ABSTRACT
AML is a genetically heterogeneous disease and understanding how different co-occurring mutations cooperate to drive leukemogenesis will be crucial for improving diagnostic and therapeutic options for patients. MIR142 mutations have been recurrently detected in IDH-mutated AML samples. Here, we have used a mouse model to investigate the interaction between these two mutations and demonstrate a striking synergy between Mir142 loss-of-function and IDH2R140Q, with only recipients of double mutant cells succumbing to leukemia. Transcriptomic analysis of the non-leukemic single and leukemic double mutant progenitors, isolated from these mice, suggested a novel mechanism of cooperation whereby Mir142 loss-of-function counteracts aberrant silencing of Hoxa cluster genes by IDH2R140Q. Our analysis suggests that IDH2R140Q is an incoherent oncogene, with both positive and negative impacts on leukemogenesis, which requires the action of cooperating mutations to alleviate repression of Hoxa genes in order to advance to leukemia. This model, therefore, provides a compelling rationale for understanding how different mutations cooperate to drive leukemogenesis and the context-dependent effects of oncogenic mutations.
Subject(s)
Gene Expression Regulation, Leukemic/physiology , Homeodomain Proteins/metabolism , Isocitrate Dehydrogenase/metabolism , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/pathology , MicroRNAs/metabolism , Animals , Carcinogenesis/genetics , Carcinogenesis/pathology , Cell Line, Tumor , Female , Gene Expression Regulation, Leukemic/genetics , Genotype , Homeodomain Proteins/genetics , Humans , Isocitrate Dehydrogenase/genetics , Leukemia, Myeloid, Acute/genetics , Male , Mice , MicroRNAs/genetics , Mutation/geneticsABSTRACT
BACKGROUND: Outcomes for patients with high-risk diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP chemotherapy are suboptimal but, to date, no alternative regimen has been shown to improve survival rates. This phase 2 trial aimed to assess the efficacy of a Burkitt-like approach for high-risk DLBCL using the dose-intense R-CODOX-M/R-IVAC regimen. PATIENTS AND METHODS: Eligible patients were aged 18-65 years with stage II-IV untreated DLBCL and an International Prognostic Index (IPI) score of 3-5. Patients received alternating cycles of CODOX-M (cyclophosphamide, vincristine, doxorubicin and high-dose methotrexate) alternating with IVAC chemotherapy (ifosfamide, etoposide and high-dose cytarabine) plus eight doses of rituximab. Response was assessed by computed tomography after completing all four cycles of chemotherapy. The primary end point was 2-year progression-free survival (PFS). RESULTS: A total of 111 eligible patients were registered; median age was 50 years, IPI score was 3 (60.4%) or 4/5 (39.6%), 54% had a performance status ≥2 and 9% had central nervous system involvement. A total of 85 patients (76.6%) completed all four cycles of chemotherapy. There were five treatment-related deaths (4.3%), all in patients with performance status of 3 and aged >50 years. Two-year PFS for the whole cohort was 67.9% [90% confidence interval (CI) 59.9-74.6] and 2-year overall survival was 76.0% (90% CI 68.5-82.0). The ability to tolerate and complete treatment was lower in patients with performance status ≥2 who were aged >50 years, where 2-year PFS was 43.5% (90% CI 27.9-58.0). CONCLUSIONS: This trial demonstrates that R-CODOX-M/R-IVAC is a feasible and effective regimen for the treatment of younger and/or fit patients with high-risk DLBCL. These encouraging survival rates demonstrate that this regimen warrants further investigation against standard of care. TRIAL REGISTRATION: ClinicalTrials.gov (NCT00974792) and EudraCT (2005-003479-19).
Subject(s)
Burkitt Lymphoma , Lymphoma, Large B-Cell, Diffuse , Adolescent , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Burkitt Lymphoma/drug therapy , Cyclophosphamide/therapeutic use , Disease-Free Survival , Doxorubicin/therapeutic use , Humans , Ifosfamide/therapeutic use , Lymphoma, Large B-Cell, Diffuse/drug therapy , Middle Aged , Prednisone/therapeutic use , Rituximab/therapeutic use , United Kingdom , Vincristine/therapeutic use , Young AdultABSTRACT
BACKGROUND: Central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is associated with a dismal prognosis. Here, we report an analysis of CNS relapse for patients treated within the UK NCRI phase III R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) 14 versus 21 randomised trial. PATIENTS AND METHODS: The R-CHOP 14 versus 21 trial compared R-CHOP administered two- versus three weekly in previously untreated patients aged ≥18 years with bulky stage I-IV DLBCL (n = 1080). Details of CNS prophylaxis were retrospectively collected from participating sites. The incidence and risk factors for CNS relapse including application of the CNS-IPI were evaluated. RESULTS: 177/984 patients (18.0%) received prophylaxis (intrathecal (IT) methotrexate (MTX) n = 163, intravenous (IV) MTX n = 2, prophylaxis type unknown n = 11 and IT MTX and cytarabine n = 1). At a median follow-up of 6.5 years, 21 cases of CNS relapse (isolated n = 11, with systemic relapse n = 10) were observed, with a cumulative incidence of 1.9%. For patients selected to receive prophylaxis, the incidence was 2.8%. Relapses predominantly involved the brain parenchyma (81.0%) and isolated leptomeningeal involvement was rare (14.3%). Univariable analysis demonstrated the following risk factors for CNS relapse: performance status 2, elevated lactate dehydrogenase, IPI, >1 extranodal site of disease and presence of a 'high-risk' extranodal site. Due to the low number of events no factor remained significant in multivariate analysis. Application of the CNS-IPI revealed a high-risk group (4-6 risk factors) with a 2- and 5-year incidence of CNS relapse of 5.2% and 6.8%, respectively. CONCLUSION: Despite very limited use of IV MTX as prophylaxis, the incidence of CNS relapse following R-CHOP was very low (1.9%) confirming the reduced incidence in the rituximab era. The CNS-IPI identified patients at highest risk for CNS recurrence. CLINICALTRIALS.GOV: ISCRTN number 16017947 (R-CHOP14v21); EudraCT number 2004-002197-34.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Central Nervous System Neoplasms/pathology , Lymphoma, Large B-Cell, Diffuse/drug therapy , Antibodies, Monoclonal, Murine-Derived/administration & dosage , Cyclophosphamide/administration & dosage , Doxorubicin/administration & dosage , Drug Administration Schedule , Female , Humans , Lymphoma, Large B-Cell, Diffuse/pathology , Male , Middle Aged , Neoplasm Recurrence, Local/pathology , Prednisone/administration & dosage , Prospective Studies , Rituximab/administration & dosage , Vincristine/administration & dosageABSTRACT
BACKGROUND: There is an on-going debate whether 2- or 3-weekly administration of R-CHOP is the preferred first-line treatment for elderly patients with diffuse large B-cell lymphoma (DLBCL). The UK NCRI R-CHOP14v21 randomized phase 3 trial did not demonstrate a difference in outcomes between R-CHOP-14 and R-CHOP-21 in newly diagnosed DLBCL patients aged 19-88 years, but data on elderly patients have not been reported in detail so far. Here, we provide a subgroup analysis of patients ≥60 years treated on the R-CHOP14v21 trial with extended follow-up. PATIENTS AND METHODS: Six hundred and four R-CHOP14v21 patients ≥60 years were included in this subgroup analysis, with a median follow-up of 77.7 months. To assess the impact of MYC rearrangements (MYC-R) and double-hit-lymphoma (DHL) on outcome in elderly patients, we performed a joint analysis of cases with available molecular data from the R-CHOP14v21 (N = 217) and RICOVER-60 (N = 204) trials. RESULTS: Elderly DLBCL patients received high dose intensities with median total doses of ≥98% for all agents. Toxicities were similar in both arms with the exception of more grade ≥3 neutropenia (P < 0.0001) and fewer grade ≥3 thrombocytopenia (P = 0.05) in R-CHOP-21 versus R-CHOP-14. The elderly patient population had a favorable 5-year overall survival (OS) of 69% (95% CI: 65-73). We did not identify any subgroup of patients that showed differential response to either regimen. In multivariable analysis including individual factors of the IPI, gender, bulk, B2M and albumin levels, only age and B2M were of independent prognostic significance for OS. Molecular analyses demonstrated a significant impact of MYC-R (HR = 1.96; 95% CI: 1.22-3.16; P = 0.01) and DHL (HR = 2.21; 95% CI: 1.18-4.11; P = 0.01) on OS in the combined trial cohorts, independent of other prognostic factors. CONCLUSIONS: Our data support equivalence of both R-CHOP application forms in elderly DLBCL patients. Elderly MYC-R and DHL patients have inferior prognosis and should be considered for alternative treatment approaches. TRIAL NUMBERS: ISCRTN 16017947 (R-CHOP14v21); NCT00052936 (RICOVER-60).
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Biomarkers, Tumor/genetics , Lymphoma, Large B-Cell, Diffuse/drug therapy , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-6/genetics , Proto-Oncogene Proteins c-myc/genetics , Age Factors , Aged , Aged, 80 and over , Antibodies, Monoclonal, Murine-Derived/administration & dosage , Antibodies, Monoclonal, Murine-Derived/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Doxorubicin/administration & dosage , Doxorubicin/adverse effects , Drug Administration Schedule , Female , Gene Rearrangement , Humans , Kaplan-Meier Estimate , Lymphoma, Large B-Cell, Diffuse/genetics , Lymphoma, Large B-Cell, Diffuse/mortality , Lymphoma, Large B-Cell, Diffuse/pathology , Male , Middle Aged , Multivariate Analysis , Patient Selection , Precision Medicine , Prednisone/administration & dosage , Prednisone/adverse effects , Risk Factors , Rituximab , Time Factors , Treatment Outcome , United Kingdom , Vincristine/administration & dosage , Vincristine/adverse effectsABSTRACT
In the CORAL study, 255 chemosensitive relapses with diffuse large B-cell lymphoma (DLBCL) were consolidated with autologous stem cell transplantation (ASCT), and 75 of them relapsed thereafter. The median time between ASCT and progression was 7.1 months. The median age was 56.1 years; tertiary International Prognosis Index (tIPI) observed at relapse was 0-2 in 71.6% of the patients and >2 in 28.4%. The overall response rate to third-line chemotherapy was 44%. The median overall survival (OS) was 10.0 months (median follow-up: 32.8 months). Thirteen patients received an allogeneic SCT, and three a second ASCT. The median OS was shorter among patients who relapsed <6 months (5.7 months) compared with those relapsing ⩾12 months after ASCT (12.6 months, P=0.0221). The median OS in patients achieving CR, PR or no response after the third-line regimen was 37.7 (P<0.0001), 10.0 (P=0.03) and 6.3 months, respectively. The median OS varied according to tIPI: 0-2: 12.6 months and >2: 5.3 months (P=0.0007). In multivariate analysis, tIPI >2, achievement of response and remission lasting <6 months predicted the OS. This report identifies the prognostic factors for DLBCL relapsing after ASCT and thus helps to select patients for experimental therapy.
Subject(s)
Lymphoma, Large B-Cell, Diffuse/mortality , Lymphoma, Large B-Cell, Diffuse/therapy , Stem Cell Transplantation , Adolescent , Adult , Aged , Autografts , Disease-Free Survival , Female , Humans , Male , Middle Aged , Recurrence , Survival RateSubject(s)
Lymphoma/therapy , Transplantation Conditioning/methods , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carmustine/therapeutic use , Cytarabine/therapeutic use , Etoposide/therapeutic use , Female , Hematopoietic Stem Cell Transplantation/methods , Hematopoietic Stem Cell Transplantation/mortality , Humans , Lomustine/therapeutic use , Lymphoma/mortality , Male , Melphalan/therapeutic use , Middle Aged , Retrospective Studies , Salvage Therapy/methods , Survival Analysis , Transplantation Conditioning/mortality , Transplantation Conditioning/standards , Transplantation, AutologousABSTRACT
PTEN gene inactivation by mutation or deletion is common in pediatric T-cell acute lymphoblastic leukemia (T-ALL), but the impact on outcome is unclear, particularly in patients with NOTCH1/FBXW7 mutations. We screened samples from 145 patients treated on the MRC UKALL2003 trial for PTEN mutations using heteroduplex analysis and gene deletions using single nucleotide polymorphism arrays, and related genotype to response to therapy and long-term outcome. PTEN loss-of-function mutations/gene deletions were detected in 22% (PTEN(ABN)). Quantification of mutant level indicated that 67% of mutated cases harbored more than one mutant, with up to four mutants detected, consistent with the presence of multiple leukemic sub-clones. Overall, 41% of PTEN(ABN) cases were considered to have biallelic abnormalities (mutation and/or deletion) with complete loss of PTEN in a proportion of cells. In addition, 9% of cases had N- or K-RAS mutations. Neither PTEN nor RAS genotype significantly impacted on response to therapy or long-term outcome, irrespective of mutant level, and there was no evidence that they changed the highly favorable outcome of patients with double NOTCH1/FBXW7 mutations. These results indicate that, for pediatric patients treated according to current protocols, routine screening for PTEN or RAS abnormalities at diagnosis is not warranted to further refine risk stratification.
Subject(s)
Mutation , PTEN Phosphohydrolase/genetics , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Adolescent , Adult , Cell Cycle Proteins/genetics , Child , Child, Preschool , F-Box Proteins/genetics , F-Box-WD Repeat-Containing Protein 7 , Female , Gene Dosage , Genes, ras , Humans , Infant , Male , Polymorphism, Single Nucleotide , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/therapy , Receptor, Notch1/genetics , Ubiquitin-Protein Ligases/geneticsABSTRACT
Salvage chemotherapy followed by autologous stem cell transplantation (ASCT) is the standard second-line treatment for relapsed and refractory diffuse large B-cell lymphoma (DLBCL). However, the strategy is less clear in patients who require third-line treatment. Updated outcomes of 203 patients who could not proceed to scheduled ASCT in the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) are herein reviewed. In the intent-to-treat analysis, overall response rate to third-line chemotherapy was 39%, with 27% CR or CR unconfirmed, and 12% PR. Among the 203 patients, 64 (31.5%) were eventually transplanted (ASCT 56, allogeneic SCT 8). Median overall survival (OS) of the entire population was 4.4 months. OS was significantly improved in patients with lower tertiary International Prognostic Index (IPI), patients responding to third-line treatment and patients transplanted with a 1-year OS of 41.6% compared with 16.3% for the not transplanted (P<0.0001). In multivariate analysis, IPI at relapse (hazard ratio (HR) 2.409) and transplantation (HR 0.375) independently predicted OS. Third-line salvage chemotherapy can lead to response followed by transplantation and long-term survival in DLBCL patients. However, improvement of salvage efficacy is an urgent need with new drugs.
Subject(s)
Lymphoma, Large B-Cell, Diffuse/mortality , Lymphoma, Large B-Cell, Diffuse/therapy , Salvage Therapy/methods , Stem Cell Transplantation , Adolescent , Adult , Aged , Autografts , Disease-Free Survival , Female , Humans , Lymphoma, Large B-Cell, Diffuse/pathology , Male , Middle Aged , Recurrence , Survival RateSubject(s)
DNA Mutational Analysis/methods , DNA-Binding Proteins/genetics , DNA/blood , DNA/genetics , Leukemia/genetics , Mutation/genetics , Proto-Oncogene Proteins/genetics , Aged , Aged, 80 and over , Amino Acid Sequence , Base Sequence , Cohort Studies , Dioxygenases , Female , Follow-Up Studies , Humans , Male , Molecular Sequence Data , PrognosisABSTRACT
Several different mutations collaborate with the fusion proteins in core-binding factor acute myeloid leukemia (CBF-AML) to induce leukemogenesis, but their prognostic significance remains unclear. We screened 354 predominantly younger (<60 years) adults with t(8;21) (n=199) or inv(16) (n=155) entered into UK MRC trials for KIT, FLT3 tyrosine kinase domain (FLT3(TKD)), N-RAS, K-RAS and c-CBL mutations and FLT3 internal tandem duplications (FLT3(ITD)) and assessed the impact of relative mutant level on outcome. Overall, 28% had KIT, 6% FLT3(ITD), 10% FLT3(TKD), 27% RAS and 6% CBL mutations. Mutant levels for all genes/loci were highly variable. KIT mutations were associated with a higher cumulative incidence of relapse but in multivariate analysis this was only significant for cases with a higher mutant level of 25% or greater (95% confidence interval (CI)=1.01-1.52, P=0.04). Similarly, only FLT3(ITD-HIGH) was a significant adverse factor for overall survival (OS; CI=1.27-5.39, P=0.004). Conversely, FLT3(TKD-HIGH) and CBL(HIGH) were both favorable factors for OS (CI= 0.31-0.89, P=0.01 and CI=0.05-0.85, P=0.02, respectively). KIT mutations were frequently lost at relapse, which is relevant to minimal residual disease detection and the clinical use of KIT inhibitors. These results indicate that relative mutant level should be taken into account when evaluating the impact of mutations in CBF-AML.
Subject(s)
Core Binding Factors/genetics , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/genetics , Mutation , Proto-Oncogene Proteins c-cbl/genetics , Proto-Oncogene Proteins c-kit/genetics , fms-Like Tyrosine Kinase 3/genetics , Adolescent , Adult , Aged , Chromosome Aberrations , Cohort Studies , Exons , Female , Genotype , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/mortality , Male , Middle Aged , Prognosis , Recurrence , Remission Induction , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: Women treated with supradiaphragmatic radiotherapy (sRT) for Hodgkin lymphoma (HL) at young ages have a substantially increased breast cancer risk. Little is known about how menarcheal and reproductive factors modify this risk. METHODS: We examined the effects of menarcheal age, pregnancy, and menopausal age on breast cancer risk following sRT in case-control data from questionnaires completed by 2497 women from a cohort of 5002 treated with sRT for HL at ages <36 during 1956-2003. RESULTS: Two-hundred and sixty women had been diagnosed with breast cancer. Breast cancer risk was significantly increased in patients treated within 6 months of menarche (odds ratio (OR) 5.52, 95% confidence interval (CI) (1.97-15.46)), and increased significantly with proximity of sRT to menarche (Ptrend<0.001). It was greatest when sRT was close to a late menarche, but based on small numbers and needing reexamination elsewhere. Risk was not significantly affected by full-term pregnancies before or after treatment. Risk was significantly reduced by early menopause (OR 0.55, 95% CI (0.35-0.85)), and increased with number of premenopausal years after treatment (Ptrend=0.003). CONCLUSION: In summary, this paper shows for the first time that sRT close to menarche substantially increases breast cancer risk. Careful consideration should be given to follow-up of these women, and to measures that might reduce their future breast cancer risk.
Subject(s)
Breast Neoplasms/epidemiology , Hodgkin Disease/radiotherapy , Neoplasms, Radiation-Induced/epidemiology , Adult , Age Factors , Breast Neoplasms/etiology , Case-Control Studies , Cohort Studies , England/epidemiology , Female , Humans , Menarche , Middle Aged , Neoplasms, Radiation-Induced/etiology , Pregnancy , Reproductive History , Wales/epidemiologySubject(s)
Hodgkin Disease/surgery , Positron-Emission Tomography , Stem Cell Transplantation , Adult , Female , Fluorodeoxyglucose F18 , Humans , Male , Middle Aged , Recurrence , Treatment Outcome , Young AdultABSTRACT
Activating mutations in the NOTCH1 pathway are frequent in pediatric T-cell acute lymphoblastic leukemia (T-ALL) but their role in refining risk stratification is unclear. We screened 162 pediatric T-ALL patients treated on the MRC UKALL2003 trial for NOTCH1/FBXW7 gene mutations and related genotype to response to therapy and long-term outcome. Overall, 35% were wild-type (WT) for both genes (NOTCH1(WT)FBXW7(WT)), 38% single NOTCH1 mutant (NOTCH1(Single)FBXW7(WT)), 3% just FBXW7 mutant (NOTCH1(WT)FBXW7(MUT)) and 24% either double NOTCH1 mutant (NOTCH1(Double)FBXW7(WT)) or mutant in both genes (NOTCH1(MUT)FBXW7(MUT)), hereafter called as NOTCH1±FBXW7(Double). There was no difference between groups in early response to therapy, but NOTCH1±FBXW7(Double) patients were more likely to be associated with negative minimal residual disease (MRD) post-induction than NOTCH1(WT)FBXW7(WT) patients (71% versus 40%, P=0.004). Outcome improved according to the number of mutations, overall survival at 5 years 82%, 88% and 100% for NOTCH1(WT)FBXW7(WT), NOTCH1(Single)FBXW7(WT) and NOTCH1±FBXW7(Double) patients, respectively (log-rank P for trend=0.005). Although 14 NOTCH1±FBXW7(Double) patients were classified as high risk (slow response and/or MRD positive), only two had disease progression and all remain alive. Patients with double NOTCH1 and/or FBXW7 mutations have a very good outcome and should not be considered for more intensive therapy in first remission, even if slow early responders or MRD positive after induction therapy.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cell Cycle Proteins/genetics , F-Box Proteins/genetics , Mutation/genetics , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/mortality , Receptor, Notch1/genetics , Ubiquitin-Protein Ligases/genetics , Adolescent , Adult , Asparaginase/administration & dosage , Child , Child, Preschool , Cohort Studies , DNA, Neoplasm/genetics , Daunorubicin/administration & dosage , Dexamethasone/administration & dosage , F-Box-WD Repeat-Containing Protein 7 , Female , Genotype , Humans , Infant , Male , Polymerase Chain Reaction , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Prognosis , Remission Induction , Survival Rate , Vincristine/administration & dosage , Young AdultABSTRACT
This study compares outcome of reduced-intensity conditioned transplant (RIT) with outcome of conventional non-transplant therapy in patients with Hodgkin's lymphoma relapsing following autograft. There were 72 patients in two groups who had relapsed, and received salvage therapy with chemotherapy+/-radiotherapy. One group (n=38) then underwent alemtuzumab-containing RIT. The second group-historical controls (n=34), relapsing before the advent of RIT-had no further high-dose therapy. This group was required to respond to salvage therapy and live for over 12 months post-relapse, demonstrating potential eligibility for RIT, had this been available. Overall survival (OS) from diagnosis was superior following RIT (48% at 10 years versus 15%; P=0.0014), as was survival from autograft (65% at 5 years versus 15%; P< or =0.0001). For the RIT group, OS at 5 years from allograft was 51%, and in chemoresponsive patients was 58%, with current progression-free survival of 42%. Responses were seen in 8 of 15 patients receiving donor lymphocyte infusions (DLI) for relapse/progression, with durable remission in five patients at median follow-up from DLI of 45 months (28-55). These data demonstrate the potential efficacy of RIT in heavily pre-treated patients whose outlook with conventional therapy is dismal, and provide evidence of a clinically relevant graft-versus-lymphoma effect.
Subject(s)
Graft vs Tumor Effect , Hodgkin Disease/mortality , Hodgkin Disease/prevention & control , Stem Cell Transplantation , Transplantation Conditioning , Adolescent , Adult , Disease-Free Survival , Female , Humans , Male , Middle Aged , Recurrence , Retrospective Studies , Survival Rate , Time Factors , Transplantation, Autologous , Transplantation, HomologousABSTRACT
Treatment options for patients who relapse following autologous transplantation for Hodgkin's lymphoma are limited. There are anecdotal reports of lengthy remissions following second autologous procedures, although treatment-related toxicity can be significant. We report a single centre experience of second autologous transplant performed in seven highly selected patients, who relapsed following initial high-dose therapy. They were all young and had slow tempo disease, which was still sensitive to conventional dose chemotherapy. All received BEAM conditioning for the first transplant, and six of the seven received BEAM for the second. All six of these patients regenerated successfully and with no delay, the final patient dying during the procedure following alternative conditioning. Only one case of presumed carmustine-related pneumonitis was seen, which responded rapidly to corticosteroid therapy. Four patients have subsequently relapsed, of whom three have died at 29, 33, and 38 months postprocedure. One is alive with active disease at 68 months, and the final two are alive and in continuing complete remission at 104 and 68 months.
Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Hodgkin Disease/therapy , Transplantation, Autologous/methods , Adult , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carmustine/therapeutic use , Cytarabine/therapeutic use , Female , Follow-Up Studies , Graft Survival , Hematopoietic Stem Cell Transplantation/mortality , Hodgkin Disease/mortality , Humans , Male , Melphalan/therapeutic use , Podophyllotoxin/therapeutic use , Prognosis , Recurrence , Remission Induction , Retrospective Studies , Transplantation ConditioningABSTRACT
Granulocyte colony-stimulating factor (G-CSF) is widely used following myeloablative chemotherapy (high-dose therapy; HDT) and peripheral blood progenitor cell rescue (PBPCR) to reduce neutrophil engraftment time. The dose and duration required to gain maximum clinical and economic benefit has not been fully investigated. This double blind placebo-controlled randomised trial was performed to determine whether short course low-dose or standard-dose Lenograstim (L) would influence recovery of haematopoiesis following HDT and PBPCR. Sixty-one patients were randomised between May 1999 and November 2004, to receive standard-dose lenograstim (263 microg/d), low-dose lenograstim (105 microg/d) or placebo injections. These commenced on day +5 following PBPCR and continued until neutrophil engraftment [absolute neutrophil count (ANC)] > or = 0.5 x 10(9)/l. Patients received standard supportive care until haemopoietic recovery. Both standard- and low-dose lenograstim resulted in a significantly shorter median time to neutrophil recovery (ANC > or = 0.1 x 10(9)/l:10.0 vs. 11.0 d, P = 0.025; ANC > or = 0.5 x 10(9)/l:11.0 vs. 14.0 d, P = 0.0002) compared with placebo. There was no significant difference in blood product support, antibiotic usage, documented infection, overall survival or relapse-free survival between the groups. Short course low-dose lenograstim is as effective as standard-dose in reducing neutrophil engraftment time following HDT and PBPCR.
Subject(s)
Granulocyte Colony-Stimulating Factor/administration & dosage , Neutrophils/pathology , Peripheral Blood Stem Cell Transplantation , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Blood Cell Count , Combined Modality Therapy , Disease-Free Survival , Double-Blind Method , Drug Administration Schedule , Female , Granulocyte Colony-Stimulating Factor/therapeutic use , Hodgkin Disease/drug therapy , Hodgkin Disease/mortality , Hodgkin Disease/surgery , Humans , Lenograstim , Lymphoma, Non-Hodgkin/drug therapy , Lymphoma, Non-Hodgkin/mortality , Lymphoma, Non-Hodgkin/surgery , Male , Middle Aged , Myeloablative Agonists/therapeutic use , Prospective Studies , Recombinant Proteins/administration & dosage , Recombinant Proteins/therapeutic useABSTRACT
INTRODUCTION: Sequential high dose (SHiDo) chemotherapy with stem cell support has been shown to prolong the event-free survival in patients with diffuse large B-cell lymphoma. METHODS: To confirm this result in a multicenter trial, we randomized patients with aggressive NHL, to receive either eight cycles of CHOP or SHiDo. The primary endpoint was overall survival. RESULTS: 129 evaluable patients were randomized to receive either CHOP or SHiDo: median age, 48 years; 62% male; stage III+IV: 73%; age adjusted International Prognostic Index 1/2/3: 21%/52%/27%. Toxicity grades 3+4 were more pronounced in the SHiDo-arm with 13% versus 3% of patients with fever; 34% versus 13% with infections; 13% versus 2% with esophagitis/dysphagia/gastric ulcer. The remission rates were similar in SHiDo and CHOP arms with 34%/37% complete remissions and 31%/31% partial remissions, respectively. After a median observation time of 48 months, there was no difference in overall survival at 3 years, with 46% for SHiDo and 53% for CHOP (P = 0.48). CONCLUSION: In this multicenter trial, early intensification with SHiDo did not confer any survival benefit in previously untreated patients with aggressive NHL and was associated with a higher incidence of grades 3/4 toxicity.