Addition Of High-dose Cytarabine Research Articles

PB2085: UPFRONT TREATMENT OF MANTLE CELL LYMPHOMA (MCL) WITH R-HDAC (RITUXIMAB-HIGH DOSE CYTARABINE + DEXAMETHASONE) IN YOUNG, HIGH RISK PATIENTS IS WELL TOLERATED AND LEADS TO DURABLE RESPONSES.

Background: MCL commonly presents as aggressive disease with a low cure rate and multiply relapsing/remitting course. Treatment of classical MCL with upfront intensive chemoimmunotherapy (CIT) consolidated with an autologous stem cell transplant (ASCT) is considered best practice in younger patients. There is no gold standard intensive CIT regimen. Common approaches include alternating RCHOP/RDHAP (Nordic) and R-Hyper-CVAD.(1) The addition of high dose Cytarabine (HDAC) has been shown to improve time to treatment failure (TTF), complete response (CR) rates and progression free survival (PFS). Aims: There is little published on the efficacy of R-HDAC in treatment-naive MCL, however a 2013 case series (Forbes et al) reported good early efficacy (CR in 16/18), with no detriment to harvest success. We describe tolerability and efficacy of upfront R-HDAC in a high risk cohort of younger patients with MCL. Methods: We identified 28 patients who received upfront R-HDAC in 3 UK centres from 2010–2021. Data were collected, anonymized and transferred centrally for analysis using Kaplan-Meier survival curves. Results: For baseline characteristics see Table 1. Treatment regimen: Dexamethasone 40mg d1-d4, Rituximab 500mg d1, Cytarabine 3000mg/m2 BD d2-d3 in 21day cycles. 22/28 (79%) completed their planned quota of 4-6cycles; 6/28 (21%) did not. Of these n=5 had progressive disease (PD), n=1 ceased with toxicity. 4/28 incurred cycle delays. 1 patient developed PD after completing R-HDAC. Haematological toxicity ≥ Grade 3 CTCAE: Anaemia 71%; Thrombocytopenia 93%; Neutropenia 93%. Fatigue (57%), Nausea 25%, Vomiting 7%, Constipation 21%, Diarrhoea 11%, Cardiac toxicity 11%, Pulmonary toxicity 18%, Rash 11%. 20/28 (71%) underwent stem cell transplant consolidation of which 19 had an ASCT. The median CD34+ stem cell harvest was 8.3x109^L/Kg (2.56-40.9) with no harvest failures. One patient underwent an allogeneic SCT. Of those who didn’t undergo transplant: 1/8 declined; 1/8 was ineligible; 6/8 had PD and switched to 2nd line therapy. Overall Response Rate (ORR) (RECIST) was 78%, CR 41%; PR (Partial response) 37%; and PD 22%. The median PFS was 3.39years (95% CI 0-7.937). 5y OS was 64.3% (95% CI 44.9-83.7%), median OS 8.7years (95% CI 2.634 – 14.894). Image:Summary/Conclusion: Our cohort showed higher rates of haematological toxicity, but lower gastrointestinal toxicity than those reported with the Nordic approach.(1) There were no incidents of treatment related mortality (TRM). More intensive regimens e.g. R-Hyper-CVAD have documented TRM rates of up to 8%. Only 1 patient in our cohort ceased treatment because of toxicity. Whilst our ORR is lower than those published in trial data on commonly used regimens (78% vs MCL Younger trial ORR: RCHOP arm 90%/Cytarabine arm 94%) our cohort’s baseline demographics are comparably much higher risk: MIPIb High 53% vs 25/20%; Blastoid disease 25% vs 9/8%. Of those with PD in our cohort, 4/6 had high MIPIb and blastoid disease. Despite this disparity, R-HDAC retains a comparable CR rate (41% vs 38%) and 5y OS (64.3% vs 65%). Whilst this observational retrospective study has limitations, it has shown that R-HDAC is an option for younger patients with high risk MCL. Using fewer CIT drugs could reduce toxicity and reserve more agents for use in future relapse.

Prospective PhaseⅡ Study of Reduced Toxicity Conditioning Consisted of High Dose-Cytarabine, Fludarabine, Cyclophosphamide +/- Total Body Irradiation Followed By Allogeneic Stem Cell Transplantation

Introduction: Allogeneic hematopoietic stem cell transplantation (allo-SCT) using reduced intensity conditioning (RIC) has been widely applied to elderly or frail patients who are not eligible for conventional conditioning regimen. However, benefit provided by reduced toxicity has been often offset by increased incidence of relapse. So far, the optimal conditioning for those patients has not been established. Here, to investigate whether addition of high dose cytarabine (AraC) to RIC regimen consisting of fludarabine (Flu) and cyclophosphamide (Cy) +/- total body irradiation (TBI) can be available for elderly or frail recipients, phase II study has been designed.Methods: This study was conducted from April 2011 to December 2015. The protocol was approved by each institutional review board (Trial identifier: UMIN000007281). Patients aged from 55 to 70, or patients who have some organ damage or a history of SCT aged from 20 to 54 with hematologic malignancies were enrolled after obtaining written informed consent. Bone marrow (BM), peripheral blood (PB), or cord blood (CB) was used as stem cell sources. Pretransplant conditioning regimen consisted of 30 mg/m2 of Flu for 5 days (total 150 mg/m2), 4 g/m2 of AraC for 2-4 days (divided by 2 daily, total 8-16 g/m2) and 50mg/kg of Cy for a day. Four gray of TBI was used for all CB transplant recipients, whereas 2 gray of TBI was used in other stem cell sources except a matched related donor according to each institutional policy. Calcineurine inhibitors (cyclosporine or tacrolimus) and short term methotrexate were used as GVHD prophylaxis. Donor cell engraftment and 60 day-survival were assessed as a primary end point to evaluate feasibility of this protocol.Results: Thirty nine patients including 7 recipients with a history of SCT were enrolled. Median age was 61 (28-69), 21 were male, and 18 were female. Nineteen were acute myeloid leukemia, 11 myelodysplastic syndrome, 6 malignant lymphoma and 3 acute lymphoblastic leukemia. Donors were 4 matched related PB, 8 matched unrelated BM, 5 1-Ag/allele-mismatched unrelated BM, and 22 ≤2-Ag-mismatched CB. Thirty seven (94.9%) patients have passed 60-day-point post-transplant. In 38 (97.4%) recipients, engraftment was obtained, a patient died before engraftment due to sepsis caused by enterococcus faecium (male CB recipient, 55y, day15). Median neutrophil recovery to over 500/μl was obtained on day 19 (16-38). Fourteen blood stream infections (13 bacteremias and 1 candidemia) judged as grade 3 toxicity and 2 cases (1 sepsis and 1 endotoxemia ) of grade 4 toxicity were observed within 60 days post-transplant. There were 2 deaths of post-engraftment due to cerebral bleeding (1 female CB recipient, 64y, day 46) and GVHD (1 male CB recipient, 60y, day 77) within 100 days. Although no relapse was observed up to day 60, 7 relapses were observed up to 1 year. Overall survival and disease-free survival were estimated to be 82.1% and 73.8 % at 1 year post-transplant, respectively.Conclusions: RIC using Flu/high dose AraC /Cy +/- TBI was well tolerated with acceptable low toxicities and was sufficient to allow donor cell-engraftment post allo-SCT for elderly or frail patients with hematologic malignancies. Longer follow up and another prospective study enrolling more patients are required to evaluate the eventual survival benefit by reducing relapse. DisclosuresNo relevant conflicts of interest to declare.

A risk-stratified therapy for infants with acute lymphoblastic leukemia: a report from the JPLSG MLL-10 trial

AbstractThe prognosis for infants with acute lymphoblastic leukemia (ALL), particularly those with KMT2A gene rearrangement (KMT2A-r), is dismal. Continuous efforts have been made in Japan to investigate the role of hematopoietic stem cell transplantation (HSCT) for infants with KMT2A-r ALL, but improvement in outcome was modest. In the Japanese Pediatric Leukemia/Lymphoma Study Group MLL-10 trial, infants with ALL were stratified into 3 risk groups (low risk [LR], intermediate risk [IR], and high risk [HR]) according to KMT2A status, age, and presence of central nervous system leukemia. Children's Oncology Group AALL0631 modified chemotherapy with the addition of high-dose cytarabine in early intensification was introduced to KMT2A-r patients, and the option of HSCT was restricted to HR patients only. The role of minimal residual disease (MRD) was also evaluated. Ninety eligible infants were stratified into LR (n = 15), IR (n = 19), or HR (n = 56) risk groups. The 3-year event-free survival (EFS) rate for patients with KMT2A-r ALL (IR + HR) was 66.2% (standard error [SE], 5.6%), and for those with germline KMT2A (KMT2A-g) ALL (LR), the 3-year EFS rate was 93.3% (SE, 6.4%). The 3-year EFS rate was 94.4% (SE, 5.4%) for IR patients and 56.6% (SE, 6.8%) for HR patients. In multivariable analysis, female sex and MRD ≥0.01% at the end of early consolidation were significant factors for poor prognosis. Risk stratification and introduction of intensive chemotherapy in this study were effective and were able to eliminate HSCT for a subset of infants with KMT2A-r ALL. Early clearance of MRD seems to have translated into favorable outcomes and should be incorporated into risk stratifications in future trials. This trial was registered at the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) as #UMIN000004801.

Bortezomib prevents cytarabine resistance in MCL, which is characterized by down-regulation of dCK and up-regulation of SPIB resulting in high NF-\u03baB activity

BackgroundThe addition of high-dose cytarabine to the treatment of mantle cell lymphoma (MCL) has significantly prolonged survival of patients, but relapses are common and are normally associated with increased resistance. To elucidate the mechanisms responsible for cytarabine resistance, and to create a tool for drug discovery investigations, we established a unique and molecularly reproducible cytarabine resistant model from the Z138 MCL cell line.MethodsEffects of different substances on cytarabine-sensitive and resistant cells were evaluated by assessment of cell proliferation using [methyl-14C]-thymidine incorporation and molecular changes were investigated by protein and gene expression analyses.ResultsGene expression profiling revealed that major transcriptional changes occur during the initial phase of adaptation to cellular growth in cytarabine containing media, and only few key genes, including SPIB, are deregulated upon the later development of resistance. Resistance was shown to be mediated by down-regulation of the deoxycytidine kinase (dCK) protein, responsible for activation of nucleoside analogue prodrugs. This key event, emphasized by cross-resistance to other nucleoside analogues, did not only effect resistance but also levels of SPIB and NF-κB, as assessed through forced overexpression in resistant cells. Thus, for the first time we show that regulation of drug resistance through prevention of conversion of pro-drug into active drug are closely linked to increased proliferation and resistance to apoptosis in MCL. Using drug libraries, we identify several substances with growth reducing effect on cytarabine resistant cells. We further hypothesized that co-treatment with bortezomib could prevent resistance development. This was confirmed and show that the dCK levels are retained upon co-treatment, indicating a clinical use for bortezomib treatment in combination with cytarabine to avoid development of resistance. The possibility to predict cytarabine resistance in diagnostic samples was assessed, but analysis show that a majority of patients have moderate to high expression of dCK at diagnosis, corresponding well to the initial clinical response to cytarabine treatment.ConclusionWe show that cytarabine resistance potentially can be avoided or at least delayed through co-treatment with bortezomib, and that down-regulation of dCK and up-regulation of SPIB and NF-κB are the main molecular events driving cytarabine resistance development.

Efficacy of High-Dose Cytarabine Added to Cyclophosphamide/Total-Body Irradiation in the Conditioning Regimen of Allogeneic Hematopoietic Cell Transplantation for Myeloid Malignancy

INTRODUCTIONAllogeneic hematopoietic cell transplantation (HCT) is an effective therapeutic option for adults with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) after the conventional cyclophosphamide and total-body irradiation (CY/TBI) regimen, but post-transplant relapse is still of high importance. High-dose cytarabine (HDCA) can be added to CY/TBI for an intensified regimen; however, its additional effects have not yet been completely elucidated.METHODSWe conducted a cohort study to compare the prognosis of HDCA/CY/TBI and CY/TBI in HCT for AML/MDS, using a Japanese transplant registry database. Inclusion criteria are adult patients (aged 16 years or older) who underwent a single-unit cord blood transplantation (CBT) or bone marrow or peripheral blood stem cell transplantation (BMT/PBSCT) as a first HCT after CY/TBI (CY, 60 mg/kg for 2 days; TBI, 10-12 Gy divided into 4-6 fractions) or CY/TBI plus HDCA (HDCA/CY/TBI) between January 2000 and December 2012. HDCA was defined as cytarabine administration of 2 to 3 g/m2 twice a day for 2 to 3 days (total dose, 6-12 g/m2) before HCT.Overall survival (OS) was calculated with the Kaplan-Meier method and compared using log-rank tests for each covariant related to pre-transplant patient characteristics. Factors with significance or borderline significance (p < 0.1) in the univariate analysis were subjected to a multivariate analysis using the Cox proportional hazards model. The Fine-Gray proportional hazards model was used in multivariate analyses for tumor-related mortality and non-relapse mortality (NRM).Our protocol complied with the Declaration of Helsinki, and it was approved by the Registry Data Management Committee and by the Ethics Committee of Kyoto University, where the study was performed. Written informed consent was obtained from each patient at each institution.RESULTSWe analyzed data on 3,031 patients in total, composed of the HDCA/CY/TBI group (n = 1,052) and the CY/TBI group (n = 1,979) after CBT (n = 929) and BMT/PBSCT (n= 2,102). The median age was 38 years, and 86.1% of the patients had AML; high-risk disease was observed in 55.5% of the patients. In BMT/PBSCT, unrelated donors comprised 54.6%, and 63.9% of donors were HLA-matched. The median follow-up period after HCT was approximately 3.2 years. In CBT, OS was significantly superior in the HDCA/CY/TBI group compared to the CY/TBI group (adjusted hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.45-0.69; p < 0.01), while in BMT/PBSCT improvement of OS was not observed in the HDCA/CY/TBI group (HR, 1.14; p = 0.13) (refer to Figure). Tumor-related mortality was lower in HDCA/CY/TBI than CY/TBI after CBT (HR, 0.50; p < 0.01); in BMT/PBSCT, however, post-transplant relapse and tumor-related mortality were not suppressed by the addition of HDCA (HR, 0.89 and 0.90; p = 0.58 and 0.34, respectively). The incidence of grade II to IV acute graft-versus-host disease (GVHD) and chronic GVHD was significantly higher in the HDCA/CY/TBI group than the CY/TBI group after CBT (HR, 1.33 and 2.30; p = 0.02 and < 0.01, respectively), whereas there were no differences in BMT/PBSCT (HR, 0.95 and 1.04; p = 0.54 and 0.64, respectively). Incidence of infectious episodes (bacterial, viral, and fungal) showed no significant differences between regimens in both donor sources. Hemorrhagic cystitis and thrombotic microangiopathy increased in HDCA/CY/TBI compared to CY/TBI after BMT/PBSCT (HR, 1.47 and 1.60; p = 0.06 and 0.04, respectively), leading to significantly higher NRM in this group (HR, 1.48, p < 0.01). On the other hand, NRM was not increased by the addition of HDCA after CBT (HR, 0.94; p = 0.73).CONCLUSIONThis study is the first to show the differences between HDCA/CY/TBI and CY/TBI after HCT for AML/MDS using a large cohort. Superiority of HDCA/CY/TBI to CY/TBI in CBT was clearly indicated, while these merits were not applied to BMT/PBSCT. The higher incidence of GVHD and stronger graft-versus-leukemia (GVL) effects may be involved in these differences between donor sources (BMT/PBSCT compared to CBT). A large-scale prospective study is warranted to validate these results and to establish the suitable conditioning regimens including HDCA administration. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Clinical significance of high-dose cytarabine added to cyclophosphamide/total-body irradiation in bone marrow or peripheral blood stem cell transplantation for myeloid malignancy.

BackgroundAddition of high-dose cytarabine (HDCA) to the conventional cyclophosphamide/total-body irradiation (CY/TBI) regimen significantly improved prognosis after cord blood transplantation (CBT) for adult acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). The efficacy of HDCA in bone marrow or peripheral blood stem cell transplantation (BMT/PBSCT), however, has not yet been elucidated.FindingsWe conducted a cohort study to compare the prognosis of HDCA/CY/TBI (N = 435) and CY/TBI (N = 1667) in BMT/PBSCT for AML/MDS using a Japanese transplant registry database. The median age was 38 years, and 86.0 % of the patients had AML. Unrelated donors comprised 54.6 %, and 63.9 % of donors were human leukocyte antigen (HLA)-matched. Overall survival (OS) was not improved in the HDCA/CY/TBI group (adjusted hazard ratio (HR), 1.14; p = 0.13). Neutrophil engraftment was inferior (HR, 0.80; p < 0.01), and the incidence of hemorrhagic cystitis and thrombotic microangiopathy increased in HDCA/CY/TBI (HR, 1.47 and 1.60; p = 0.06 and 0.04, respectively), leading to significantly higher non-relapse mortality (NRM; HR, 1.48; p < 0.01). Post-transplant relapse and tumor-related mortality were not suppressed by the addition of HDCA.ConclusionsThis study indicated the inefficacy of HDCA/CY/TBI in BMT/PBSCT for AML/MDS. Our results should be validated in large-scale prospective studies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-015-0201-x) contains supplementary material, which is available to authorized users.

Efficiency of high-dose cytarabine added to CY/TBI in cord blood transplantation for myeloid malignancy

AbstractCord blood transplantation (CBT) is an effective therapeutic option for adults with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) after the conventional cyclophosphamide and total body irradiation (CY/TBI) regimen, but posttransplant relapse is still of high importance. High-dose cytarabine (HDCA) can be added to CY/TBI for an intensified regimen; however, its additional effects have not yet been completely elucidated. Therefore, we conducted a cohort study to compare the prognosis of HDCA/CY/TBI (n = 617) and CY/TBI (n = 312) in CBT for AML/MDS, using a Japanese transplant registry database. The median age was 40 years, and 86.2% of the patients had AML; high-risk disease was observed in 56.2% of the patients. The median follow-up period after CBT was approximately 3.5 years. Overall survival was significantly superior in the HDCA/CY/TBI group (adjusted hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.45-0.69; P < .01), and tumor-related mortality was lower (HR, 0.50; P < .01). The incidence of grade II to IV acute graft-vs-host disease (aGVHD) and chronic GVHD was significantly higher in the HDCA/CY/TBI group (HR, 1.33 and 2.30, respectively), but not grade III to IV aGVHD. Incidence of infectious episodes showed no significant difference. Nonrelapse mortality was not increased by the addition of HDCA. Higher-dose CA (12 rather than 8 g/m2) was more effective, particularly in patients at high-risk for disease. This study is the first to show the superiority of HDCA/CY/TBI to CY/TBI in CBT for AML/MDS. A large-scale prospective study is warranted to establish new conditioning regimens including HDCA administration.

CHOP-R and High-Dose Methotrexate In The Primary CNS Lymphoma Revisited. 10-Year Experience and 92 Patients From a Single Institution

BackgroundCurrently recommended treatment for the primary CNS lymphoma (PCNSL) involves high-dose methotrexate (HM) preferably in combination with high-dose cytarabine (HA). However, nearly half of the patients present with locally advanced disease and poor performance status (PS) prohibiting the use of this biologically challenging therapy. On the other hand, CHOP±Rituximab with or without HM is considered suboptimal due to generaly negative, if any, published results, and a strong belief in the existence of blood-brain barrier preventing bioavailability of doxorubicin to CNS tissue. In effect, patients with DLBCL of the CNS which is the most common type of PCNSL miss the benefits of the optimal treatment for DLBCL. We evaluated the outcome of patients treated at our institution with variety of regimens evolving over time including CHOP/CHOP-like + HM, HM ± HA, and CHOP-R (rituximab) + HM. Varying proportion of patients received whole brain radiotherapy (WBRT) as well. Patients and MethodsBetween 2000 and 2011, 92 patients diagnosed with PCNSL were treated. Median age (range) was 59 (19 – 79) years, female: 55%, ECOG performance score (PS) 0-1: 30%, 2: 21%, 3-4: 49%. Most common symptoms at diagnosis were: memory loss (56%), focal symptoms (54%), confusion (36%), depression (20%), seizures (20%), agitation (13%). Diagnosis was established by stereotactic biopsy (50%), craniotomy (48%), and cerebro-spinal fluid flow cytometry in two cases. Total resection of tumor was done in 22%, tumor gross resection (debulking) in 27%, and biopsy only in 51% of patients. Cerebral / spinal parenchyma was involved in 52%, deep brain sites - in 48%. Mass effect and brain edema were present in 70% and 81%, respectively. Multiple brain lesions were present in 39% of patients. Patients were treated on 3 consecutive protocols: 2000-2006 (n=27): CHOP/CHOP-like+HM [median (range) HM total dose: 6.3 g (1.9-21)] with WBRT in 67%, 2006-2010 (n=13): HM±HA including „Bonn“ protocol [median (range) HM total dose 16.8 g (3-25.3) and median (range) HA total dose: 12 g(8-41)] with WBRT in 23%, 2009-2011 (n=19): CHOP-R + HM [median (range) HM total dose: 20 g (3-42)] with WBRT in 26% of patients. 33 patients (36%) received variety of treatments with a palliative intent. ResultsIn all 92 patients, 1-, 2-, and 4-year overall survival (OS) was 50%, 41%, and 24% respectively. In patients treated with a radical approach including intended HM dose of 3 g/m2 per cycle (n=59): 1-, 2-, and 4-year OS was 63%, 59%, and 35%, respectively. In this group, event-free survival (EFS) was 58%, 49%, and 32%, respectively. In patients with PS 0-1, 2, and 3-4, 3-year OS was 67%, 26%, and 8%, respectively. 3-year EFS in these patients was 56%, 27%, and 8%, respectivly (p=0.00). Two-year OS in patients with total tumor resection, debulking, or biopsy only, was 78%, 62%, and 14%, respectively (p=0.00). Deep structure involvement vs cerebral parenchyma was not predictive of OS or EFS (p=0.33). In patients treated with CHOP/CHOP-like+HM with a median follow-up (FU) of 122 months, 1-, 2-, and 4-year OS was 59%, 55%, and 37%, and corresponding EFS was 52%, 48%, and 29%, respectively. 4 patients (15%) died of treatment-related toxicity (TRT). In patients treated with HM±HA, with a median FU of 39 months, 1-, 2-, and 4-year OS was 61%, 54%, and 18%, and corresponding EFS was 53%, 38%, and 20%, respectively. 2 patients (15%) died of TRT. In patients treated with CHOP-R+HM, with a median FU of 30 months, 1-, 2-, and 4-year OS was 68%, 68%, and 49%, and corresponding EFS was 68%, 57%, and 57%, respectively. 12 of 19 patients in this group are alive with no evidence of disease.7 patients died, 3 from disease progression, and 3 (16%) from TRT. ConclusionOutcome of PCNSL patients was highly dependent on the baseline performance score with only few patients with PS 3-4 surviving 3 years. Extent of primary surgery was also predictive of survival. In our series of 92 patients treated on consecutive clincal protocols over a period of 10 years, no benefit to methotreaxte dose escalation or addition of high-dose cytarabine could be demonstrated. The most favorable outcome was achieved with CHOP-R combined with HM at a dose of 3 g/m² per cycle.▪▪ Disclosures:No relevant conflicts of interest to declare.

Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Diffuse large B-cell non-Hodgkin's lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Diffuse large B-cell non-Hodgkin's lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Trials and tribulations in primary CNS lymphoma

A minority of patients with primary central nervous system lymphoma (PCNSL) achieve a complete response to therapy and most patients have a poor prognosis. A recent randomized phase II trial demonstrated that the addition of high-dose cytarabine to high-dose methotrexate increases the complete response rate and improves patient outcome.

Prognostic Factors in Elderly Patients with AML and the Implications for Treatment

The outcome of older patients with acute myeloid leukemia (AML) has not improved in the last three decades. These patients are more likely to have comorbid illness, poor performance status, and impaired organ function. These clinical features limit their ability to tolerate intensive cytotoxic chemotherapy and result in greater early mortality. The AML seen in elderly patients is also more likely to have evolved from a prior hematologic disorder, and the leukemic blasts are more likely to have poor-risk structural and numeric cytogenetic abnormalities and expression of multidrug resistance protein (MDR1). These blast features have been associated with greater resistance to therapy. Attempts to improve outcome have generally been unsuccessful. Priming of leukemic blasts with granulocyte colony-stimulating factors during cytarabine therapy, granulocyte colony-stimulating factor support to speed neutrophil recovery following induction therapy, inhibition of the MDR1 p-glycoprotein efflux pump, the use of alternative anthracyclines, and the addition of high-dose cytarabine have all been investigated in the last three decades. Further manipulation of standard cytotoxic chemotherapy alone is unlikely to improve the outcome for the majority of patients with AML. Incorporation of molecularly targeted therapies may prove to be less toxic and/or more efficacious. However, patient selection for clinical trials will continue to confound the interpretation of treatment outcomes on clinical trials of older patients with AML.

Significance of additional high-dose cytarabine in combination with cyclophosphamide plus total body irradiation regimen for allogeneic stem cell transplantation

The combination of cyclophosphamide (CY) and total body irradiation (TBI) has been used as a standard conditioning regimen for allogeneic transplantation. Several studies showed an advantage of adding high-dose cytarabine (HDCA) to this regimen. To clarify the significance of additional HDCA, we conducted a retrospective multicenter study and compared the clinical results of these two regimens. From June 1985 to March 2003, 219 patients with hematological malignancies underwent allogeneic transplantation after conditioning with CY+TBI 12Gy (n=73) or CA+CY+TBI 12Gy (n=146). Engraftment, overall survival, transplant-related mortality (TRM), relapse rate and incidence of graft-versus-host disease (GVHD) were compared according to risks and donors. Addition of HDCA had no impact on the relapse rate in all subgroups, and it was associated with lower TRM among standard-risk patients after related transplantation, and with higher TRM and worse survival among standard-risk patients after unrelated transplantation. The incidence of acute GVHD was not significantly different between the two regimens, and HDCA resulted in a higher incidence of chronic GVHD among standard-risk patients after related transplantation. In summary, addition of HDCA is not beneficial for high-risk patients, and is not recommended for standard-risk patients receiving unrelated transplantation.