant chemoradiotherapy was administered to one metastatic patient obtaining a complete remission. Two patients relapsed at 3 and 8years from diagnosis: they were treated with salvage chemotherapy (high-dose sequential chemotherapy with myeloablative regimen in one case), surgery, and radiotherapy achieving complete remission (CR). All six patients are in complete continuous remission (CCR) at a median follow-up of 12.8years. Pediatric patients with this peculiar disease need to be referred to specialized pediatric cancer centers that can provide multidisciplinary treatment after a centralized pathology review. Our experience highlights the role of chemotherapy and radiotherapy in adjuvant and relapse setting. The final prognosis is relatively optimistic, but with a careful follow-up due to the high risk of recurrence.

Long-term results of a phase-I/II study of sequential high-dose chemotherapy with autologous stem cell transplantation in the initial treatment of aggressive non-Hodgkin's lymphoma.

To improve the survival of patients with aggressive non-Hodgkin's lymphoma, we evaluated a risk-adapted therapeutic approach using high-dose (HD) or conventional-dose (CD) chemotherapy (CT) for poor-risk and good-risk patients, respectively. Twenty patients were treated in each group. In both groups, the first chemotherapy cycle consisted of dexamethasone, vincristine, ifosfamide, and etoposide. Thereafter, the CD or HD patients received 3 or 2 cycles of dexamethasone, vincristine, epirubicin, and cyclophosphamide, respectively, followed by 1 cycle of dexamethasone, carboplatin, and etoposide. In the HD group cyclophosphamide, epirubicin, carboplatin, and etoposide were dose-escalated by a factor of 6, 3, 3, and 3, respectively, as compared to the CD group, and autologous peripheral blood stem cells were administered after each HD-CT cycle. Grade III-IV toxicities were neutropenia and thrombocytopenia (100%), anemia (55%), and stomatitis (30%) in patients with HD-CT, and neutropenia (90%) in patients with CD-CT. One toxic death occurred in a patient with HD-CT. The overall response rate was 100% in HD-CT patients, including 70% complete remissions, and 80% in CD-CT patients, including 60% complete remissions. The 10-year overall survival was 55% for patients with HD-CT and 80% for patients with CD-CT. The risk-adapted treatment approach showed tolerable toxicities and was associated with encouraging results.

Response to first-line treatment and histology are associated with achieving complete remission after the first salvage high-dose chemotherapy in relapsing germ cell tumor patients.

Sequential high-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) is a curative option in relapsing germ cell tumor (GCT) patients, and complete remission (CR) after the first ASCT (early CR2) is associated with favorable outcome. Prognostic factors predicting early CR2 have not been investigated so far. We analyzed consecutive patients with a first relapse of GCT treated with three sequential cycles of carboplatin/etoposide-based HDCT with ASCT in the two largest academic centers in Switzerland. The cohort comprised 96 relapsing GCT patients, with 19 (19.8%) patients achieving early CR2 after the first HDCT cycle. The median progression-free survival and overall survival were not reached in patients achieving early CR2, whereas they were 9.6 months (P = 0.0301) and 34.8 months (P = 0.0684) for patients missing early CR2. Patients with early CR2 more often had CR1 after first-line bleomycin, etoposide, and cisplatin chemotherapy (68.4 vs. 31.6%; P = 0.0037) and an interval longer than 2 years between initial diagnosis and first HDCT (36.8 vs. 15.6%; P = 0.0373), but less often a histology of mixed nonseminomatous tumor (46.8 vs. 21.1%; P = 0.0418). These data suggest that response to first-line chemotherapy, late relapse, and histology are associated with achieving early CR2 after a first HDCT with ASCT in relapsing GCT patients.

Conventional-Dose versus High-Dose Chemotherapy for Relapsed Germ Cell Tumors.

The majority of metastatic germ cell tumors (GCTs) are cured with cisplatin-based chemotherapy, but 20–30% of patients will relapse after first-line chemotherapy and require additional salvage strategies. The two major salvage approaches in this scenario are high-dose chemotherapy (HDCT) with autologous stem cell transplant (ASCT) or conventional-dose chemotherapy (CDCT). Both CDCT and HDCT have curative potential in the management of relapsed/refractory GCT. However, due to a lack of conclusive randomized trials, it remains unknown whether sequential HDCT or CDCT represents the optimal initial salvage approach, with practice varying between tertiary institutions. This represents the most pressing question remaining for defining GCT treatment standards and optimizing outcomes. The authors review prognostic factors in the initial salvage setting as well as the major studies assessing the efficacy of CDCT, HDCT, or both, describing the strengths and weaknesses that formed the rationale behind the ongoing international phase III “TIGER” trial.

Infusional gemcitabine + docetaxel/melphalan/carboplatin (GemDMC) ± bevacizumab (BEV) as an effective high-dose chemotherapy (HDC) regimen for refractory of poor-risk relapsed germ-cell tumors (GCT).

4519 Background: Tandem HDC with carbo/etoposide (CE) is curative for a portion of relapsed GCT pts. However, outcomes of refractory or high-risk relapsed pts remain poor. We tested a new HDC regimen of GemDMC, based on DNA damage repair inhibition. We combined BEV with HDC given their potential synergy and the high vascularity of GCT metastases. Methods: Eligibility: Intermediate (int)/high-risk (Beyer Model), creatinine ≤1.8 mg/dL and adequate organ function. HDC included BEV (5 mg/kg) preceding GemDMC (HDC #1) and ifosfamide/CE (ICE) (HDC #2). Following accrual of 42 pts, we amended the trial omitting BEV. The trial was powered to distinguish a target 50% 2-yr RFS from an expected 25% in this population. Results: We enrolled 69 male pts in cohorts 1 (BEV, N=42) and 2 (no BEV, N=27) (Table). Pts were heavily pretreated and most had refractory tumors. Main AE: mucositis and renal (4 HDC-related deaths in cohort 1, 1 in cohort 2). Tumor markers normalized in 90% pts with active tumors at HDC. After HDC, 19 pts were in CR and 28 in PRm- (of these, 22 had residual lesions resected with no viable tumor found in 20/22, 2 xRT, 4 monitored). Median f/u = 39 (2-105) mo. The 2-yr RFS rates in cohorts 1 and 2 = 52% and 78%, respectively. Their respective 2-yr OS rates = 55% and 81%. Conclusions: Sequential HDC with GemDMC–ICE shows encouraging outcomes in heavily pretreated and refractory GCT, exceeding the anticipated results. Addition of BEV increases toxicity but not tumor control. Clinical trial information: NCT00936936. [Table: see text]

Long-term neuropsychological follow-up of young children with medulloblastoma treated with sequential high-dose chemotherapy and irradiation sparing approach.

High-dose chemotherapy (HDC) strategies were developed in brain tumor protocols for young children to prevent neuropsychological (NP) impairments associated with radiotherapy. However, comprehensive NP evaluations of these children treated with such strategies remain limited. We examined the long-term neurocognitive outcomes of young children (<6 years) with medulloblastoma, treated similarly, with a HDC strategy "according to" the chemotherapy regimen of the protocol CCG 99703. This retrospective study included young children less than 6 years of age at diagnosis of medulloblastoma treated from 1998 to 2011 at 7 North American institutions. Twenty-four patients who had at least one NP assessment post-treatment are the focus of the current study. Of 24 patients in this review, 15 (63%) were male and the mean age at diagnosis was 29.4 months (SD = 13.5). Posterior fossa syndrome (PFs) was reported in five patients (21%). Nine (37.5%) received radiotherapy (5 focal, 4 craniospinal). On average, children were assessed 3.5 years (SD = 1.8) post-diagnosis, and full-scale intellectual quotient (FSIQ) scores ranged from 56 to 119 ([Formula: see text]= 92; SD = 16.8). The majority of children (74%) had low-average to average NP functioning. Very young children treated with radiotherapy, who needed hearing support or with PFs had worse neurocognitive outcomes. Clinically significant deficits (<10th percentile) in at least one area of NP functioning were found in 25% of the children. NP data obtained from this sample of survivors of medulloblastoma in early childhood, all treated with sequential HDC and 1/3 with radiotherapy, describe NP functioning within average normal limits overall. However, almost 25% of children had significant deficits in specific domains.

Identification of DNA Copy Number Variations Associated with the Clinical Outcome in Young Mantle Cell Lymphoma Patients Treated with Cytarabine-Based High Dose Sequential Chemotherapy and Autologous Stem Cell Transplantation in the Prospective from the MCL0208 Phase III Trial from Fondazione Italiana Linfomi (FIL)

Background. Mantle Cell Lymphoma (MCL)represents an aggressive lymphoma for which an effective treatment has still to be determined. The FIL-MCL0208 phase III trial (EudraCTNumber: 2009-012807-25) is exploring R-CHOP followed byi) high-dose cytarabine, autologous stem cell transplantation, and ii) randomization between lenalidomide maintenance vs observation (Cortelazzo et al, EHA 2015). We performed genome-wide DNA profiling to identify unbalanced copy number variations (CNVs) with a clinical significance in patients enrolled in the FIL-MCL0208 phase III trial.Patients and Methods. The study included untreated, advanced stage MCL patients (<65 years) enrolled into the MCL0208 trial. Clinical results of the first interim analysis (without random unblinding) have been already reported and are the basis of the present analysis: median follow-up of alive patients was 26 months, and at 2-years, 79% of patients were progression free and 91% alive (Cortelazzo et al EHA 2015). DNA profiling with the Illumina HumanOmni2.5 arrays was performed on 174 DNA samples derived from baseline bone marrow CD19+ purified tumor cells. Genomic profiles were segmented with the Fast First-derivative Segmentation Algorithm (Rinaldi et al, BJH 2013; Kwee et al, bioRxiv 2016). Recurrent CNVs were defined applying both the minimal common regions and the GISTIC algorithms (Lenz et al, PNAS 2008; Mermel et al, Genome Biol 2011). CNVs were integrated with somatic mutational data obtained for 8 genes recurrently affected in MCL (ATM, BIRC3, CCND1, KMT2D, TP53, TRAF2, WHSC1, NOTCH1) (Rossi et al, ASH 2015). Progression free survival (PFS) was the primary endpoint of the analysis.Results. 161 patients were currently evaluable for CNVs and clinical outcome. Patients had an intermediate/high-risk MIPI and a Ki67 ³ 30% in 43% and 42% of the cases, respectively. Twenty-five recurrent unbalanced CNVs were defined (Table 1). By multiple test corrected univariate analysis, seven CNVs had a negative impact on PFS: +3, 7p gain, 9p loss (CDKN2A), 17p loss (TP53), 8p loss, and 2 losses at 22q (Table 1). MIPI (intermediate/high vs low risk), Ki67+ and the TP53/KMT2D model (Rossi et al, ASH 2015) were also statistically significant. Combining CNVs and mutations, TP53 was inactivated in 27/147 cases (18%): mutated/deleted in 7/147 (5%), deleted but not mutated in 14/147 (10%), and mutated but not deleted in 6/147 (4%). The negative prognostic impact was equal for all the 3 inactivation modalities, which were then considered as a single group for further analyses. ATM was inactive in 69/147 (47%): mutated/deleted in 24/147 (16.3%), deleted in 12/147 (8%), and mutated in 33/147 (22.4%). KMT2D (MLL2) was inactive in 18/147 (12%): mutated/deleted in 1/147 (<1%), deleted in 1/147 (<1%), and mutated in 16/147 (11%).The lesions with a significant impact at univariate were included in a multivariate analysis alongside MIPI, KMT2D inactivation and Ki67+ as continuous variable. Only TP53 inactivation by deletion and/or mutation, 7p22.2-p12.1 gain and KMT2D inactivation maintained their independent prognostic significance.Conclusions. Genome wide DNA profiling in the FIL-MCL0208 phase III trial identified lesions, namely TP53 and KMT2D inactivation and gains at 7p, which maintain a poor outcome significance in young MCL patients even following high-dose cytarabine and autologous stem cell transplantation. [Display omitted] DisclosuresRossi:Gilead: Honoraria, Research Funding; Abbvie: Honoraria; Janseen: Honoraria. Stelitano:Azienda Ospedaliera: Employment. Gaidano:Janssen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Morphosys: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria.

Clinical, Pathological, and Molecular Characterization of Infant Medulloblastomas Treated with Sequential High-Dose Chemotherapy.

High-dose chemotherapy (HDC) strategies were developed to avoid unacceptable neurotoxicity associated with craniospinal irradiation in infants with embryonal brain tumors. However, the impact of molecular and pathological characterizations in such approaches and long-term outcome have not been widely described in young children. We retrospectively collected information from seven North American institutions, on young children with medulloblastoma (MB) treated with sequential HDC, as per the CCG 99703 protocol. Data collection included clinical presentation, histology, molecular subgroup, irradiation, ototoxicity, and neurocognitive evaluations. The cohort included 53 patients diagnosed at a median age of 24 months (2.9-63.2). Seventeen patients (32.1%) had nodular desmoplatic MB, all belonging to the sonic Hedgehog (SHH) subgroup, as did 30% of classic MB. The 5-year progression-free survival (PFS) and overall survival (OS) was 69.6% (±6·9%) and 76.1% (±6.5%), respectively. Seventeen (32.1%) patients received irradiation (nine adjuvant radiotherapy [RT]). Patients with SHH and group 3 MB had a 5-year PFS of 86·2% (±7.4%) and 49·1% (±14%), respectively (P = 0.03). The 5-year PFS radiation free for group 3 MB was 46.4%. Patients with macroscopic metastasis (M2 and M3) had a worst survival. Fifteen (45.5%) patients had significant ototoxicity. Mean Full Scale Intellectual Quotient (FSIQ) for 24 survivors was 91.6 (range 52-119). This HDC strategy led to an encouraging OS while only 20% of the patients received adjuvant RT. SHH MB, irrespective of histological subgroup, had an excellent outcome. Such intensive therapy may not be needed for this subgroup. Patients with classic histology or group 3 had an encouraging PFS of 58% and 46.4%, respectively, in the absence of adjuvant RT. The neurocognitive profile of the survivors appears to be within the normal range.

A Molecular Model for the Prediction of Progression Free Survival in Young Mantle Cell Lymphoma Patients Treated with Cytarabine-Based High Dose Sequential Chemotherapy and Autologous Stem Cell Transplantation: Results from the MCL0208 Phase III Trial from Fondazione Italiana Linfomi (FIL)

Background. Recent studies have described the landscape of recurrently mutated genes in mantle cell lymphoma (MCL), including genes involved in DNA damage response/cell cycle (ATM, TP53, CCND1), epigenetic regulation (KMT2D also known as MLL2, WHSC1), and cell signaling (BIRC3, TRAF2, NOTCH1). However, with the exception of TP53 abnormalities, little is known about the clinical relevance of recurrent mutations in MCL. Thus, we performed deep sequencing analysis of a MCL gene panel in the prospective series of patients enrolled in the ongoing FIL-MCL0208 phase III trial (EudraCTNumber: 2009-012807-25).Patients and Methods. The study included untreated, advanced stage <65 years MCL patients that: i) were eligible into MCL0208 trial (R-CHOP followed by high-dose cytarabine, autologous stem cell transplantation, and randomization between lenalidomide maintenance vs observation); ii) were provided with baseline tumor material. A targeted resequencing gene panel including coding exons and splice sites of genes recurrently mutated in MCL (ATM, BIRC3, CCND1, KMT2D, TP53, TRAF2, WHSC1, NOTCH1) has been specifically designed. The gene panel allows the recovery of at least one mutation in >70% of cases. The gene panel was analyzed in tumor DNA from baseline bone marrow CD19+ purified MCL cells and, for comparative purposes to filter out polymorphisms, in the paired normal genomic DNA (available in 55% of cases) using a TruSeq Custom Amplicon target enrichment system followed by deep next generation sequencing (Illumina, median depth of coverage 2356x). Variants represented in >10% of the alleles were called with VarScan2 with the somatic function when the paired germline DNA was available. For patients lacking germline DNA, a bioinformatic pipeline including a number of stringent filters was applied to protect against the misclassification of polymorphisms as somatic variants. Primary endpoint of the analysis was progression free survival (PFS).Results. Out of the enrolled patients, 151 are currently evaluable for mutations and clinical outcome (median age: 57 years, range 35-66; males 75%). Among prognostic factors, the MIPI was intermediate or high-risk in 49% of patients, the Ki67 ≥30% in 39%, and blastoid histology occurred in 8%. At the first planned interim analysis, median follow-up of alive patients was 26 months. At 2-years, 79% of patients were progression free and 91% alive (Cortelazzo et al EHA 2015). Overall, at least one mutation was detected in 106/151 cases (70%), including mutations of ATM in 42% of cases, CCND1 in 14%, WHSC1 in 13%, KMT2D in 12%, TP53 in 7%, NOTCH1 in 6%, BIRC3 in 5% and TRAF2 in 1% (Figure 1A). By univariate analysis, mutations of TP53 (2-years PFS 48% vs 82%; p<0.0001) and KMT2D (2-years PFS 67% vs 81%; p=0.004) associated with a significantly shorter PFS. By multivariate analysis, mutations of TP53 (HR: 4.39) and KMT2D (HR: 2.38) associated with an increase of the hazard of progression after adjusting for the MIPI. The hierarchical order of relevance in predicting PFS among molecular lesions was established by recursive partitioning analysis. TP53 mutations were the most predictive variable in the survival tree, followed by KMT2D mutations, thus providing the rationale to utilize these molecular features in the development of a model to predict PFS. By this approach, three MCL subgroups were hierarchically classified (Figure 1B). The high-risk category accounted for 8% of the cohort and included patients harboring TP53 mutations independent of the co-occurrence of KMT2D mutations (2-year PFS: 48%). The intermediate risk category accounted for 9% of the cohort and included patients harboring KMT2D mutations in the absence of TP53 mutations (2-year PFS: 74%). The low-risk category accounted for 83% of the cohort and comprised patients lacking both TP53 and KMT2D mutations (2-year PFS: 83%). The low number of events so far recorded prevented any analysis on overall survival.Conclusions. Though limited by the short follow-up, our data show that: i) the combination of two genetic biomarkers (i.e. TP53 and KMT2D mutations) allows to predict the benefit that young MCL patients can gain from a cytarabine-based high dose sequential chemotherapy followed by autologous stem cell transplantation; ii) intensive chemotherapy does not overcome the negative prognostic impact of TP53 mutations; and iii) KMT2D mutations may represent a novel genetic biomarker in MCL patients. [Display omitted] DisclosuresSantoro:Celgene: Research Funding.

Sequential high-dose chemotherapy (HDCT) for relapsed or refractory germ cell cancer (rGCC): Results of a unicentric standardized approach.

e15551 Background: HDCT with carboplatin and etoposide (CE) followed by residual tumor resection (RTR) is a routine regimen for patients (pts) with rGCC. We evaluated the results of a unicentric ap...

Neurocognitive evaluation of long term survivors of atypical teratoid rhabdoid tumors (ATRT): The Canadian registry experience.

Because atypical teratoid rhabdoid tumor(ATRT) is a rare disease of infancy carrying a grim prognosis, focus on long-term outcome, especially neurocognitive remained very limited. With new era of multimodality therapy, an increasing proportion of patients are now long-term survivors. Retrospective review of neuropsychological (NP) status of survivors from the Canadian ATRT registry. Among 77 patients diagnosed between 1995-2012, 16(22%) were survivors. Formal NP assessments were available in eight patients. Partial information on academic achievement was available on three additional patients. There were four girls and seven boys diagnosed at a median age of 27.5 months. Seven patients underwent complete resection and three had metastatic disease. All but one received sequential high dose chemotherapy. Five patients received intrathecal chemotherapy. Three patients underwent radiation. Median age at time of formal NP assessment was 7.6 years (3.9-9.8). Full Scale Intellectual Quotient (FSIQ) ranged from less than 50-119 (mean 78). Simple expressive and receptive language appeared relatively preserved. Three recently diagnosed patients (median time assessment from diagnosis 2.6 years (1.6-4.7)) had average to high average FSIQ, academic and visual spatial skills, visual, and verbal memory. Five other patients diagnosed earlier and tested at a median time of 4.9 years (3.3-8.3) post-diagnosis had a FSIQ ranging from <50 to 71. Approximately 50% of their scores were in the impaired range. Overall this cohort appears significantly impaired at school age despite the absence of systematic radiotherapy. Larger series focusing on neurocognitive outcome are needed in the current context where treatment strategies include adjuvant radiation.

High-dose sequential chemotherapy (HDS) versus PEB chemotherapy as first-line treatment of patients with poor prognosis germ-cell tumors: mature results of an Italian randomized phase II study

BackgroundIn the late 1990s, the use of high-dose chemotherapy (HDCT) and stem-cell rescue held promise for patients with advanced and poor prognosis germ-cell tumors (GCT). We started a randomized phase II trial to assess the efficacy of sequential HDCT compared with cisplatin, etoposide, and bleomycin (PEB). Patients and methodsPatients were randomly assigned to receive four cycles of PEB every 3 weeks or two cycles of PEB followed by a high-dose sequence (HDS) comprising HD-cyclophosphamide (7.0 g/m2), 2 courses of cisplatin and HD-etoposide (2.4 g/m2) with stem-cell support, and a single course of HD-carboplatin [area under the curve (AUC) 27mg/ml × min] with autologous stem-cell transplant. Postchemotherapy surgery was planned on responding residual disease in both arms. The primary end point was progression-free survival (PFS). The study was designed to detect a 30% improvement of 5-year PFS (from 40% to 70%), with 80% power and two-sided α at 5%. ResultsFrom December 1996 to March 2007, 85 patients were randomized: 43 in PEB and 42 in HDS arm. Median follow-up was 114.2 months [interquartile range (IQR): 87.7–165.8]. Complete or partial response with normal markers (PRm-) were obtained in 28 (65.1%) and 29 (69.1%) patients, respectively. Five-year PFS was 55.8% [95% confidence interval (CI) 42.8–72.8] and 54.8% (95% CI 41.6%–72.1%) in PEB and HDS arm, respectively (log-rank test P = 0.726). Five-year overall survival was 62.8% (95% CI 49.9–79.0) and 59.3% (95% CI 46.1–76.3). One toxic death (PEB arm) was recorded. ConclusionsThe study failed to meet the primary end point. Furthermore, survival estimates of conventional-dose chemotherapy higher than expected should be accounted for and will likely limit further improvements in the first-line setting. ClinicalTrials.govNCT02161692.

SWOG S0410/BMT CTN 0703: A Phase II Trial of Tandem Autologous Stem Cell Transplantation (AHCT) for Patients with Primary Progressive or Recurrent Hodgkin Lymphoma (HL) (ClinicalTrials.gov Identifier: NCT00233987)

Background: The SWOG 9011 trial of augmented conditioning regimens (12 Gy TBI or BCNU 15mg/kg with both etoposide 60 mg/kg and cyclophosphamide 100 mg/kg) prior to single AHCT for pts with relapsed or refractory HL demonstrated 5-yr PFS and OS of 41% and 54% respectively in 74 treated pts. Among 46 previously irradiated pts with 2-3 high risk features, the 5-yr OS was 38% compared with 60% for pts with 0-1 risk features. Post-AHCT relapse was the major cause of failure (Stiff et al. BBMT 2003; 9:529). The strategy of sequential high-dose (HD) chemotherapy + tandem AHCT for poor prognosis HL patients was investigated in a City of Hope (COH) & Loyola University (LU) pilot trial of tandem AHCT in 46 HL pts with primary progressive or relapsed HL with at least 1 poor-risk feature. Trial results were promising, with 5-yr OS, EFS and FFP of 54%, 49% and 55% respectively and 100-day TRM of 4% (Fung et al. BBMT 2007;13:594). The purpose of the SWOG led trial S0410 was to evaluate the COH/LU regimen in a phase II cooperative group setting, with the primary endpoint of 2-yr PFS.Methods: Pts with refractory/relapsed HL, eligible ages 15 -70, were enrolled after salvage therapy & stem cell collection (minimum 3.5 X 10.6 CD34/kg). Pts with relapse after prior CR received minimum of 2 cycles salvage chemotherapy or minimum of 25 Gy involved field radiation therapy (IFRT) to determine if they had sensitive or resistant HL. Pts with late relapse (> 12 months after 1st CR) responsive to salvage therapy were excluded. Pts with > 5cm bulk disease after salvage had to agree to 18 Gy IFRT pre-AHCT. A designed sample size of 85 pts over 2-yrs with 18 months follow-up was chosen to have 86% power by 0.025 one-sided alpha test to detect a 15% increase in 2-yr PFS as compared to the historical 2-yr PFS of 45% in S9011. After IFRT to bulk disease pre-AHCT, pts were treated with cycle 1 HD-Melphalan (150 mg/m2) + AHCT. If response after cycle 1 AHCT was SD or better, pts had 2nd AHCT with one of the two HD regimens used in SWOG 9011. Interval between day zero of 1st and 2nd AHCT had to be at least 28 days & not greater than 60 days.Results: 98 patients enrolled from 10 institutions including the BMT CTN. Six ineligible pts had inadequate PFTs (1), incomplete baseline testing (3) or failure to confirm pathology by central review (2). Median age was 34 yrs (range 18-60), 45% had refractory disease, 42% had B symptoms, and 24% had extranodal disease at transplant. Of the 92 eligible pts, 89 were treated, 82 completed both cycles of AHCT and 7 pts did not have 2nd AHCT (1 progressed, 1 declined TBI, 4 with > 60 days since 1st AHCT, 1 poor graft after C1.) Of 89 pts assessed for toxicities, 70 had grade 4 AEs, primarily hematologic and 14 of those pts had grade 4 non-hematologic AEs. Treatment-related mortality was 0%. With median follow-up of 5.4 yrs (range 2 -7.6 yrs), the 2-yr PFS was 63% (95% CI: 52%, 72%) and 2-yr OS was 91% (95% CI 83, 95%), as shown in figures 1 and 2 respectively. There were 15 deaths in eligible pts, 2 deaths in ineligible pts, and 3 deaths in inevaluable pts who did not receive protocol therapy. Of the 15 deaths in eligible and evaluable patients, there were 11 deaths due to progressive HL, 1 death due to non-treatment related respiratory failure, 1 death due to disseminated CMV infection and 2 deaths with primary cause not reported. Late malignancies were mylelodysplasia in 2 pts, thyroid cancer in 1 pt, and 2 pts with non-melanoma skin cancer.Conclusions: The 2-yr PFS of 63% in pts treated with tandem AHCT on S0410 met the predicted study endpoint of at least 15% improvement compared with the 2-yr PFS of 45% in the S9011 trial of augmented HCT conditioning prior to single AHCT. The better-than-expected OS of 91% in S0410 is attributed to the current treatment strategies for progressive or relapsed HL after AHCT, including brentuximab vedotin (BV) salvage and allogeneic HCT, which can lead to a significant percentage of long term survivors. Analysis of prognostic features will be conducted to ascertain if a model can be developed to identify a very high-risk group of HL pts who should be considered for early allogeneic HCT. Next steps will need to take into consideration results of the recently completed trial of BV consolidation after single AHCT; however, the S0410 results are very promising considering the patients had poor-risk relapsed and refractory HL.Support: CA32102, CA38926 [Display omitted] [Display omitted] DisclosuresFisher:Johnson & Johnson : Consultancy; MorphoSys AG: Consultancy.

High Doses of Antimetabolites Followed By High-Dose Sequential Chemoimmunotherapy and Autologous Stem Cell Transplant in Patients with Systemic B-Cell Lymphoma and Secondary Central Nervous System Involvement: Final Results of a Multicenter Phase II Trial

Abstract INTRODUCTION: Secondary central nervous system (CNS) dissemination is a lethal event in patients (pts) with aggressive lymphomas. A few studies focused on the treatment of this condition are available, confirming the dismal prognosis and the high rate of severe neurotoxicity in pts managed with radiotherapy-based induction. Thus, the most effective treatment for secondary CNS lymphoma remains an important, unmet clinical need. Herein, we report the final results of a multicenter phase II trial addressing a new treatment in pts with aggressive B-cell lymphoma and CNS involvement (NCT00801216). Experimental treatment is based on the encouraging experiences with high doses of antimetabolites in pts with primary CNS lymphoma (Ferreri et al. Lancet 2009), and with high-dose sequential chemotherapy combined with rituximab (R-HDS) and supported by autologous stem cell transplant (ASCT) in pts with relapsed aggressive B-cell lymphoma (Tarella et al. JCO 2008). METHODS: Selection criteria were: 1) histological diagnosis of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma blastoid variant (MCLb) or grade-3 follicular lymphoma (FL); 2) secondary CNS involvement at diagnosis or relapse; 3) age 18-70 years; 4) ECOG PS ≤3; 5) absence of HIV infection; 6) adequate organ functions. Pts with primary CNS lymphoma (exclusive CNS disease at diagnosis) were excluded. Experimental treatment consisted of an induction phase with 2 courses of methotrexate 3.5 g/m2 d1 + cytarabine 2 g/m2 x2/d d2-3, followed by an intensification phase with R-HDS (cyclophosphamide 7 g/m2 d1; cytarabine 2 g/m2 x2/d d22-25; pts with residual extra-CNS disease received also etoposide 2 g/m2 d43) and a consolidation phase with BCNU-thiotepa conditioning + ASCT (figure). Treatment included 8 doses of rituximab and 4 of intrathecal liposomal cytarabine. The primary endpoint was 2-year PFS; the planned accrual was 38 pts. RESULTS: 39 pts were registered (age 32-70 ys, median 59; M/F ratio 1.5): 33 had DLBCL, 3 MCLb, 3 FL. CNS disease (brain 21, meninges 5, spinal cord 2, multiple 11) was detected at diagnosis in 16 pts (all with extra-CNS disease) and at relapse in 23 (8 with extra-CNS disease). The median TTP from the previous treatment line was 3 months (range 0-77 months). Thirty-four pts completed the induction phase; 73 (93%) of 78 planned courses were actually delivered; G4 neutropenia, thrombocytopenia and anemia were recorded in 77%, 63% and 5% of courses, G3-4 febrile neutropenia in 16%, CMV reactivation in 3 pts. Transient G4 transaminases increase (3% of courses) was the only G4 non-hematological toxicity. Drugs dose reduction was indicated in 3 pts. Response after induction phase was complete in 11 pts and partial in 19 (ORR= 77%; 95%CI=64-90%). Thirty pts were referred to intensification phase (figure); 58 (97%) of 60 planned courses were actually delivered; G4 neutropenia, thrombocytopenia and anemia were recorded in 67%, 60% and 7% of courses, G3-4 febrile neutropenia in 22%, G4 sepsis in 8%. CMV reactivation was diagnosed in 4 pts, pulmonary aspergillosis in 1. No cases of G4 extra-hematological toxicity were recorded. Response after intensification phase (before conditioning) was complete in 22 pts and partial in 2 (ORR= 62%; 95%CI=47-77%). ASCs were collected in 21/22 (95%) pts (median 9.5 x 106/kg; range 6-19); 20 pts underwent ASCT. Response at the end of the whole program was complete in 23 pts and partial in 1 (ORR= 62%, 95%CI= 47-77%), 1 pt had SD, 10 experienced PD (all in the CNS), and 4 died of toxicity (sepsis 2, stroke, acute tracheal obstruction). Importantly, no pt was irradiated to the brain to achieve lymphoma remission, and no evidence of neurotoxicity was recorded in pts with a survival longer than 3 years. One pt was referred to sibling-donor transplant due to sMDS, and is alive and NED at 91 months of follow-up. At a median follow-up of 42 months, 16 pts remain relapse-free, with a 2-yr PFS of 42±8%. Sixteen pts are alive, with a 2-yr OS of 42±8%; 2-yr OS of transplanted pts was 72±11%. Extra-CNS and/or meningeal disease did not affect outcome, and survival was similar in both pts treated at presentation or at relapse. CONCLUSION: This radiotherapy-free combination of high doses of antimetabolites, R-HDS and ASCT is feasible and effective in pts ≤70 ys with secondary CNS lymphoma. Toxicity is usually haematological and manageable. Survival benefit is attainable also in pts with meningeal and/or concomitant extra-CNS disease. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.