High-dose Myeloablative Chemotherapy Research Articles

Consolidation Regimen and Cerebral Atrophy in Patients with Primary Central Nervous System Lymphoma

BackgroundIn primary central nervous system lymphoma (PCNSL), the extent to which post-methotrexate consolidation contributes to neurotoxicity is unclear. Concerns for neurotoxicity from standard-dose whole-brain radiotherapy (WBRT) have led to declining use. Cerebral atrophy is an established surrogate for neurotoxicity; however, the relative extent to which modern consolidation (i.e., reduced-dose [RD-]WBRT £24Gy, autologous hematopoietic cell transplant [AHCT]) contributes to cerebral atrophy is unclear. MethodsPatients with PCNSL from 2000–2020 who achieved complete response to consolidation following MTX-based induction were included. Inclusion criteria were pre-consolidation MRI (baseline) and ≥1 MRI showing sustained remission at 1, 3, 5, or 10 years. An expert neuroradiologist longitudinally measured parenchymal volume loss via ventricular volumetric change. Linear mixed effects models were performed to estimate absolute and annual volumetric change rates. FindingsOf 139 patients (median follow-up 4.5 years), most were XXXX Center Recursive Partitioning Analysis (RPA) class 2 (age ≥50, Karnofsky performance score [KPS] ≥70). Consolidation therapies included non-myeloablative chemotherapy (n=57; 41%), high-dose myeloablative chemotherapy with AHCT (n=50; 36%), and RD-WBRT (n=28; 20%). Higher RPA class was associated with greater baseline ventricular volume (p<0.001). Overall adjusted annual ventricular volume change rates were greater than those published in healthy controls (4.3% vs. 1.8%) and generally increased by age/decade at diagnosis: 40–49-year-olds 1.8% (95%CI: -1.4%, 5.0%), 50–59-year-olds 3.1% (95%CI: 0.7%, 5.5%), 60–69-year-olds 4.8% (95%CI: 2.4%, 7.3%), 70–79-year-olds 7.2% (95%CI: 4.3%, 10.2%), and 80–89-year-olds 4.2% (95%CI: -1.1%, 9.6%). There were no significant associations between consolidation strategy and ventricular volume change rates accounting for age, KPS, gender, baseline ventricular volume, or interaction between age and consolidation. InterpretationThese findings demonstrate accelerated cerebral atrophy in PCNSL after consolidation compared to healthy adults. However, atrophy did not differ by consolidation strategy. These long-term results suggest acceptable neurotoxicity following RD-WBRT.

MDB-83. OUTCOMES OF INFANTS AND YOUNG CHILDREN WITH NEWLY DIAGNOSED SHH MEDULLOBLASTOMA TREATED ON THE NEXT CONSORTIUM “HEAD START” 4 PROTOCOL

Abstract BACKGROUND Infants and young children with SHH medulloblastoma were demonstrated to have a favorable outcome on “Head Start (HS)” III clinical trial utilizing five cycles of induction followed by one myeloablative high-dose chemotherapy (HDCT) cycle. We present the results of “Head Start” 4 (HS-4) trial where SHH subgroup patients received either three or five cycles of induction based on response followed by one HDCT cycle (similar to HS III). METHODS Eligibility included children &amp;lt;6 years of age at diagnosis of localized medulloblastoma and &amp;lt;10 years for patients with disseminated disease. Eligible patients with SHH medulloblastoma were considered “low-risk” and non-randomly assigned to receive three cycles (five cycles if &amp;lt;complete response) of induction chemotherapy (vincristine, cisplatin, cyclophosphamide, etoposide, and high-dose methotrexate) followed by consolidation with single HDCT cycle (thiotepa, carboplatin, etoposide) and autologous hematopoietic stem-cell rescue. RESULTS Thirty-nine children with SHH medulloblastoma were enrolled on HS-4 with median age of 2.18 years (range: 0.28-6.88 years). Median follow-up for this cohort is 41 months (range: 18-67 months). Patients with localized SHH medulloblastoma (n=28) had significantly better 3-year event-free (EFS) compared to disseminated patients (n=11): 96.4% (95% CI: 90-100%) and 36.4% (95% CI: 16.6-79.5%), respectively (p&amp;lt;0.0001); however, there was no significant difference in 3-year overall survival (OS) between the two groups: 100% and 90.0% (95% CI: 73.2-100%), respectively (p=0.10). The estimated 3-year EFS for localized SHH subtype 1 and 2 patients was 100% and 95%, respectively (p=0.63). None of trial patients received irradiation prior to progression. All patients, except for four, underwent three cycles of induction. Germline variants were detected in 27% of patients tested (8/30). CONCLUSION We report excellent results for young children with localized SHH medulloblastoma when treated with only three cycles (reduced) of induction and single HDCT cycle on HS-4 trial without irradiation. Molecular data will be presented.

A nationwide phase II study of delayed local treatment for children with high-risk neuroblastoma: The Japan Children's Cancer Group Neuroblastoma Committee Trial JN-H-11.

Survival rates of patients with high-risk neuroblastoma are unacceptable. A time-intensified treatment strategy with delayed local treatment to control systemic diseases has been developed in Japan. We conducted a nationwide, prospective, single-arm clinical trial with delayed local treatment. This study evaluated the safety and efficacy of delayed surgery to increase treatment intensity. Seventy-five patients with high-risk neuroblastoma were enrolled in this study between May 2011 and September 2015. Delayed local treatment consisted of five courses of induction chemotherapy (cisplatin, pirarubicin, vincristine, and cyclophosphamide) and myeloablative high-dose chemotherapy (melphalan, etoposide, and carboplatin), followed by local tumor extirpation with surgery and irradiation. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), response rate, adverse events, and surgical complications. Seventy-five patients were enrolled, and 64 were evaluable (stage 3, n=8; stage 4, n=56). The estimated 3-year PFS and OS rates (95% confidence interval [CI]) were 44.4% [31.8%-56.3%] and 80.7% [68.5%-88.5%], resspectively. The response rate of INRC after completion of the treatment protocol was 66% (42/64; 95% CI: 53%-77%; 23 CR [complete response], 10 VGPR [very good partial response], and nine PR [partial response]). None of the patients died during the protocol treatment or within 30days of completion. Grade 4 adverse effects, excluding hematological adverse effects, occurred in 48% of patients [31/64; 95% CI: 36%-61%]. Major Surgical complications were observed in 25% of patients [13/51; 95% CI: 14%-40%]. This study indicates that delayed local treatment is feasible and shows promising efficacy, suggesting that this treatment should be considered further in a comparative study of high-risk neuroblastoma.

Combinational therapy of CAR T-cell and HDT/ASCT demonstrates impressive clinical efficacy and improved CAR T-cell behavior in relapsed/refractory large B-cell lymphoma

BackgroundApproximately two-thirds of patients with relapsed or refractory large B-cell lymphoma (R/R LBCL) do not respond to or relapse after anti-CD19 chimeric antigen receptor T (CAR T)-cell therapy, leading to...

Etoposide plus cytarabine versus cyclophosphamide or melphalan in busulfan-based preparative regimens for autologous stem cell transplantation in adults with acute myeloid leukemia in first complete remission: a study from the Acute Leukemia Working Party of the EBMT.

We retrospectively compared the impact of the conditioning regimen in adult patients with acute myeloid leukemia (AML) in first complete remission (CR1) that received high-dose myeloablative chemotherapy followed by autologous stem cell transplantation (ASCT) from 2010 to 2021 with either high-dose cytarabine, etoposide and busulfan (BEA), busulfan with cyclophosphamide (BUCY) or busulfan and high-dose melphalan (BUMEL) registered in the EBMT database. Overall 1560 patients underwent ASCT, of which 156, 1143 and 261 received BEA, BUCY and BUMEL, respectively. Compared to BUCY and BUMEL, BEA patients were younger (p < 0.001) and less frequently had NPM1 mutations (p = 0.03). Transplant outcomes at 5 years with BEA, BUCY and BUMEL were: cumulative incidence of relapse 41.8%, 46.6% and 51.6%; non-relapse mortality (NRM) 1.5%, 5.2% and 7.3%; probability of leukemia-free survival (LFS) 56.7%, 48.2% and 41.1%; and overall survival (OS) 71.3%, 62.3% and 56%, respectively. In multivariable analysis the BEA regimen showed significant improvement in OS compared to BUCY (hazard ratio [HR] 0.65; 95% CI, 0.42-0.83; p = 0.048) and BUMEL (HR 0.59; 95% CI, 0.37-0.94; p = 0.029). In conclusion, high-dose myeloablative combination chemotherapy with BEA offered improved outcomes compared to classical BUCY or BUMEL in patients with AML in CR1 undergoing ASCT.

Transplant in Diffuse Large B-Cell Lymphoma

Abstract: Diffuse large B-cell lymphoma is the most common type of aggressive lymphoma. Patients that don’t respond to first-line therapy have a poor prognosis. Bone marrow transplant represents an effective and established salvage treatment for those patients, with curative potential. Autologous transplant uses the patient stem cell for rescue after high-dose myeloablative chemotherapy, while allogenic transplant relies on a different stem cell for a graft-versus-lymphoma effect. With distinct toxicity and capacity to induce remission, those therapies have great value in the management of patients with relapsed and refractory diffuse large B-cell lymphoma.

The Role of Autologous Stem Cell Transplantation in the Treatment of Diffuse Large B-cell Lymphoma in the Era of CAR-T Cell Therapy.

For many years now and based on the results of the PARMA trial, relapsed Diffuse Large B-cell Lymphoma (DLBCL) is treated with salvage combination cytotoxic chemotherapy (most often platinum-based) followed by high dose myeloablative chemotherapy and autologous stem cell transplantation (auto-HCT). This approach has resulted in long-term disease free survival in about half of the patients. With the incorporation of rituximab in the upfront treatment (RCHOP), more patients with DLBCL are cured but there has been a signal of inferior outcomes with auto-HCT if DLBCL relapses. Nevertheless, a careful review of the literature still shows very good outcomes with auto-HCT for DLBCL with complete remission to salvage chemotherapy. For those who do not respond well to classic salvage other approaches are reviewed here including chimeric antigen receptor (CAR) T-cell therapy and treatment with antibody-drug conjugates (ADCs) as well as bispecific T-cell engagers (BiTEs). The outcome of auto-HCT after successful treatment with ADCs or BITEs is unknown. It is also unknown if CAR-T cell therapy should be reserved for those who have failed 2 lines of chemotherapy or it should be moved earlier. Finally, we review here the effects of Myc and bcl2 amplifications or translocations to the outcome of the auto-HCT. Some attempts to improve the salvage or conditioning regimens are mentioned. We also discuss the role of allogeneic stem cell transplantation (allo-HCT) in the paradigm of treatment for relapsed DLBCL.

Definitive Tumor Resection after Myeloablative High Dose Chemotherapy Is a Feasible and Effective Option in the Multimodal Treatment of High-Risk Neuroblastoma: A Single Institution Experience

Background/PurposeThe delayed local treatment approach (DL) in high-risk neuroblastoma (HR-NB) refers to the process in which tumor resection is performed after the completion of all the courses of chemotherapy, including myeloablative high-dose chemotherapy (HDC). Alternatively, in the conventional local treatment approach (CL), tumor resection is performed during induction chemotherapy. In this study, we compared the surgical outcomes in HR-NB patients treated by CL and DL. MethodForty-seven patients with abdominal HR-NB underwent primary tumor resection from 2002 to 2018. The timing of surgery was generally determined by following the trials and guidelines available at the time. The outcomes and surgical complications between the two strategies were compared. ResultOperation time, blood loss, and postoperative WBC counts were lower in the DL group (n = 25) when compared to the CL group (n = 22), statistical significance notwithstanding. Major vascular structures were less frequently encased in the DL group tumors, while immediate surgical complications were significantly more frequent in the CL group (P < 0.05). Furthermore, the 3-year EFSs were 50.0% and 53.9% in the DL and CL groups, respectively. ConclusionDL appears to be a feasible and effective treatment option for HR-NB. Nonetheless, further verifications using larger cohorts are warranted. Level of evidenceTreatment study, Level III.

Feasibility of High-dose Iodine-131-metaiodobenzylguanidine Therapy for High-risk Neuroblastoma Preceding Myeloablative Chemotherapy and Hematopoietic Stem Cell Transplantation: a Study Protocol.

Objective(s):High-risk neuroblastoma is a childhood cancer with poor prognosis despite modern multimodality therapy. Internal radiotherapy using 131I-metaiodobenzylguanidine (MIBG) is effective for treating the disease even if it is resistant to chemotherapy. The aim of this study is to evaluate the safety and efficacy of 131I-MIBG radiotherapy combined with myeloablative high-dose chemotherapy and hematopoietic stem cell transplantation.Methods:Patients with high-risk neuroblastoma will be enrolled in this study. A total of 8 patients will be registered. Patients will receive 666 MBq/kg of 131I-MIBG and after safety evaluation will undergo high-dose chemotherapy and hematopoietic stem cell transplantation. Autologous and allogeneic stem cell sources will be accepted. After engraftment or 28 days after hematopoietic stem cell transplantation, the safety and response will be evaluated.Conclusion: This is the first prospective study of 131I-MIBG with high-dose chemotherapy and hematopoietic stem cell transplantation in Japan. The results will be the basis of a future nationwide clinical trial.

HG-54THE ROLE OF HIGH-DOSE MYELOABLATIVE CHEMOTHERAPY (HDCT) WITH HAEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT) IN CHILDREN WITH HIGH GRADE GLIOMAS (HGG) OR DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG): RESULTS OF A SYSTEMATIC REVIEW

HG-54. THE ROLE OF HIGH-DOSE MYELOABLATIVE CHEMOTHERAPY (HDCT) WITH HAEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT) IN CHILDREN WITH HIGH GRADE GLIOMAS (HGG) OR DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG): RESULTS OF A SYSTEMATIC REVIEW Caroline Main1, Madeline Adams2, Katherine Cooper3, Sophie Wilne4, Bob Phillips5, Martin English6, Pamela R. Kearns1,6, Barry Pizer3, Simon P. Stevens1, Keith Wheatley1, and Jayne S. Wilson1; Cancer Research UK Clinical Trials Unit; University of Birmingham, Birmingham, UK; Bristol Children’s Hospital, Bristol, UK; Alder Hey Children’s NHS Foundation Trust, Liverpool, UK; Nottingham University Hospitals’ NHS Trust, Nottingham, UK; UK Centre for Reviews and Dissemination, University of York, UK; Birmingham Children’s Hospital NHS Foundation Trust, Birmingham, UK OBJECTIVES: To assess the impact of HDCT/HSCT in children with HGG or DIPG. METHODS: Ten electronic databases were searched from 1985 to Oct 2015 for studies assessing HDCT/HSCT in HGG and DIPG. Outcomes included overall survival (OS), response rates (RR), adverse events and treatment related mortality (TRM). Standard systematic review methods were used to minimise bias. RESULTS: For HGG, 167 patients were included, 56% newly diagnosed and 44% relapsed. Mean age was 8.7 years. Mean follow-up was 2.8-years (range: 0.2-5.4). HDCT mainly consisted of one cycle, with preor post radiotherapy (RT) used in 59% of patients. Median OS for newly diagnosed HGG was between 9-14 months (range: 1-65) (n 1⁄4 27), with one and four year OS 73%+13% (n 1⁄4 11) and 43% (n 1⁄4 21) respectively. Overall RR was 30% (n 1⁄4 26). For relapsed HGG median OS was 12.7months (n 1⁄4 18). Across the studies nine TRM occurred. Sixty-two patients with DIPG were included, 68% newly diagnosed and 32% relapsed. Mean age was 6.8-years. Median follow-up was 1.5 years (range: 0.1-7). HDCT consisted of one cycle, with 77% patients receiving prior RT. For newly diagnosed patients with DIPG, median OS was 10-11.4 months (range: 6.4-17.1) (n 1⁄4 42), and for relapsed patients 4.8 months (0.1-18.7) (n 1⁄4 16). Across the studies five toxicity related deaths occurred (8%). CONCLUSIONS: The limited evidence on HDCT/HSCT in children with HGG or DIPG does not allow reliable conclusions to be drawn. However, use of HDCT/HSCT in these patient groups is associated with a significant toxicity profile and TRM. Neuro-Oncology 18:iii48–iii77, 2016. doi:10.1093/neuonc/now073.50 #The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

The role of high-dose myeloablative chemotherapy with haematopoietic stem cell transplantation (HSCT) in children with central nervous system (CNS) tumours: protocol for a systematic review and meta-analysis.

ObjectivesThe objective of the study is to conduct a systematic review to compare the effects of high-dose chemotherapy (HDCT) with autologous haematopoietic stem cell transplantation (HSCT) versus standard-dose chemotherapy (SDCT) in children with malignant central nervous system (CNS) tumours.MethodsStandard systematic review methods aimed at minimising bias will be employed for study identification, selection and data extraction. Ten electronic databases will be searched, along with citation searching and reference checking. Studies assessing the effects of HDCT with HSCT in children with CNS tumours will be included. The outcomes are survival (overall, progression-free, event-free, disease-free), response rates, short- and long-term adverse events and health-related quality of life (HRQoL). Two reviewers will independently screen and select randomised and non-randomised controlled trials and controlled and uncontrolled observational studies for inclusion. Quality assessment will be tailored to the different study designs. Where possible data will be summarised using combined estimates of effect for the hazard ratio for survival outcomes and the risk ratio for response rates. A fixed effect model will be used; sub-group analyses and meta-regression will be used to explore potential sources of heterogeneity between studies.DiscussionGiven the poor prognosis of malignant brain tumours in children in terms of survival and quality of life, this review will help guide clinical practice by summarising the current evidence on the use of high-dose myeloblative chemotherapy with stem cell support in children with CNS tumours.

P16 * METASTATIC MEDULLOBLASTOMA - UK RESULTS WITH INDUCTION AND HIGH DOSE CHEMOTHERAPY WITH HYPERFRACTIONATED ACCELERATED RADIOTHERAPY (THE MILAN STRATEGY)

INTRODUCTION: Historically, the 5-year overall survival (OS) for metastatic medulloblastoma (MMB) is less than 40%. The Milan Strategy of post-operative induction chemotherapy (IC) followed by hyperfractionated accelerated radiotherapy (HART) and response directed myeloablative high dose chemotherapy (HDC) or maintenance chemotherapy was reported in a study of 33 patients with MMB to improve 3-year OS to 77% (95% CI 61, 93) and 5-year OS to 73% (59, 87). We report the outcomes of patients treated using this strategy in UK centres. METHOD: Questionnaires were sent to all 20 UK paediatric oncology centres to collect retrospective data on treatment delivered, toxicity and survival with the Milan strategy. RESULTS: Between February 2009 and October 2011, 34 patients with MMB in 14 centres fulfilled the entry criteria of the original study. The median age at presentation was 7 years (range 3-15). Median interval from surgery to HART was 109 versus 85 days in the Milan series. The incidence of grade 3 haematological toxicities with IC and HDC was 83-100%. 16/16 patients who achieved CR by the end of therapy remain alive and in remission but only 3/18 with lesser responses are still alive (p < 0.0001). With follow up of 30-60 months, we estimate 3-year OS of 55% (95% Cl 38, 71). This result is outside the 95% CI of the Milan results and encompasses the historical result of 40%. We did not observe major late neurotoxicity. CONCLUSION: We did not replicate the improved results reported by the Milan group. The reasons could include differences in patient sub-groups and protocol compliance.

Reovirus as a successful ex vivo purging modality for multiple myeloma

Autologous stem cell rescue (ASCT) following high-dose myeloablative chemotherapy is considered to be a therapeutic option for many multiple myeloma (MM) patients; however relapse post ASCT presents a major challenge. The oncolytic potential of reovirus has been previously demonstrated and is currently undergoing phase I monotherapy clinical trials for MM and phase II/III clinical trials for solid tumors. Here we tested the hypothesis that reovirus can successfully purge MM in a murine model that partially recapitulates human MM. RPMI 8226, MM1S, H929 and U266 human myeloma cell lines were exposed to reovirus and oncolysis was assessed. Apheresis product admixed with MM cells was purged with live reovirus (LV) or dead virus (DV) and purging efficacy was monitored via flow cytometry, reverse transcribed-PCR (RT-PCR) and disease relapse in non obese diabetic/severe combined immune deficient (NOD/SCID) mice. Significant LV purging was seen with MM1S, H929 and U266 and the complete ex vivo purging achieved with RPMI 8226 was confirmed by flow cytometry, RT-PCR and absence of disease relapse in vivo. Mice that received LV-purged autografts exhibited 100% survival in comparison to mice that received DV-purged controls. Reovirus's unique ability to kill MM while sparing hematopoietic stem cells places it as an attractive purging agent for MM during ASCT.

Myeloablative chemotherapy and autologous stem cell transplantation in patients with relapsed or progressed central nervous system germ cell tumors: results of Korean Society of Pediatric Neuro-Oncology (KSPNO) S-053 study

The present study evaluated the feasibility and effectiveness of myeloablative high-dose chemotherapy and autologous stem cell transplantation in patients with relapsed or progressed central nervous system germ cell tumors (CNS-GCTs). Eleven patients with non-germinomatous germ cell tumors and nine patients with germinomas were enrolled. Patients received between two and eight cycles of conventional chemotherapy prior to HDCT/autoSCT with or without radiotherapy. Overall, 16 patients proceeded to the first HDCT/autoSCT, and nine proceeded to the second HDCT/autoSCT. CTE (carboplatin-thiotepa-etoposide) and cyclophosphamide-melphalan (CM) regimens were used for the first and second HDCT, respectively. Toxicities during HDCT/autoSCT were acceptable, and there were no treatment-related deaths. Twelve patients experienced relapse or progression; however, four patients with germinomas remain alive after subsequent RT. Therefore, a total of 12 patients (four NGGCTs and eight germinomas) remain alive with a median follow-up of 47 months (range 22-90) after relapse or progression. The probability of 3-year overall survival was 59.1 ± 11.2 % (36.4 ± 14.5 % for NGGCTs vs. 88.9 ± 10.5 % for germinomas, P = 0.028). RT, particularly craniospinal RT, was associated with a better tumor response prior to HDCT/autoSCT and a better final outcome. In conclusion, HDCT/autoSCT was feasible, and survival rates were encouraging. Further study with a larger cohort of patients is needed to elucidate the role of HDCT/autoSCT in the treatment of relapsed or progressed CNS-GCTs.

Busulfan pharmacokinetics following intravenous and oral dosing regimens in children receiving high-dose myeloablative chemotherapy for high-risk neuroblastoma as part of the HR-NBL-1/SIOPEN trial

IntroductionBusulfan is widely used in a neuroblastoma setting, with several studies reporting marked inter-patient variability in busulfan pharmacokinetics and pharmacodynamics. The current study reports on the pharmacokinetics of oral versus intravenous (IV) busulfan in high-risk neuroblastoma patients treated on the European HR-NBL-1/SIOPEN study. MethodsBusulfan was administered four times daily for 4days to children aged 0.7–13.1years, either orally (1.45–1.55mg/kg) or by the IV route (0.8–1.2mg/kg according to body weight strata). Blood samples were obtained prior to administration, 2, 4, and 6h after the start of administration on dose 1. Busulfan analysis was carried out by gas chromatography–mass spectrometry and data analysed using a NONMEM population pharmacokinetic approach. ResultsBusulfan plasma concentrations obtained from 38 patients receiving IV busulfan and 25 patients receiving oral busulfan, were fitted simultaneously using a one-compartment pharmacokinetic model. Lower variability in drug exposure was observed following IV administration, with a mean busulfan area under the plasma concentration versus time curve (AUC) of 1146±187μM.min (range 838–1622), as compared to 953±290μM.min (range 434–1427) following oral busulfan. A total of 87% of children treated with IV busulfan achieved AUC values within the target of 900–1500μM.min versus 56% of patients following oral busulfan. Busulfan AUC values were significantly higher in HR-NBL-1/SIOPEN trial patients who experienced hepatic toxicity or veno-occlusive disease (VOD) (1177±189μM.min versus 913±256μM.min; p=0.0086). Further stratification based on route of administration suggested that the incidence of hepatic toxicity was related to both high busulfan AUC and oral drug administration. ConclusionThe reduced pharmacokinetic variability and improved control of busulfan AUC observed following IV administration support its utility within the ongoing HR-NBL-1/SIOPEN trial.

Reduced-Intensity Allogeneic Hematopoietic Transplantation Should Be Considered a Standard of Care for Older Patients with Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is primarily a disease of older people with a median age greater than 65 years. The treatment of AML in elderly patients remains a major challenge. Older patients are more likely to have high-risk cytogenetic abnormalities, and age itself confers a poor prognosis. There has been little progress with standard forms of chemotherapy [1-3]. Allogeneic stem cell transplantation (SCT) were originally developed as a means of delivering high-dose myeloablative chemotherapy or radiation with the transplant to provide hematologic recovery after the myeloablative therapy [4]. This approach is associated with considerable toxicity, and could only be performed in relatively young patients in excellent general medical condition. We have come to appreciate that much of the benefit is derived from the graft-versus-leukemia effect mediated by donor immune cells [5,6]. This realization has supported the development of reduced-intensity or nonmyeloablative preparative regimens involving lower doses of chemotherapy and/or total-body radiation, which are sufficiently immunosuppressive to prevent rejection and allow development of the graft-versus-leukemia effect [7-10]. These reduced-intensity regimens allow treatment of older or medically infirm patients who were not previously eligible for allogeneic stem cell transplantation [11]. Reduced-intensity regimens may be associated with a higher risk of relapse compared with myeloablative conditioning, but leukemia-free survival is similar in most studies [12,13]. Patients up to age 75 years have been treated with this approach. Similar results are reported with matched related or unrelated donors [14,15]. A number of studies have shown promising results of reduced-intensity transplants in patients with AML. In this issue, Farag et al. [16] evaluate the results of treatment for patients age 60 to 70 years, comparing the results of reduced-intensity allogeneic transplantations reported to the Center for International Blood and Marrow Transplant Research with patients receiving standard chemotherapy on Cancer and Leukemia Group B protocols. The 2 groups had similar patients characteristics and prognostic factors. The transplant recipients were slightly younger than the chemotherapy group. Patients receiving allogeneic HCT had a significantly lower risk of relapse (32% versus 81% at 3 years; P < .001), and longer leukemia-free survival (32% versus 15% at 3 years; P < .001). Allogeneic stem cell transplantation is a high-risk procedure, and as expected, there was a higher risk of nonrelapse mortality at 3 years (36% versus 4%; P < .001). Overall survival was 37% versus 25% at 3 years (P = .08). One limitation of this type of analysis is the effect of patient selection. Older patients undergoing SCT are selected to be in good enough medical condition to undergo SCT and are a self-selected, highly motivated group of patients. Allogeneic SCT involves a major commitment on the part of the patient, requiring close medical monitoring for at least several months. It frequently requires patients and their caregivers to relocate temporarily to another city to be near the transplant center. Allogeneic hematopoietic transplantation is not a feasible or desirable choice for many elderly patients. These considerations make it almost impossible to conduct a prospective randomized study. However, this and other studies demonstrate that allogeneic SCT provides durable complete remission in a high fraction of older patients, and the reported results consistently compare favorably to those achieved with alternative conventional treatments [17]. Age alone should not be considered a contraindication to allogeneic SCT for AML [15]. Allogeneic hematopoietic transplantation using a reduced-intensity regimen should be considered an effective treatment option and an established standard of care for older patients with AML.

A randomized, double-blind, placebo-controlled trial of misoprostol for oral mucositis secondary to high-dose chemotherapy

Misoprostol, a synthetic analog of prostaglandin E1, has anti-inflammatory and mucosa-protecting properties. The objective of this study was to evaluate the efficacy of misoprostol oral rinse in reducing the severity of oral mucosal injury caused by high-dose chemotherapy. The study used a randomized, double-blind, placebo-controlled, parallel-group design. Oncology patients receiving myeloablative high-dose chemotherapy, in preparation for a hematopoietic stem cell transplant, were randomized to misoprostol or placebo rinse. The primary outcome measure was the severity of oral mucositis, measured using the modified Oral Mucositis Index. Additional outcome measures included the severity of mouth pain (measured using a Visual Analog Scale and the Pain Affect Faces Scale), duration of hospital stay, and days on total parenteral nutrition. This study was originally planned to accrue 160 subjects but was terminated early due to revised sponsor research priorities. The intent-to-treat population consisted of 22 subjects randomized to misoprostol rinse and 26 subjects randomized to placebo rinse. There was no significant difference between the two groups in mucositis or pain severity. In both groups, duration of hospital stay was approximately 19 days, and number of days on total parenteral nutrition was 17-18 days. There were no serious adverse events attributable to misoprostol rinse. Although this study did not find a beneficial effect of a misoprostol rinse in mucositis secondary to high-dose chemotherapy, the small sample size limits the strength of this conclusion. Given the proposed importance of the prostaglandin pathway in the pathogenesis of oral mucositis, additional studies are warranted.

Use of Rasch Analysis in the Evaluation of the Oropharyngeal Mucositis Quality of Life Scale

Oropharyngeal mucositis (OM) is a significant clinical problem causing profound impairment of health-related quality of life (HQoL) for patients undergoing cancer therapy. The Oropharyngeal Mucositis-Specific Health-Related Quality of Life Measure (OMQoL) was developed using classical test theory to measure the self-perceived HQoL of patients with mucositis. The aim of this study was to analyze the OMQoL according to the Rasch model and, on the basis of results, determine whether improvements could be made. A multicenter approach was used, and 210 patients treated with stomatotoxic chemotherapy (36%), high-dose myeloablative chemotherapy ± total body irradiation (10%), or head and neck irradiation ± chemotherapy (54%) completed the OMQoL. The Partial Credit Model of Rasch analysis was applied to evaluate the 31-item OMQoL using WINSTEPS and R software. Unidimensionality (measurement of a single construct), item fit, response category performance, person separation reliability, targeting of item difficulty to person ability, and differential item functioning (DIF) were examined. Of 31 items, 5 were removed due to misfit; the OMQoL was reduced to 26 items with acceptable information weighted fit/outlier-sensitive fit indices (within 0.7-1.3) and eigenvalue units (≤2.0), confirming the unidimensionality of the reduced OMQoL. The OMQoL and its four subscales showed ordered category thresholds, and the person separation reliability was high (person separation index >0.2 with reliability >.8). Nevertheless, some of the items in the OMQoL might not be targeted effectively to patients with low levels of OM. Significant uniform and nonuniform DIFs were not found for gender (uniform DIF, p = .26; nonuniform DIF, p= .24) and age (uniform DIF, p = .95; nonuniform DIF, p = .65). Rasch analysis reveals that the reduced 26-item OMQoL is unidimensional and is adequate to measure HQoL for patients with OM regardless of gender and age group. This improved version can provide a common platform for nurses to use in their assessment, caring, and treatment of patients with OM.

Supportive Care for Oncology Treatment: Not Just Icing on the Cake

Oral mucositis (OM) is a frequent and, occasionally severe complication of chemotherapy and radiation therapy to treat cancer. The patient’s experience of OM can range from mild odynophagia to severe tissue inflammation, edema, and mucosal bleeding which prevents all alimentation, and can require -- in its most severe form -- intubation to protect a patient’s airway. As patients experience progressive mucositis during treatment, a vicious cycle can ensue, including worsening pain and dysphagia, resulting in reduced oral intake, leading to malnutrition, weight loss, fatigue and deconditioning. At the same time, ulceration in the oral cavity can lead to bacterial and fungal colonization and local infection, putting immune compromised patients at risk for systemic infection. While best characterized in the setting of myeloablative high-dose chemotherapy for patients undergoing hematological stem cell transplantation (HCST), OM is a common toxicity of a wide range of chemotherapy agents used to treat cancers such as breast, lung, colorectal, and lymphoma.(1) The World Health Organization’s scoring for grading OM ranges from 0 to 4, with 0 being no evidence of mucositis, grade 1 including soreness with or without erythema but no ulcerations, while grade 2 to 4 includes erythema and ulceration and a progressive loss of the ability to eat. Grade 2 classifies patients who can still swallow some solid foods, while grade 3 characterizes patients who cannot swallow any solid food. Grade 4 is reserved for those patients who are not able to tolerate any p.o. intake. (2) Despite its clinical impact, OM has not been studied with the fervor and intensity of new anti-cancer agents that are designed to eliminate tumor burdens and cure patients or prolong their survival. Hence, it has been viewed as the “icing on the cake” of cancer therapy, to the detriments of cancer patients who suffer from the complications of this very real clinical problem. Given the severity and significant complications from oral mucositis, a number of interventions have been developed and tested to reduce the severity of this complication. Good oral hygiene, aggressive use of narcotic analgesics, and frequent physician evaluations are critical. Additional interventions that have been studied include cryotherapy using ice chips, and drugs such as benzydamine, amifostine, and more recently palifermin. Palifermin is a recombinant human keratinocyte growth factor (KGF) which targets the KGF/FGFR2b receptor. Stimulating this growth factor receptor can have a potent stimulating effect on epithelial cell proliferation. When initially tested in patients undergoing autologous HCST, palifermin was found to reduce the percentage of patients experiencing severe (grade 3/4) OM as well as its duration. (3) This positive study led to FDA approval in December, 2004. Subsequent studies of palifermin in colorectal patients treated with 5-fluorouracil as well as head and neck patients treated with radiation therapy have found improvements in mucositis, dysphagia and xerostomia in select patient groups. However, while approved as part of the conditioning regimen in HSCT, palifermin is not currently recommended for inclusion in other treatment modalities based on the consensus statements from groups such as the American Society of Clinical Oncology and the Multinational Association of Supportive Care in Cancer (1,2). In this issue of the Annals, Vadhan-Raj and colleagues describe the effects of palifermin therapy in patients undergoing intensive treatment for solid tumor malignancies. (4) Using a randomized placebo-controlled phase II study design, they found that patients treated with doxorubicin-based chemotherapy for sarcomas had a significant improvement in the severity and duration of grade 2-4 mucositis. Patients in the trial received a single dose of 180 micrograms//kg instead of the standard three daily dosages prior to chemotherapy. Further, patients on the placebo arm were allowed to cross over to palifermin after treatment assignments were unblinded; all such patients experienced improvement in their OM in subsequent rounds of chemotherapy. In short, this is a positive study that met its endpoint. The importance of supportive care in assisting patients undergoing intensive anticancer therapy cannot be overemphasized. Accordingly, we believe such supportive care interventions such as the use of palifermin should be assessed based on four principles.

Severe oral mucositis associated with cancer therapy: impact on oral functional status and quality of life

This study determined the incidence of severe oral mucositis (OM), patients' self-reported moderate and severe oral symptoms, and change of quality of life (QoL), as well as examined whether OM severity and pain scores predicted the impairment of oral function and QoL. A multicenter approach was used and 137 patients treated with stomatotoxic chemotherapy (45%), high-dose myeloablative chemotherapy with or without concomitant total body irradiation (12%), head and neck irradiation with or without concomitant chemotherapy (44%) completed the OM-specific QoL measure (OMQoL) once or twice weekly over a 4- or 10-week period, along with concurrent measures of OM using WHO Mucositis Grading System and oral symptoms using 10 cm visual analog scale. The incidence of severe OM was 50% (n = 68). About 77-80% of patients with severe OM reported moderate or severe mouth or throat pain, and 66-78% reported moderate or severe oral functional problems. The oral symptoms peak and area-under-the-curve (AUC) scores of patients with severe OM (peak 5.6 to 6.8; AUC 3.8 to 5.2) were significantly higher than those without OM and those with mild OM (p < 0.01). The OMQoL subscales peak and AUC scores of patients with severe OM (peak 47.9 to 62.1; AUC -40.1 to -25.8) were significantly lower than those without OM and those with mild OM (p < 0.01). Of those with severe OM, 88-94% had a drop in the OMQoL subscale scores to at least 10 points from the baseline. Pain resulting from OM, in particular throat pain, is most predictive of oral functional impairment (standardized β = 0.53-0.83). Severe OM can cause profound pain and oral functional incapability and clinical significant impairment of QoL.