Favourable outcomes for high-risk diffuse large B-cell lymphoma (IPI 3-5) treated with front-line R-CODOX-M/R-IVAC chemotherapy: results of a phase 2 UK NCRI trial.

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).

Breast cancer risk following Hodgkin lymphoma radiotherapy in relation to menstrual and reproductive factors.

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.

Superiority of reduced-intensity allogeneic transplantation over conventional treatment for relapse of Hodgkin's lymphoma following autologous stem cell transplantation.

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.

Identification of three accessory cell populations in human bone marrow with erythroid burst-promoting properties.

Several laboratories have demonstrated a requirement for burst-promoting activity (BPA), a product of T cells, or T cell/monocyte collaboration in the induction of differentiation of peripheral blood erythroid burst-forming units (BFU-E) in vitro. The physiologic significance of this finding is brought into question by patients with severe mature T cell deficiency who have normal in vivo erythropoiesis. The studies described here were designed to determine whether the burst-promoting effects of marrow T cells and adherent cells are similar to those of peripheral blood, to define whether a third population of marrow cells is capable of production of BPA, and to describe the BPA requirements of immature and mature marrow erythroid progenitors. To that end we prepared adherence- and E-depleted low-density peripheral blood mononuclear cells as a source of BFU-E and demonstrated that their optimal erythropoietin-induced differentiation requires BPA. We then determined that both bone marrow and peripheral blood T cells and monocytes could provide the necessary BPA to induce their erythropoietin dependent differentiation. BPA production by T cells was sensitive to irradiation, but that of the whole bone marrow low-density population was considerably less sensitive. This in itself demonstrated that BPA production in marrow is not T cell dependent. We further demonstrated a potent, albeit infrequent, third population of BPA-producing marrow cells. These proved to be nonadherent, E receptor-negative, granulocyte antigen-negative, and gamma-Fc receptor-positive. Finally, we separated all of these BPA-producing cells from marrow erythroid progenitors and concentrated the latter into a population in which they comprised 6% of the cells. With this population we demonstrated that both immature (BFU-E) and mature (colony-forming units [CFU-E]) erythroid progenitors require BPA in addition to erythropoietin to induce them to form erythroid colonies in vitro. These results may explain the normal erythropoiesis found in patients with mature T cell deficiency. Though the differentiation of both BFU-E and CFU-E requires BPA, this need can be met by a special class of nonadherent, radioresistant, E receptor-negative, granulocyte antigen-negative, and gamma-Fc-positive cells.

Influence of cell cycle phase-specific agents on simian fetal hemoglobin synthesis.

To determine the influence of cell cycle-specific agents on primate hematopoiesis and fetal hemoglobin production, two juvenile cynomolgus monkeys (Macaca fascicularis) were repeatedly bled to maintain their hemoglobins at approximately 6.5 g/dl and fetal hemoglobin levels at 3-5%. Six separate 5-d courses of hydroxyurea at 100 mg/kg per d were then administered over the next 200 d while phlebotomy was continued. These courses of hydroxyurea progressively raised the fetal hemoglobin levels to 17 and 18%, respectively. The drug had very little effect on the frequency of immature erythroid progenitors (BFU-E) in the bone marrow, but caused a marked reduction in the frequency of later progenitors (CFU-E) and a transient fall in the reticulocyte count. Following the courses of hydroxyurea, the number of F cells and the fetal hemoglobin level fell to base line over a period of 4 wk. Two control animals which were not phlebotomized showed no detectable increase in F cells or fetal hemoglobin when treated with the same regimen of hydroxyurea. A 5-d course of 5-azacytidine at 8 mg/kg per d was then given to each of the phlebotomized animals. This produced a more profound, albeit transient, reticulocytopenia, a fall in the CFU-E/BFU-E ratio, and a prompt increase in the fetal hemoglobin to levels even higher than were seen following a single 5-d course of hydroxyurea at 100 mg/kg/d. Subsequently, the animals were given a single dose of vinblastine at 0.4 mg/kg which reduced reticulocytes and CFU-E to the same extent as hydroxyurea; however, vinblastine at this dose had no effect on hemoglobin F (HbF) production. In contrast, when vinblastine was administered to the phlebotomized monkeys as a 5-d course at 0.2 mg/kg/d, prolonged reticulocytopenia followed by dramatic F cell and HbF responses were seen. Combinations of single dose vinblastine and a 5-d course of hydroxyurea were subsequently administered using two different schedules. When the animals received vinblastine on the first day of a 5-d course of hydroxyurea, the F cell response was double that seen following hydroxyurea treatment alone. In contrast, when vinblastine was administered on the final day of hydroxyurea treatment, the magnitude of the F cell response was the same as that which occurred following hydroxyurea treatment alone, but the onset of the rise was delayed for 4 d and HbF/F cell response was much higher. These results establish several important features of the fetal hemoglobin response to cytotoxic agents in the primate model. The response requires accelerated erythropoiesis and is preceded by transient reticulocytopenia. The response is produced by S phase- and M phase-specific agents when given in sufficient doses and at appropriate schedules. Passage of erythrocyte progenitors through M phase appears to be necessary for expression of the effect produced by S phase agents. The fetal hemoglobin response induced by cytotoxic drug administration occurs during the recovery of erythropoiesis following marrow suppression.

Determination of the hemoglobin F program in human progenitor-derived erythroid cells.

The absolute adult and fetal hemoglobin (HbF) contents of the erythroid cells derived from the differentiation of normal human and simian erythroid progenitors and of the peripheral blood erythroid burst-forming units (BFU-E) of patients with nondeletion hemoglobinopathies have been measured with a sensitive radioligand immunoassay. The HbF content varied between 0.13 and 2.96 pg/cell, representing between 0.7% and 19.6% of the total hemoglobin with a mean value of 7.0%. The absolute content of HbF was indistinguishable in the well-hemoglobinized progeny of marrow erythroid colony-forming units, marrow or blood BFU-E, or of mixed colony-forming units. The term HbF program refers to this inherent capacity to produce fetal hemoglobin (HbF) in the erythroid cells derived from these progenitors in vitro. The HbF content of marrow erythroblasts as determined by the same radioligand immunoassay was similar to that found in the peripheral blood, suggesting that the switch off of gamma-chain production occurs after the erythroid colony-forming unit stage of maturation. Increasing concentrations of a crude erythropoietin-containing preparation induced higher numbers of erythroid colonies, which were larger in size, but the HbF program was unaffected. In contrast to the hemoglobin accumulation in human progenitor-derived colonies, simian progenitor-derived colonies produced considerably more HbF, and the amount of HbF was strongly influenced by progenitor maturity. Assays of the HbF content of erythroblasts derived from culture of the peripheral blood BFU-E of patients with nondeletion hemoglobinopathies and their parents showed that the HbF program in the progenitors of such patients is highly variable. Some produce only a slight excess of HbF in progenitor-derived erythroblasts, whereas others have extraordinarily high HbF programs. The molecular basis of this variability is presently unknown.

Investigations of the simian ontogenic switch from fetal to adult hemoglobin at the progenitor cell level.

The ontogenic switch from fetal to adult hemoglobin could result from discontinuous events, such as replacement of fetal erythroid progenitor cells by adult ones, or gradual modulation of the hemoglobin program of a single progenitor cell pool. The former would result in progenitors at midswitch with skewed fractional beta-globin synthesis programs, the latter in a Gaussian distribution. For these studies, we obtained bone marrow from rhesus monkey fetuses at 141-153 d (midswitch). Mononuclear cells were cultured in methyl cellulose with erythropoietin, and single BFU-E-derived colonies were removed and incubated with [3H]leucine. Globin synthesis was examined by gel electrophoresis and fluorography. The beta-globin synthesis pattern of single fetal colonies was skewed, and did not fit a normal distribution. The fetal pattern resembled the pattern of an artificial mixture of fetal and adult progenitors, suggesting that the fetal progenitor pool could contain populations with different beta-globin programs. This non-Gaussian distribution in the progenitors of midswitch fetuses is consistent with a discontinuous model for hemoglobin switching during ontogeny.

A second autologous transplant may be efficacious in selected patients with Hodgkin's lymphoma relapsing after a previous autograft.

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.

Primary sciatic nerve lymphoma: a case report and review of the literature.

A patient with primary B cell non-Hodgkin's lymphoma of the sciatic nerve is described. He presented with neuropathic symptoms in the left leg, initially diagnosed as tarsal tunnel syndrome. Magnetic resonance imaging (MRI) identified the abnormality in the sciatic nerve. A fascicular biopsy of the sciatic nerve showed a diffuse large B cell non-Hodgkin's lymphoma. The patient was treated with chemotherapy and rituximab (anti-CD20 monoclonal antibody). Four months later he was in remission, and remains so 48 months from presentation. Primary lymphoma of single peripheral nerves may be a unique subtype of extranodal lymphoma, which usually follows an aggressive course and has a variable response to current therapeutic strategies. MRI is useful, alongside electrophysiological studies, in patients with atypical peripheral nerve symptoms.

PI3-kinase/Akt is constitutively active in primary acute myeloid leukaemia cells and regulates survival and chemoresistance via NF-kappaB, Mapkinase and p53 pathways.

The phosphoinositide 3-kinase (PI3-kinase) signalling pathway plays a key role in the regulation of cell survival and proliferation. We show that the PI3-kinase/Akt pathway is constitutively active in primary acute myeloid leukaemia (AML) cells and that blockade by the selective inhibitor LY294002 reduces survival of the total blast population (mean 52%). The ERK/MAPK module is also constitutively active and treatment with the MAPKK inhibitor U0126 reduces cell survival by 22%. In 10 of 18 samples, PI3-kinase contributes to MAPK activation as incubation with LY294002 leads to a marked reduction in its phosphorylation. PI3-kinase inhibition reduces survival of the CD34+38- AML progenitor subset by 44%, whereas MAPKK inhibition has little effect. Reporter assays in primary AML cells show that blocking PI3-kinase leads to a marked reduction of constitutive NF-kappaB activity and promotes p53-mediated transcription. This is associated with a synergistic interaction between LY294002 and Ara-C. An inducible activated form of Akt protects normal myeloid cells from Ara-C and etoposide-mediated apoptosis. These results show that blocking PI3-kinase has direct antileukaemic effects and potentiates the response to conventional cytotoxics via a number of targets including NF-kappaB, p53 and MAPK. Inhibitors of PI3-kinase and Akt may be useful in the treatment of AML.

Impact of PTEN abnormalities on outcome in pediatric patients with T-cell acute lymphoblastic leukemia treated on the MRC UKALL2003 trial.

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.

The phosphorylation state of the retinoblastoma (RB) protein in G0/G1 is dependent on growth status.

The product of the retinoblastoma gene (RB) is a nuclear phosphoprotein which is thought to regulate the proliferation of cells. Its phosphorylation state changes with passage through the cell cycle and it has been proposed that RB protein in its hypo-phosphorylated form prevents cells proliferating. We have investigated the phosphorylation state of the RB protein in an actively-dividing human B-lymphoblastoid cell line and after cell cycle arrest caused by alpha-Interferon (alpha-IFN). We show that the phosphorylation state of the RB protein in cells with 2N DNA content depends on whether the cells are actively cycling. Our data is compatible with the proposal that dephosphorylation of the RB protein allows cells to enter a quiescent state. This study sheds light on the molecular mechanisms which may mediate the cytostatic effects of alpha-IFN.

The relationship between mitogen-induced membrane potential changes and intracellular free calcium in human T-lymphocytes.

We have investigated the effects of mitogenic lectins on human T-lymphocytes, isolated from peripheral blood, and cells from the T-cell clone, HPB-ALL, using the fluorescent dyes, bis-thiobarbiturate tri-methineoxonol (bisoxonol) and quin2 to sense changes in membrane potential and intracellular free [Ca2+], respectively. The resting potential of both cell types is close to the K+ equilibrium potential. Changes from the resting level occur when mitogenic concentrations of either concanavalin A or phytohaemagglutinin are added. T-lymphocytes undergo a decrease in emission, maximal at 1 to 2 min, corresponding to a small membrane hyperpolarization. This is followed by a depolarization to approximately the resting level. HPB-ALL cells, on the other hand, respond to the mitogens by a sustained increase in fluorescence, denoting a depolarization, that is maximal at 4 to 5 min and 7 to 9 min, respectively. The Ca2+-dependence of these phenomena indicates that the membrane potential response, in both cell types, is the resultant of two opposing effects: a Ca2+-sensitive ion movement tending to hyperpolarize the cells and a Ca2+-insensitive effect that generates a depolarization. Our results suggest that Ca2+-activated K+ channels are responsible for the first effect and that an inward Na+ movement accounts for the depolarization signal in T-lymphocytes. In HPB-ALL cells only part of the depolarization is Na+-dependent. Although the effects elicited by phytohaemagglutinin occur more slowly than those produced by concanavalin A, similar membrane potential and [Ca2+]i changes occur.

BEAM chemotherapy and autologous bone marrow transplantation for patients with relapsed or refractory non-Hodgkin's lymphoma.

PURPOSE: To evaluate the outcome of patients with relapsed or resistant non-Hodgkin's lymphoma (NHL) undergoing high-dose chemotherapy and autologous bone marrow transplantation (ABMT) and to determine the main prognostic factors. PATIENTS AND METHODS: One hundred seven patients with relapsed or resistant intermediate-/high-grade NHL underwent high-dose carmustine, etoposide, cytarabine, and melphalan (BEAM) chemotherapy and ABMT at University College Hospitals between September 1981 and February 1993. The minimum follow-up duration of all patients is 6 months. RESULTS: At 3 months, the overall response rate to BEAM and ABMT was 73% (41% complete response and 32% partial response). The 5-year actuarial overall survival and progression-free survival rates were 41% and 35%, respectively. The early procedure-related mortality rate was 7% (eight of 107 patients). On multivariate analysis, the main prognostic factor was disease status at the time of ABMT. Patients with chemosensitive disease had an actuarial 5-year survival rate of 49% at 5 years compared with 13% for those with chemoresistant disease (P < .001). For patients considered to have chemosensitive disease at the time of transplantation, there is a significant difference in the actuarial progression-free survival rates for those who received high-dose therapy after attaining a partial response to first-line therapy (69% at 5 years) as compared with those with sensitive but relapsed disease (32% at 5 years) (P = .003). CONCLUSION: Patients with chemosensitive disease benefit most from high-dose chemotherapy, and those who receive such therapy early after achieving a partial response to first-line therapy have a high rate of cure.

LOPP alternating with EVAP is superior to LOPP alone in the initial treatment of advanced Hodgkin's disease: results of a British National Lymphoma Investigation trial.

PURPOSE: The purpose of this randomized trial was to compare the efficacy of eight cycles of chlorambucil, vincristine, procarbazine, and prednisone (LOPP) with four cycles of LOPP that alternate with four cycles of etoposide, vinblastine, Adriamycin (doxorubicin; Familitalia Carlo Erba, Ltd, UK), and prednisone (EVAP) in patients with advanced Hodgkin's disease. PATIENTS AND METHODS: Between June 1983 and December 1989, 594 patients were entered onto the study. Of the 594, 295 patients were allocated to receive LOPP, and 299 were allocated to receive LOPP/EVAP. RESULTS: The complete remission (CR) rates were 57% and 64%, respectively, after initial chemotherapy (difference not significant [NS]), and 65% and 75%, respectively, after the subsequent administration of radiotherapy to residual masses (P less than .01). The procedure associated mortality in the LOPP and LOPP/EVAP arms was 1% and 3%, respectively. The actuarial CR relapse-free survival was significantly greater in the LOPP/EVAP arm (P less than .001) as was the overall survival (P less than .05). The CR relapse-free rate, disease-free survival (DFS) rate, and overall survival rate at 5 years were 52%, 32%, and 66%, respectively, in the LOPP arm, compared with 72%, 47%, and 75% in the LOPP/EVAP arm, respectively. CONCLUSION: These results indicate that LOPP and EVAP is superior to LOPP alone as initial treatment for advanced Hodgkin's disease.

Effectiveness of high-dose combination chemotherapy and autologous bone marrow transplantation for patients with non-Hodgkin's lymphomas who are still responsive to conventional-dose therapy.

We commenced a study in September 1981 to investigate the role of high-dose combination chemotherapy in the management of patients with non-Hodgkin's lymphomas who had failed conventional therapy. Fifty patients with diffuse intermediate- and high-grade non-Hodgkin's lymphomas were treated with high-dose combination chemotherapy with autologous bone marrow rescue (ABMT) and have a minimum follow-up of 1 year. Twenty patients had disease that was still responsive to conventional-dose chemotherapy, 15 had achieved a partial response (PR) to first-line therapy, and five were showing PR to salvage therapy after relapse. Twelve of these patients (60%) achieved complete remission (CR) (two following boost radiotherapy) and three patients have nonprogressive masses on computed tomographic (CT) scan as the only abnormality. None of these patients died during the procedure. Twenty-nine patients had disease not responsive to chemotherapy at conventional dosages: 19 had no response to first-line therapy and 10 showed no response to salvage therapy given after relapse. Only three of these patients achieved CR, all of short duration only. Only two patients in this group remain alive more than 2 years after the procedure and both have nonprogressive abnormalities on CT scan. Nine patients (31%) died of sepsis during the procedure. In those patients with disease not responsive to conventional-dose therapy, dose escalation is associated with a high procedure-related mortality and a low response rate. In those patients who still have chemotherapy-responsive disease the response rate is high and mortality is low.(ABSTRACT TRUNCATED AT 250 WORDS)

Progenitor-cell mobilization after low-dose cyclophosphamide and granulocyte colony-stimulating factor: an analysis of progenitor-cell quantity and quality and factors predicting for these parameters in 101 pretreated patients with malignant lymphoma.

PURPOSE: To define parameters that predict for rapid engraftment after peripheral-blood stem-cell (PBSC) transplantation, progenitor thresholds, the proportion of patients who achieve these thresholds with a standardized mobilization regimen, and the factors that predict for mobilization efficiency. PATIENTS AND METHODS: One hundred and one patients with pretreated lymphoma were mobilized with cyclophosphamide 1.5 g/m2 and granulocyte colony-stimulating factor (G-CSF), with the first apheresis performed when the recovery WBC count was > or = 5.0 x 10(9)/L. The relationship between the number of progenitor cells collected and patient age, sex, diagnosis, prior radiotherapy, and time since last chemotherapy was determined by multivariate analysis. The relationship between these factors, progenitor numbers returned, post-PBSC G-CSF, and hematologic recovery was performed in 81 patients following chemotherapy with carmustine (BCNU), etoposide, cytarabine, and melphalan (BEAM protocol). RESULTS: No BEAM recipients had delayed neutrophil recovery beyond 28 days. Delayed platelet recovery occurred in 7.4% and minimum and optimum thresholds of 1 x 10(6) and 3.5 x 10(6) CD34+ cells/kg and 1 x 10(5) and 3.5 x 10(5) granulocyte-macrophage colony-forming cells (GM-CFC)/kg were established. Hematologic recovery was adversely affected by prior treatment with mini-BEAM, and neutrophil recovery was accelerated by post-PBSC G-CSF. The minimum GM-CFC threshold was achieved with a single apheresis in 83% of patients and in 90% with two aphereses. The optimal threshold was achieved with two leukaphereses in 69% of patients. Prior radiotherapy adversely affected mobilization. CONCLUSION: Hematopoietic recovery following PBSC is dependent on progenitor-cell number infused and affect of previous chemotherapy on progenitor quality. Progenitor-cell mobilization is adversely affected by prior radiotherapy. The minimum threshold of GM-CFC required is achieved in most patients with a single apheresis, but an optimal collection usually requires at least two harvests.

Development of a simplified single-apheresis approach for peripheral-blood progenitor-cell transplantation in previously treated patients with lymphoma.

PURPOSE: The aims of this study were to develop a simplified, safe, and cost-effective peripheral-blood progenitor-cell (PBPC) mobilization protocol. PATIENTS AND METHODS: Twenty-six patients with relapsed or resistant lymphomas were entered onto a sequential cohort study in which schedules of various granulocyte colony-stimulating factor (G-CSF) were administered after cyclophosphamide 1.5 g/m2. Hematologic recovery after high-dose carmustine (BCNU) etoposide, cytarabine, and melphalan (BEAM) chemotherapy was compared with that of 46 patients who received autologous bone marrow transplantation (ABMT) without growth factors and 28 patients who received ABMT followed by G-CSF. RESULTS: When G-CSF (10 micrograms/kg/d) was administered from the day after the cyclophosphamide, neutropenia developed on day 8 followed by an abrupt increase in the WBC count. The optimal time for PBPC harvesting was the day on which the postnadir WBC count was greater than 8.0 x 10(9)/L, as shown by CD34+ cell counts and granulocytic-macrophage colony-forming cell (GM-CFC) assays. The reproducibility of the response was such that routine monitoring of CD34+ cell counts and GM-CFC was not necessary. A single leukapheresis on this day was adequate for prompt hematologic engraftment, and posttransplant G-CSF made little further impact on the rapid recovery. Compared with both control groups, the use of PBPC led to more rapid neutrophil recovery, markedly accelerated platelet recovery, less use of antimicrobial agents and parenteral nutrition, and more than 10 days earlier discharge from hospital. All of these differences were highly significant (P < .01). CONCLUSION: A simplified mobilization protocol is described that requires only one apheresis to achieve rapid hematologic engraftment.

Risk of second malignancy after Hodgkin's disease in a collaborative British cohort: the relation to age at treatment.

PURPOSE: To assess long-term site-specific risks of second malignancy after Hodgkin's disease in relation to age at treatment and other factors. PATIENTS AND METHODS: A cohort of 5,519 British patients with Hodgkin's disease treated during 1963 through 1993 was assembled and followed-up for second malignancy and mortality. Follow-up was 97% complete. RESULTS: Three hundred twenty-two second malignancies occurred. Relative risks of gastrointestinal, lung, breast, and bone and soft tissue cancers, and of leukemia, increased significantly with younger age at first treatment. Absolute excess risks and cumulative risks of solid cancers and leukemia, however, were greater at older ages than at younger ages. Gastrointestinal cancer risk was greatest after mixed-modality treatment (relative risk [RR] = 3.3; 95% confidence interval [CI], 2.1 to 4.8); lung cancer risks were significantly increased after chemotherapy (RR = 3. 3; 95% CI, 2.4 to 4.7), mixed-modality treatment (RR = 4.3; 95% CI, 2.9 to 6.2), and radiotherapy (RR = 2.9; 95% CI, 1.9 to 4.1); breast cancer risk was increased only after radiotherapy without chemotherapy (RR = 2.5; 95% CI, 1.4 to 4.0); and leukemia risk was significantly increased after chemotherapy (RR = 31.6; 95% CI, 19.7 to 47.6) and mixed-modality treatment (RR = 38.1; 95% CI, 24.6 to 55. 9). These risks were generally greater after treatment at younger ages: for patients treated at ages younger than 25 years, there were RRs of 18.7 (95% CI, 5.8 to 43.5) for gastrointestinal cancer after mixed-modality treatment, 14.4 (95% CI, 5.7 to 29.3) for breast cancer after radiotherapy, and 85.2 (95% CI, 45.3 to 145.7) for leukemia after chemotherapy (with or without radiotherapy). CONCLUSION: Age at treatment has a major effect on risk of second malignancy after Hodgkin's disease. Although absolute excess risks are greater for older patients, RRs of several important malignancies are much greater for patients who are treated when young. The increased risk of gastrointestinal cancers may relate particularly to mixed-modality treatment, and that of lung cancer to chemotherapy as well as radiotherapy; there are also well-known increased risks of breast cancer from radiotherapy and leukemia from chemotherapy. The roles of specific chemotherapeutic agents in the etiology of solid cancers after Hodgkin's disease require detailed investigation.