Kevin Imrie

CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group

BACKGROUND The role of rituximab in combination with different CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like chemotherapy regimens in young patients with good-prognosis diffuse large-B-cell lymphoma remains to be defined. We aimed to compare CHOP-like chemotherapy and rituximab with CHOP-like chemotherapy alone in these patients. METHODS 824 patients who were from 18 countries; aged 18-60 years; and who had no risk factors or one risk factor according to age-adjusted International Prognostic Index (IPI), stage II-IV disease, or stage I disease with bulk were enrolled. These patients were randomly assigned to six cycles of CHOP-like chemotherapy and rituximab (n=413) or to six cycles of CHOP-like chemotherapy alone (n=411). Bulky and extranodal sites received additional radiotherapy. The primary endpoint was event-free survival; secondary endpoints were response, progression under therapy, progression-free survival, overall survival, and frequency of toxic effects. Analyses were done by intention to treat and per protocol. This trial is registered at http://www.clinicaltrials.gov, NCT 00064116. FINDINGS After a median follow-up of 34 months (range 0.03-61), patients assigned chemotherapy and rituximab had increased 3-year event-free survival compared with those assigned chemotherapy alone (79% [95% CI 75-83] vs 59% [54-64]; difference between groups 20% [13-27], log-rank p<0.0001), and had increased 3-year overall survival (93% [90-95] vs 84% [80-88]; difference between groups 9% [3-13], log-rank p=0.0001). Event-free survival was affected by treatment group, presence of bulky disease, and age-adjusted IPI: after chemotherapy and rituximab, a favourable subgroup (ie, IPI=0, no bulk) could be defined from a less-favourable subgroup (ie, IPI=1 or bulk, or both). Groups did not differ in the frequency of adverse events. INTERPRETATION Rituximab added to six cycles of CHOP is an effective treatment for young patients with good-prognosis diffuse large-B-cell lymphoma. The definition of two prognostic subgroups allows for a more refined therapeutic approach for these patients.

Phase III Study of R-CVP Compared With Cyclophosphamide, Vincristine, and Prednisone Alone in Patients With Previously Untreated Advanced Follicular Lymphoma

PURPOSE To compare the long-term outcome of patients with previously untreated follicular lymphoma (FL) needing therapy, after treatment with cyclophosphamide, vincristine and prednisone (CVP) versus CVP plus rituximab (R-CVP) and to evaluate the predictive value of known prognostic factors after treatment with R-CVP. PATIENTS AND METHODS Patients with previously untreated CD20-positive stage III/IV FL were randomly assigned to eight cycles of R-CVP (n = 159) or CVP alone (n = 162). The median follow-up period was 53 months. RESULTS The primary end point-time to treatment failure (TTF), which included patients without a response after four cycles as an event-was significantly prolonged in patients receiving R-CVP versus CVP (P < .0001). Improvements in all other end points, including overall and complete response rates (P < .0001), time to progression (TTP; P < .0001), response duration (P < .0001), time to next antilymphoma treatment (P < .0001), and overall survival (OS; P = .029; 4-year OS: 83% v 77%;) were achieved with R-CVP versus CVP alone. Univariate analyses demonstrated an improvement in TTP with R-CVP versus CVP irrespective of the Follicular Lymphoma International Prognostic Index (FLIPI) subgroup, the International Prognostic Index (IPI) subgroup, baseline histology, and the presence or absence of B symptoms or bulky disease. By multivariate analysis, FLIPI retains a strong predictive power for TTP in the presence of the trial treatment effect. CONCLUSION Analysis of all outcome measures, including OS, confirm the benefit of adding R to CVP in the front-line treatment of FL.

A systematic review of the effects of resident duty hour restrictions in surgery: impact on resident wellness, training, and patient outcomes.

Background:In 2003, the Accreditation Council for Graduate Medical Education (ACGME) mandated 80-hour resident duty limits. In 2011 the ACGME mandated 16-hour duty maximums for PGY1 (post graduate year) residents. The stated goals were to improve patient safety, resident well-being, and education. A systematic review and meta-analysis were performed to evaluate the impact of resident duty hours (RDH) on clinical and educational outcomes in surgery. Methods:A systematic review (1980–2013) was executed on CINAHL, Cochrane Database, Embase, Medline, and Scopus. Quality of articles was assessed using the GRADE guidelines. Sixteen-hour shifts and night float systems were analyzed separately. Articles that examined mortality data were combined in a random-effects meta-analysis to evaluate the impact of RDH on patient mortality. Results:A total of 135 articles met the inclusion criteria. Among these, 42% (N = 57) were considered moderate-high quality. There was no overall improvement in patient outcomes as a result of RDH; however, some studies suggest increased complication rates in high-acuity patients. There was no improvement in education related to RDH restrictions, and performance on certification examinations has declined in some specialties. Survey studies revealed a perception of worsened education and patient safety. There were improvements in resident wellness after the 80-hour workweek, but there was little improvement or negative effects on wellness after 16-hour duty maximums were implemented. Conclusions:Recent RDH changes are not consistently associated with improvements in resident well-being, and have negative impacts on patient outcomes and performance on certification examinations. Greater flexibility to accommodate resident training needs is required. Further erosion of training time should be considered with great caution.

Isolated chloroma: the effect of early antileukemic therapy.

Chloroma is an extramedullary tumor of granulocytic lineage that has a long-recognized association with acute myeloid leukemia [1]. It usually occurs in patients with acute myeloid leukemia, myeloproliferative disorders, or myelodysplasia but can develop in patients with no known hematologic disorders (isolated chloroma) [2, 3]. Several case reports of isolated chloroma are documented, but only two series include more than 10 cases [2, 4]. Because most reports [2, 3, 5] describe progression to acute leukemia, several authors [2, 5, 6] recommend induction chemotherapy at diagnosis. To date, however, no clear evidence has shown that early treatment of isolated chloroma with chemotherapy alters progression to leukemia or prolongs survival. To address this issue, we reviewed our experience and did an analysis of a comprehensive retrospective review of the medical literature. Methods To identify all patients with isolated chloroma, we did a retrospective review of records from 1980 to 1994 at three teaching hospitals associated with the University of Toronto. In all cases, the diagnosis was reviewed by one of three reference hematopathologists, and the histologic diagnosis was confirmed using a naphthol-ASD-chloroacetate esterase stain and appropriate enzyme cytochemistry and immunocytochemistry. We excluded all patients with a history of a myeloproliferative syndrome, myelodysplasia, or acute myeloid leukemia diagnosed before or concurrent with diagnosis of chloroma. A normal complete blood count and bone marrow aspirate at diagnosis were required for inclusion. Patient characteristics evaluated were age, sex, site of chloroma, and treatment given at diagnosis, including surgical resection, chemotherapy, radiotherapy, and bone marrow transplantation. The chemotherapy regimen was judged to be an acute myeloid leukemia induction regimen if cytosine arabinoside was incorporated. Consolidation or maintenance therapy was not evaluated. Outcome measures included survival from diagnosis of chloroma and the interval between diagnosis of chloroma and the development of leukemia. We did a MEDLINE search of the English-language literature from 1980 to 1994 and identified all articles in which the following terms appeared in the title or abstract: granulocytic sarcoma, chloroma, and myelosarcoma. Inclusion and exclusion criteria were identical to those used for locally identified cases but, in addition, we excluded patients for whom therapy or outcome was not reported. Survival from diagnosis of chloroma was estimated using the Kaplan-Meier method [7]. We evaluated the effect of the following variables on survival and the development of leukemia: patient age, site of chloroma, and chemotherapy, local radiotherapy, or surgical resection done at diagnosis. We tested for the significance of the effect of the type of initial therapy on the development of leukemia using the Pearson chi-square test. The effect of treatment on disease-free survival and overall survival was tested using the log-rank test. Multivariate analysis was done using Cox regression analysis. All statistical testing was done using SPS for Windows version 6.1. Results Review of the literature showed 208 English-language papers with one of the requisite keywords in the title or abstract. A total of 149 reports were excluded: Eighty-one included only patients with a previous or concurrent diagnosis of acute myeloid leukemia, the nature of therapy or outcome was not evaluable in 30, the final diagnosis was not chloroma in 21, and 17 referred only to patients with previous myeloproliferative or myelodysplastic disorders. The remaining 59 reports, describing a total of 83 cases, were included. Seven patients from three hospitals in Toronto were identified in the defined time period. Details of the entire group of 90 cases are summarized in Table 1. The median age at diagnosis was 35 years. Sixty-eight percent of patients were male. The site of chloroma was visceral in 38% of patients, soft tissue or skin in 20%, head or neck in 16%, bone in 12%, the central nervous system in 6%, and other sites in 8%. Eleven patients (13%) had multiple lesions. Cytogenetic analysis at diagnosis of chloroma was not available from biopsy material in any patients due to lack of marrow involvement and a low index of suspicion before biopsy. Table 1. Patient Characteristics Forty-nine of the 90 patients (54%) received chemotherapy at diagnosis. Of these, 24 received standard leukemia induction chemotherapy and 20 received other treatment including chemotherapy for lymphoma or palliation. Data were insufficient to assess consolidation or maintenance chemotherapy. In 5 patients, the type of chemotherapy given could not be determined. Thirty-seven patients (41%) had surgical resection and 56 (62%) had local irradiation at diagnosis. Fifty-nine of the 90 patients (66%) developed acute myeloid leukemia at a median of 9 months (95% CI, 7 to 13 months) after diagnosis of chloroma. The FAB subtype of the leukemia at relapse was described in only 8 patients (9%): It was M2 in 3 patients, M4 in 2 patients, M1 in 1 patient, M3 in 1 patient, and M7 in 1 patient. The karyotype of the malignant clone in the bone marrow at diagnosis of acute leukemia was reported in 9 patients: It was t(8;21) in 3 patients, +8 in 2 patients, inv(16) in 1 patient, t(15;17) in 1 patient, t(1;7) in 1 patient, and normal in 1 patient. Forty-eight patients (53%) received induction chemotherapy at the time of diagnosis of overt leukemia regardless of initial therapy. A significantly lower proportion of the patients who received any form of chemotherapy at initial diagnosis subsequently developed leukemia (41% 14% compared with 71% 14%; P = 0.001). In addition, leukemia occurred significantly later in those patients who received systemic chemotherapy. The median time from diagnosis of chloroma to leukemia was 36 months (CI, 12 to 66 months) in patients treated with chemotherapy compared with 6 months (CI, 4.2 to 7.8 months) in untreated patients (P < 0.001). Figure 1 is a Kaplan-Meier plot of survival for all 90 patients. Median survival was 22 months (CI, 13.2 to 30.8 months). Sex, site of chloroma, and treatment with radiotherapy or surgical resection did not influence survival or development of acute leukemia. Being more than 50 years of age was associated with a poorer prognosis (P = 0.003). Survival was significantly longer in patients receiving any form of chemotherapy at diagnosis. Median survival was 13 months (CI, 8.6 to 17.4 months) for those who did not receive chemotherapy. In contrast, median survival could not be calculated for patients who received chemotherapy, because more than half of these patients were alive with a median follow-up of 25 months (range, 1 to 192 months; P = 0.001) when their cases were submitted for publication. The group treated with chemotherapy and the untreated group did not differ with respect to age, sex, or site of chloroma. Figure 1. Survival of 90 patients with isolated chloroma. We next analyzed the difference in survival between patients receiving accepted leukemia induction and patients receiving other chemotherapy at diagnosis of isolated chloroma. Median survival was 39 months (CI, 0 to 78 months) for the latter group, whereas the median survival of the former group had not been reached at a median follow-up of 35 months (range, 1 to 144 months; P = 0.03). Cox regression analysis showed only younger age (< 51 years) and chemotherapy at diagnosis to be factors favorably affecting survival (P = 0.003 and P < 0.001, respectively). Seven patients had bone marrow transplantation (four allogeneic and three autologous), and four of the seven had transplantation done before any evidence of leukemia was seen. Six of the seven were alive in complete remission with a median follow-up of 22 months. Discussion We confirm that chloroma in patients without acute myeloid leukemia or other bone marrow disorders is associated with a poor prognosis. The median survival of 22 months found in our study is similar to that found in the two series that included 10 or more patients [2, 4]. The median age in our study is similar to that in other published series [2, 4], but is lower than the median age of onset of acute myeloid leukemia [8]. Older age is a significant adverse prognostic factor and, although this association has not previously been noted, is in keeping with the outcome for acute myeloid leukemia [9]. Our series shows a slight preponderance of men among patients with isolated chloroma (62%), similar to that seen with acute myeloid leukemia [9]. Cytogenetic and histologic data at relapse were available for only a minority of patients but were consistent with the reported association of chloroma with FAB M2 leukemia and the t(8; 21) translocation [10, 11]. We show a significantly lower rate of progression to leukemia and longer survival among patients who received any form of chemotherapy at diagnosis of chloroma; the best results were seen in those patients receiving acute myeloid leukemia induction. The nature of the chemotherapy varied because many of the published cases had initially been misdiagnosed, often as non-Hodgkin lymphoma. It is important to emphasize that our finding of longer survival in patients initially treated with chemotherapy is based on a retrospective review of case reports and short case series and is therefore subject to bias. Publication bias may exclude patients who have relapse after aggressive chemotherapy. We have attempted to minimize this effect by evaluating all reports published during a 14-year period and, specifically, by including in our review not only case series published in hematology or oncology journals but also many individual case reports in the medical, surgical, and radiology literature. Another potential confounding factor is that fewer patients with adverse prognostic features, such as poor performance status, are likely to be offered aggr

Randomized Comparison of Gemcitabine, Dexamethasone, and Cisplatin Versus Dexamethasone, Cytarabine, and Cisplatin Chemotherapy Before Autologous Stem-Cell Transplantation for Relapsed and Refractory Aggressive Lymphomas: NCIC-CTG LY.12

PURPOSE For patients with relapsed or refractory aggressive lymphoma, we hypothesized that gemcitabine-based therapy before autologous stem-cell transplantation (ASCT) is as effective as and less toxic than standard treatment. PATIENTS AND METHODS We randomly assigned 619 patients with relapsed/refractory aggressive lymphoma to treatment with gemcitabine, dexamethasone, and cisplatin (GDP) or to dexamethasone, cytarabine, and cisplatin (DHAP). Patients with B-cell lymphoma also received rituximab. Responding patients proceeded to stem-cell collection and ASCT. Coprimary end points were response rate after two treatment cycles and transplantation rate. The noninferiority margin for the response rate to GDP relative to DHAP was set at 10%. Secondary end points included event-free and overall survival, treatment toxicity, and quality of life. RESULTS For the intention-to-treat population, the response rate with GDP was 45.2%; with DHAP the response rate was 44.0% (95% CI for difference, -9.0% to 6.7%), meeting protocol-defined criteria for noninferiority of GDP (P = .005). Similar results were obtained in a per-protocol analysis. The transplantation rates were 52.1% with GDP and 49.3% with DHAP (P = .44). At a median follow-up of 53 months, no differences were detected in event-free survival (HR, 0.99; stratified log-rank P = .95) or overall survival (HR, 1.03; P = .78) between GDP and DHAP. Treatment with GDP was associated with less toxicity (P < .001) and need for hospitalization (P < .001), and preserved quality of life (P = .04). CONCLUSION For patients with relapsed or refractory aggressive lymphoma, in comparison with DHAP, treatment with GDP is associated with a noninferior response rate, similar transplantation rate, event-free survival, and overall survival, less toxicity and hospitalization, and superior quality of life.

Ovarian function after autologous bone marrow transplantation.

PURPOSE To determine the frequency of return of ovarian function after autologous bone marrow transplantation (ABMT), and the major factors that predict recovery. PATIENTS AND METHODS Records of 200 consecutive women who underwent ABMT at the University of Toronto Autologous Blood and Marrow Program (Toronto, Canada) were reviewed. Seventeen patients met the inclusion criteria, which were (1) alive at the time of evaluation, (2) disease-free at least 18 months after transplantation, (3) age younger than 50 years at transplantation, and (4) premenopausal before transplantation. Recovery of ovarian function was determined by pregnancy or regular menses, with no menopausal symptoms and an estradiol level greater than 20 pmol/L off hormonal therapy. RESULTS All 17 patients became menopausal immediately after ABMT. Five patients (29%) recovered ovarian function a median of 24 months post-ABMT (range, 6 to 48 months). The median age at transplantation of women with restored ovarian function was 19 years (range, 19 to 28 years) versus 30 years (range, 22 to 48 years) for those who did not regain function. Younger age at transplantation predicted ovarian recovery (P = .03) by means of a log-rank test. Only one of five women who regained ovarian function received total-body irradiation (TBI) compared with five of 12 women who did not. Univariate analysis suggested a trend for TBI to predict a sustained loss of ovarian function (P = .067). The number of regimens of induction or salvage chemotherapy that contained an alkylating agent ranged from none to five and was not predictive (P = .45). CONCLUSION All women became menopausal after ABMT but 29% recovered ovarian function. Younger age at transplantation predicted return of ovarian function, whereas TBI may have had a negative effect.

Peripheral blood progenitor cell collections in multiple myeloma: predictors and management of inadequate collections

Thirty‐seven patients with previously treated multiple myeloma (MM) underwent peripheral blood progenitor cell (PBPC) collection following high‐dose cyclophosphamide and GM‐CSF or sequential IL‐3 and GM‐CSF. Patients with an inadequate collection were considered for a second or third collection. 25 patients underwent subsequent autotransplant. The only variable predictive of CFU‐GM yield was the extent of prior melphalan therapy. All repeat collections were unsuccessful and patients infused with an autograft obtained from multiple sets of collections had a high incidence of delayed engraftment. We conclude that melphalan should be avoided or PBPC collection performed early in the disease course in patients who are potential transplant candidates.

The Role of Intensive Therapy and Autologous Blood and Marrow Transplantation for Chemotherapy-Sensitive Relapsed and Primary Refractory Non-Hodgkin’s Lymphoma: Identification of Major Prognostic Groups

Patients with intermediate grade non‐Hodgkins lymphoma (NHL) who relapse or fail to achieve a complete remission after anthracycline‐containing induction regimens have a poor outcome with conventional‐dose salvage treatment. This outcome may be improved with intensive therapy and autologous transplantation (ABMT) but even in patients with proven chemotherapy‐sensitive disease, relapse rates of up to 60% are observed. Reliable and powerful prognostic indicators are needed to identify appropriate patients for this expensive procedure and those subjects to whom alternative or additional treatment should be offered. We were interested in testing the hypothesis that tumour burden, and hence remission status immediately prior to transplant, is an important prognostic indicator of survival. We aggressively treated patients with conventional‐dose salvage chemotherapy to maximum tumour response, and tested, by multivariate regression analysis, predictors of outcome post‐transplant. We studied 81 consecutive patients with intermediate grade and immunoblastic NHL who achieved either a partial (PR) or complete remission (CR) following repetitive cycles of conventional‐dose salvage therapy. Intensive therapy consisted of etoposide (60 mg/kg) and intravenous melphalan (160–180 mg/m2) with or without total body irradiation (TBI) followed by infusion of autologous unpurged bone marrow and/or blood cells. The predicted 4‐year survival and progression‐free survival (PFS) with a median follow‐up of 37 months was 58% and 48% (95% confidence interval (CI) 37–55%), respectively. The only factor predictive of outcome was remission status at transplant (P = 0.0001). The PFS at 4 years for the CR group was 61% (95% CI 53–75%). In contrast, only 25% (95% CI 11–40%) of patients undergoing autotransplant in PR were progression free at 4 years. We conclude that remission status at transplant after maximum tumour reduction is a powerful prognostic indicator.

Rituximab purging and maintenance combined with auto-SCT: long-term molecular remissions and prolonged hypogammaglobulinemia in relapsed follicular lymphoma.

We enrolled 23 patients with relapsed follicular lymphoma (FL) in a prospective single-arm study of auto-SCT combined with in vivo rituximab graft purging and post transplant rituximab maintenance. Minimal residual disease was monitored with quantitative PCR testing. With a median follow-up of 74.2 months, neither median overall survival (OS) nor PFS has been reached. Here, 5-year OS and 5-year PFS are 78% (95% confidence interval (CI) 61–95%) and 59% (95% CI 38–80%), respectively. Time to progression (TTP) with the experimental regimen was significantly improved compared with TTP with the last prior treatment (P<0.001). Durable molecular remissions occurred in 11 of 13 assessable patients. PFS was significantly longer in patients who achieved a molecular remission by 3 months post-auto-SCT (P=0.001). Prolonged hypogammaglobulinemia occurred in most patients; however, no increase in major infections was observed.

Impact of central nervous system (CNS) prophylaxis on the incidence and risk factors for CNS relapse in patients with diffuse large B-cell lymphoma treated in the rituximab era: a single centre experience and review of the literature.

Central nervous system (CNS) prophylaxis for diffuse large B‐cell lymphoma (DLBCL) is controversial with even less evidence in the era of R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy. We reviewed the impact of CNS prophylaxis in DLBCL patients treated with R‐CHOP at a tertiary care centre over a 7‐year period. CNS prophylaxis was recommended for ‘higher risk’ patients and consisted of intrathecal methotrexate and/or high‐dose methotrexate. Of 214 patients 12·6% received CNS prophylaxis. With a median follow‐up of 27 months, eight patients (3·7%) developed CNS relapse (75% isolated to the CNS and 62·5% as parenchymal brain disease) at a median time of 17 months. Patients who did not receive CNS prophylaxis had lower events (2·7%) than those who did (11·1%). Half of the CNS relapses occurred in testicular lymphoma patients, 75% of whom had received CNS prophylaxis. In multivariate analysis, testicular involvement was the only significant prognostic factor for CNS relapse (hazard ratio 33·5, P < 0·001). In conclusion, CNS relapse in DLBCL appears to present as a later, more isolated parenchymal event and at a lower rate in the rituximab era compared with historical data. R‐CHOP may negate the need for CNS prophylaxis with the exception of testicular lymphoma.