Partial Remission Group Research Articles

Long-Term Prognostic Significance of Response in Hodgkin Lymphoma Before Autologous Stem Cell Transplantation :Results of the Prospective Multicenter H96 Trial by the GELA/SFGM-TC Study Group

Abstract 3070 Introduction.The standard treatment for relapsed or refractory Hodgkin lymphoma (HL) is high-dose therapy followed by autologous stem cell transplantation (HDT/ASCT). The prognostic significance of response to initial salvage therapy (i.e. prior to HDT/ASCT) has been shown in many studies. However, the existing results have been based either on retrospective studies or on prospective studies with a relatively short median follow-up, and long-term prospective data are missing. The aim of the present study was to establish the actual prognosis for the different response categories in a prospective cohort of HL patients (pts) treated with HDT/ASCT after long-term follow-up. Methods.The GELA/SFGM-TC H96 trial was a prospective, multicenter, phase II trial evaluating a risk-adapted salvage treatment with single or tandem HDT/ASCT for HL pts who experienced first-line treatment failure (Morschhauser F, J Clin Oncol 2008). Pts were stratified as follows: the poor-risk group included pts with primary refractory disease or at least two risk factors at relapse (time to relapse < 12 months, stage III or IV at relapse, or relapse within previously irradiated sites); the intermediate-risk group included pts with only one risk factor at relapse. Poor-risk and intermediate-risk pts were eligible for tandem and single HDT/ASCT, respectively. The primary end point was to evaluate the freedom from second failure (FF2F) rate in the poor- and intermediate-risk groups. Secondary end points included overall survival (OS) for both groups, FF2F and OS according to the response to salvage chemotherapy. Response was assessed according to 1999 standard guidelines: complete remission (CR), unconfirmed CR (CRu), partial remission (PR), stable disease (SD) or progressive disease (PD). Results.Between 1995 and 2002, 245 pts were enrolled. The pts characteristics at diagnosis and at time of treatment failure/relapse have been previously described (Morschhauser F, J Clin Oncol 2008). The median follow-up is now 9.2 years (yrs). In the poor-risk group (n=150 [77 pts with primary refractory HL and 73 pts with unfavorable relapse]), the 9-yr FF2F and OS were 41% and 50%, respectively, without significant difference between primary refractory HL and unfavorable relapse. In the intermediate-risk group (n=95), the 9-yr FF2F and OS were 61% and 70%, respectively. The response to salvage treatment was assessable for 243 pts.In the poor-risk group, the 9-yr FF2F according to each response category was 67% for CR/CRu (n=39), 45% for PR (n=55), 12% for SD (n=24), and 23% for PD (n=31). The 9-yr OS were 76% for CR/CRu, 60% for PR, 16% for SD, and 26% for PD. Significant differences in FF2F were found between CR/CRu and PR groups (p=0.02), between PR and SD groups (p=0.006), but not between SD and PD groups (p=0.82). For OS, no significant differences were found between CR/CRu and PR groups (p=0.09) and between SD and PD groups (p=0.89), but there was a significant difference between PR and SD groups (p=0.001).In the intermediate-risk group, the 9-yr FF2F was 66% for CR/CRu (n=65) and 60% for PR (n=26) [no SD and 3 PD]. The 9-yr OS was 71% for CR/CRu and 67% for PR. No significant differences in FF2F (p=0.98) and OS (p=0.96) were observed between the CR/CRu and PR groups.In all, 100 pts relapsed after HDT/ASCT (76 in the poor-risk group [primary refractory, n=44; unfavorable relapse, n=32] and 24 in the intermediate-risk group). Half of relapses occurred in the first yr following HDT/ASCT. In the poor-risk group, the cumulative incidence of relapse at 1, 2, 5 and 9-yr was 33%, 43%, 47% and 52%. In the intermediate-risk group, the cumulative incidence of relapse at 1, 2, 5 and 9-yr was 5%, 15%, 23% and 26%. Among relapsing pts, 21 (poor-risk group, n=16) underwent allogeneic transplantation (alloSCT). In all, 101 pts died (poor-risk group, n=76). The cause of death was PD in 78 pts (poor-risk group, n=65) or other cause in 23 pts (secondary malignancy, n=6; non-relapse mortality after alloSCT, n=5; infection, n=4; other, n=5; unknown, n=3). Secondary malignancy occurred in 11 pts (solid tumor, n=7; acute leukemia, n=4), including 2 pts in the poor-risk group (solid tumor only). Secondary cardiac toxicity occurred in 7 pts (2 pts in the poor-risk group). Conclusion.This prospective study emphasized the prognostic impact of response to salvage chemotherapy on the long-term outcome after HDT/ASCT for first relapsed/refractory HL. Disclosures:No relevant conflicts of interest to declare.

Allogeneic Hematopoietic Stem-Cell Transplantation with Reduced-Intensity Conditioning in Patients with High Risk Multiple Myeloma: Comparative Analysis of Outcomes Between Unrelated and Related Donor

Abstract 4513 Introduction:The purpose of this study was to assess the results of allogeneic stem cell transplantation (Allo-SCT) after reduced-intensity conditioning (RIC) from an unrelated donor in patients with high-risk multiple myeloma (MM) in a single centre. From January 2007 to January 2011 we consecutively transplanted 40 patients with MM. Patients and methods:Seventeen (43%) (Group 1) and 23 patients (57%) (Group 2) had unrelated and related donor respectively. The median age was 48 years (39–63) in the first group and 56 years (40–67) in the second group (P=0.0769).Thirty nine patients (98%) received one or more autologous transplantation. Ten patients (Group 1: N=5 (29%); Group 2: N=5 (22%)) were transplanted within whereas 30 patients were treated beyond (Group 1: N=12 (71%); Group 2: N=18 (78%) the first line treatment strategy. The disease status at transplantation was Complete Remission (CR) or VGPR in (35%) vs (43%), Partial remission (PR) in (59%) vs (52%) and Progression or Refractory Disease in (6%) vs (4%) (PD/RD) in the first and second group respectively (p=0.1770). Graft was peripheral blood stem cells (PBSC) in all patients in the related donor group and in 14 patients (82%) in the second group, the other 3 patients (18%) receiving marrow.Thirty-three patients (Group 1: N=14 (82%); Group 2: N=19 (83%) were treated with a RIC based on Fludarabine (30mg/m2/d × 5); Busulfan (4 mg/kg/d p.o. or 3.2 mg/kg/d IV over 2 to 3 days) and rabbit ATG (2.5 mg/kg/d × 2). Seven patients received Fludarabine (25mg/kg/d for 3 days) and 2 Gys total body irradiation (TBI).Post-graft immunosuppression consisted of cyclosporine (CSA) alone in 26 patients (65%), CSA and mycophenolate mofetil in 14 patients (35%). Result:The median follow-up was 22 months (1–49). None of our patient experienced a graft rejection. The cumulative incidence of grade II-III acute graft versus-host disease (GVHD) tended to be higher after unrelated donor graft (41% vs 17%) (p= 0.12). The cumulative incidence of chronic GVHD was no different between the first and second group (24% vs 30% respectively). At last follow up 24 patients (group 1: N=11 (65%); Group 2:N=14 (61%) were still alive of whom 17 are in CR (group 1: N=9 (53%); Group 2:N=8 (35%), 5 in PR (group 1: N=1 (6%); Group 2:N=4 (17%)and 2 in progressive disease (group 1: N=1; Group 2:N=1).The estimated probability of non relapse mortality (NRM) at day 100 was 0% in the two groups and not statically different at 2 years. (12% vs. 22% (P=0.4)) Also 2 year overall and progression-free survivals were not statiscally different after unrelated and related donor transplants (59% vs. 66% (P=0.110) and 42% vs. 44% (p=0.241)). The incidence of acute GVHD, OS, PFS and NRM were not significantly different between the two groups. Conclusion:Our experience, although limited, supports that high risk MM patients can benefit from a RIC Allo-SCT with unrelated donor when a HLA matched sibling donor is not available conducting to acceptable and comparable outcomes. This deserves further analysis in larger populations. Disclosures:No relevant conflicts of interest to declare.

Predictive value of remission status after 6 months induction therapy in patients with proliferative lupus nephritis: a retrospective analysis

The objective of this study was to evaluate whether remission status after completion of induction therapy can be used to predict long-term renal outcomes, including renal relapse and chronic renal failure (CRF) in patients with proliferative lupus nephritis (LN). Of 201 patients with biopsy proven LN between 1998 and 2008, 117 were reviewed. Fifty nine (50.4%), 33 (28.2%), and 25 (21.4%) were assigned to the complete remission (CR), partial remission (PR), and non-remission (NR) groups, respectively. The 24-h urinary protein level was significantly lower in the CR than in the PR and NR groups. Induction therapy after the first detection of nephritis signs was initiated earlier in the CR than in the PR and NR groups. During follow-up, 36 (39.1%) patients suffered relapse. Multivariate analysis showed that longer latency period and a lack of CR were independent predictors of renal relapse. Seventeen (14.5%) patients experienced CRF. Multivariate analysis showed that higher baseline creatinine concentration and a lack of CR after induction therapy were independent predictors of CRF. We found that renal outcomes were related to remission status after 6months induction therapy in patients with proliferative LN. Further, poor outcomes were associated with delayed intervention and higher creatinine concentration.

Allogeneic T-Cell Therapy for Epstein-Barr Virus-Positive Posttransplant Lymphoproliferative Disease: Long-Term Follow-Up

Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disease (PTLD) is an important cause of morbidity and mortality in transplant patients. EBV-specific cytotoxic T-cell line (CTL) that are in vitro grown and donor derived have been used to prevent and treat EBV-positive PTLD in hematopoietic stem-cell transplant recipients (1). However, donor-derived T cells are neither generally available nor appropriate for PTLD arising after solid organ transplantation. Furthermore, although monitoring EBV load in blood may indicate a risk of PTLD after hematopoietic stem-cell transplant, allowing time for CTL preparation, this monitoring gives less convincing results after solid organ transplantation. Additionally, the alternative strategy of generating autologous CTL after PTLD diagnosis often produces unacceptable delays in treatment. To counter these problems, we generated a bank of 100 EBV-specific CTL from healthy blood donors covering more than 95% of common UK human leukocyte antigen (HLA) haplotypes and treated a patient with PTLD with a partially HLA-matched CTL line that resulted in complete tumor regression (2, 3). Subsequently, we used these cell lines in a phase 2 multicenter clinical trial to treat PTLD in a best HLA match basis (4). All 33 trial participants had progressive disease, despite conventional treatments. Our trial recorded a response rate of 52% at 6 months, with 14 patients achieving complete remission (CR), three patients with partial remission (PR), and 16 patients showed no response (NR); five of whom died during the CTL treatment. Significantly better response rates were seen in patients with closer HLA matches and higher numbers of CD4+ T cells in the infused CTL. We now report the long-term outcome of trial participants. We obtained follow-up data from 32 of the 33 trial participants, 4 to 9 years after their last CTL infusion. At 6 months, 15 of the 32 patients showed NR and 17 patients were responders (three PR and 14 CR). All those in the PR and NR groups, but none of the CR group, received further PTLD treatment after CTL therapy. Nineteen (59%) of the 32 patients are alive to date and 13 (41%) have died. Of the 14 patients who achieved CR at 6 months, 12 patients (86%) survived and are still in CR after 4 to 9 years. Two patients (14%) from the CR group had died; one at 10 months post-CTL therapy from relapsed PTLD and the other at 5 years from a chest infection while PTLD was in CR. Of the 19 surviving trial participants, 13 participants (68%) were responders (one PR and 12 CR) and six participants (32%) were NR at 6 months. In contrast, of the 13 patients who have died, nine patients (69%) were NR and four patients (31%) were responders (two PR and two CR) at 6 months. There was a significantly increased survival rate among the PR and CR group compared with the NR group (P=0.018; Fig. 1).FIGURE 1.: The Kaplan-Meier overall survival rate. There was a significantly increased survival rate in patients who achieved complete response (CR) and partial response (PR) compared with those who showed no response (NR) to cytotoxic T-cell (CTL) therapy (Log-rank test; P=0.018).Our clinical trial showed allogeneic T-cell therapy for PTLD to be safe and effective in the short term, and this 4- to 9-year follow-up data are important in showing that, although of indeterminate life-span in vivo, CTL induces long-term remission of PTLD in patients with refractory disease. Therefore, it seems appropriate to use this therapy early in PTLD and for prophylaxis in high-risk cases. We are generating a new bank of clinical-grade EBV-specific CTL under good manufacturing practice conditions to provide partially matched CTL internationally on a not-for-profit basis, funded by The Wellcome Trust, UK. Tanzina Haque1 Karen A. McAulay2 Deirdre Kelly3 Dorothy H. Crawford2 1 Department of Virology Royal Free Hospital UCL Medical School London, United Kingdom 2 Clinical and Molecular Virology Laboratory University of Edinburgh Edinburgh, United Kingdom 3 Liver Unit Birmingham Children's Hospital Birmingham, United Kingdom

CLINICAL AND HISTOLOGIC RESPONSE TO METHYLPREDNISOLONE PULSE THERAPY IN GLOMERULONEPHRITIS

We retrospectively analyzed the data of the first and second renal biopsies to investigate the adverse effects as well as the clinical and histologic responses of methylprednisolone pulse therapy in patients with chronic glomerulonephritis. At the time of the second renal biopsy, the activity index had decreased significantly and the chronicity index was well preserved. The activity index and interstitial fibrosis were improved in the complete and partial remission groups, but not in the nonresponse group. These findings indicate that methylprednisolone pulse therapy is effective in patients with chronic glomerulonephritis and has an acceptably low risk of side effects.

Partial remission indicates poor functioning and a high level of psychiatric symptoms: A 3-phase 6-year follow-up study on major depression

Patients with depression in partial remission are at high risk of relapse, but factors associated with being in this outcome group are not well known. We conducted a clinical survey to examine the course of major depression in 87 patients during a follow-up period of 6 years. Beck Depression Inventory (BDI) scores indicated the outcome of depression, i.e. remission, partial remission or fully symptomatic, at 6, 12 and 24 months and after 6 years. The prevalence of partial remission varied from 16% to 23% at different follow-ups. All symptom and functioning scale scores indicated at every assessment that the partial depression group managed better than those in the fully symptomatic group, but worse than those in remission. Partial remission was associated with a significant impairment in psychosocial functioning and a high level of symptoms throughout the follow-up. The partial remission group must be recognized and actively treated.

Primary systemic therapy does not eradicate disseminated tumor cells in breast cancer patients

The presence of disseminated tumor cells in the bone marrow of breast cancer patients has proven to be an independent prognostic factor. The aim of this study was to investigate the status of tumor cell dissemination after primary systemic therapy in relation to therapy response. Bone marrow aspirates were obtained from 120 patients after completion of primary systemic therapy. Disseminated tumor cells were detected by immunocytochemistry using the APAAP method. Bone marrow status was correlated with clinicopathological factors as well as tumor response to primary systemic therapy. Sixty out of 120 patients had disseminated tumor cells in their bone marrow aspirates (50%). Response rates were 18% for pathologic complete remission, 52% for partial remission, 28% for no change and 3% for progression. Despite complete remission, 36% of these patients were bone marrow positive. In the partial remission group, the positivity rate was 48%. About 61% of patients with stable disease had disseminated tumor cells in their bone marrow. A trend to higher positivity rates was observed in the poor responder group compared to responders (61% vs. 38%, P = 0.1). Primary systemic therapy does not completely eradicate disseminated tumor cells in the bone marrow of breast cancer patients. The biological role of persistent disseminated tumor cells needs to be further investigated to optimize current and future therapeutic strategies.

The influence of adversity and perceived social support on the outcome of major depressive disorder in subjects with different levels of depressive symptoms

Adverse life events and social support may influence the outcome of major depressive disorder (MDD). We hypothesized that outcome would depend on the level of depressive symptoms present at the outset, with those in partial remission being particularly vulnerable. In the Vantaa Depression Study (VDS), patients with DSM-IV MDD were interviewed at baseline, and at 6 and 18 months. Life events were investigated with the Interview for Recent Life Events (IRLE) and social support with the Interview Measure of Social Relationships (IMSR) and the Perceived Social Support Scale - Revised (PSSS-R). The patients were divided into three subgroups at 6 months, those in full remission (n = 68), partial remission (n = 75) or major depressive episode (MDE) (n = 50). The influence of social support and negative life events during the next 12 months on the level of depressive symptoms, measured by the Hamilton Rating Scale for Depression (HAMD), was investigated at endpoint. The severity of life events and perceived social support influenced the outcome of depression overall, even after adjusting for baseline level of depression and neuroticism. In the full remission subgroup, both severity of life events and subjective social support significantly predicted outcome. However, in the partial remission group, only the severity of events, and in the MDE group, the level of social support were significant predictors. Adverse life events and/or poor perceived social support influence the medium-term outcome of all psychiatric patients with MDD. These factors appear to have the strongest predictive value in the subgroup of patients currently in full remission.

Patients en rémission partielle ou totale d’un Épisode Dépressif Majeur dans le cadre d’un trouble dépressif récurrent : description de la population incluse dans l’étude ÉCLAIR

Some guidelines and expert consensus consider the way of care management practices for the recurrent depressive disorder, particularly according to different identified risk factors for recurrence. But, few data are available about the way that these risk factors influence the care management of depressive recurrent patients during the partial or complete remission phase. Eclair study is a longitudinal observatory multicentric and national study, which describes the different risk factors that influence the psychiatrist decision about the following of patients suffering form Major Depressive Disorder (at least 3 Major Depressive Episode (MDE) according to DSM IV). This article presents the inclusion data (V0) of patients, with a focus on their demography characteristics and history of trouble, diagnosis, symptomatology evaluation (with CGI-S, HAM-D, Carroll scale and Sheehan scale) and Cloninger's personality questionnaire (TCI). A total of 596 patients with a recurrent depression either on partial remission (PaR) or complete remission (ToR) to their last episode at the selection, have been included. Complete remission was defined by the presence of a maximum of two criteria of MDE (according to DSM IV) excepted depressed mood and diminished interest or pleasure during at least two months with a HAM-D (17 items) score < 7 and partial remission was defined by the persistence of depressed symptoms but not sufficient to complete a diagnosis of MDE (according to DSM IV) associated with a HAM-D (17 items) score between 8 and 13 included. Mean HAM-D scores at V0 were 10.3 +/- 1.6 for PaR group and 4.0 +/- 1.9 for the ToR group. Free time since last episode was 6.5 +/- 10.5 months in ToR group and 11.2 +/- 16.9 months in PaR group (n = 385). Residual symptomatology between prior episodes was systematically present for 47.6% patients in PaR group, and for 26.7% patients ToR group. The feel to have a stressful daily life persisted for 62.5% of patient in PaR group and 34.3% in ToR group; 70.3% patients in PaR group and 57.9% patients in ToR group reported persistence of causal factor. The main collected risk factors for recurrence were the number of prior depressive episodes (64.9%), familial conflict existence (52.9%) and recent events of life (45.1%). In the TCI, a significant difference in comparison with the French normative data has been found for 3 dimensions: Harm Avoidance, Cooperativeness and Self-Directedness. Some differences were obtained for Novelty Seeking, Reward Dependence, and Self-Transcendence, but without sufficient clinical significance.This study confirms various characteristics about the unipolar depressive disorder, particularly the high risk of recurrence in patients with high number of previous episodes. In the research of predictive depressive recurrence signs, it would be interesting to focus on discriminating elements between complete remitted patients and partial remitted patients.

Is the type of remission after a major depressive episode an important risk factor to relapses in a 4-year follow up?

Background: Rates of relapse and predictive relapse factors were studied over more than 4 years in a sample of Spanish outpatients with DSM-III-R criteria for unipolar major depressive episode. Methods: A final sample of 139 outpatient was followed monthly in a naturalistic study. The Structured Clinical Interview for DSM-III-R was used. Phases of evolution were recorded using the Hamilton Depression Rating Scale, applying the Frank criteria. Survival analysis, Kaplan-Meier product limit and proportional hazards models were used. Results: A higher rate of relapses was observed in the partial remission group (91.4%) compared to the complete remission one (51.3%). The four factors with predictive relapse value were: “partial remission versus complete remission”, “the intensity of clinical symptoms”, “the age” and “the number of previous depressive episodes”. The existence of partial remission was the most powerful predictive factor. Limitations: The decreasing sample size during the follow-up and the difficulty in warranting the treatment compliance. Conclusions: At medium term, relapse rates for a major depressive episode are high. Partial remission after a depressive episode seems to be an important predictive factor for relapses in a 4-year follow-up. Clinical relevance: Not reaching complete remission is a strong risk factor for relapses in a 4-year follow up study.

Attention Deficit Hyperactivity Disorder (ADHD) in personality disordered offenders and the association with disruptive behavioural problems

In this study the authors aim to establish the proportion of personality disordered patients that meet screening criteria for adult ADHD, and examine whether they are more disruptive and present with greater behavioural problems in hospital compared with a Non-ADHD Symptomatic personality disordered group. ADHD symptomology was assessed using two screening measures: (1) the Wender-Utah Rating Scale (WURS) measuring childhood symptoms, and (2) the DSM-IV Checklist of Symptoms measuring symptoms in adulthood. Behavioural problems were examined by a specially designed questionnaire administered to the participants' primary nurse and critical incidents recorded in participants' medical records. The participants were 69 males who were legally detained in hospital with a primary diagnosis of personality disorder. Fifty-four (78%) participants obtained scores consistent with a diagnosis of ADHD in childhood, but only three (6%) of them were likely to meet DSM-IV criteria for adult ADHD. Twenty (29%) of adults were classified in partial remission. The ADHD and the partial remission groups were compared with the non-ADHD and in remission groups. The symptomatic group had a significantly greater number of critical incidents of aggression than the non-symptomatic group recorded in their medical files, but there was no significant difference of staff perception of disruptive behaviour and social problems. The clinical implications of the findings are discussed in terms of how treatment for their ADHD symptoms may have a positive impact on the behavioural problems presented by this population and their long-term outcome.

Relapse of major depression after complete and partial remission during a 2-year follow-up

Background: Rates of remission and relapse were studied over more than 2 years in a sample of Spanish outpatients with DSM-III-R criteria of unipolar major depressive episodes. Methods: Patients were treated following standardised pharmacological protocols at our centre. In the first visit, the structured clinical interview for DSM-III-R (SCID) was used. The following visits were held monthly. Phases of evolution were recorded using the Hamilton Depression Rating Scale (HDRS), applying the Frank criteria. Results: A significantly greater proportion of relapse was observed in the partial remission group compared to the complete remission one. The rate of relapses for patients in complete remission was 15.18%, while for patients in partial remission was 67.61%. Partial remission was significantly associated with relapses. Limitations: The short duration of the study and the decreasing sample size during the follow-up. Conclusions: Partial remission after a depressive episode seems to be strongly associated with relapses. Moreover, this clinical factor could by itself fully predict short-term relapses. Clinical relevance: The study shows the importance of reaching complete remission to decrease the rate of short-term relapses.

Anti-CD20 antibody therapy is highly effective in the treatment of follicular lymphoma

A group of French researchers have found that rituximab (a chimeric anti-CD20 monoclonal antibody) is an effective first-line therapy in follicular lymphoma patients with a low tumor burden. The multicenter trial, led by Dr Philippe Solal-Celigny from Centre Jean Bernard in Le Mans, looked at rates of molecular and clinical remission in 50 previously untreated patients following four weekly intravenous infusions of rituximab. All patients completed the course of treatment and experienced only mild toxicity. A month after the last infusion, 36 of 49 patients showed a positive response, of whom ten were in complete remission, three were in unconfirmed complete remission and 23 were in partial remission. However, during the first year after treatment, disease progression was found in one patient in the complete remission group, nine patients in the partial remission group and five patients with stable disease. At the molecular level they found that 17 of 30 patients were negative for the bcl-2-(J)H rearrangement in peripheral blood and nine of 29 tested negative in bone marrow, one month after treatment. The molecular response was maintained in 16 of 26 patients, one year after treatment. The investigators conclude that, ‘Rituximab, as a single agent, induces a molecular response rate that has not been reported with any other cytotoxic agent.’ It is hoped that larger Phase III trials will be undertaken, possibly in combination with other forms of chemotherapy. Blood (2001) 97, 101–106 HM

Intensive Therapy with Autologous Stem Cell Transplantation as First-Line Therapy in Poor-Risk Hodgkin's Disease and Analysis of Predictive Factors of Outcome

The value of high-dose therapy with autologous stem cell transplantation as first-line therapy in poor prognosis Hodgkin's disease is controversial and we report the results of evaluation of twenty-six patients who were selected for this procedure from February 1989 to July 1994. They were all patients with stage IV at diagnosis with at least two other unfavourable characteristics, i.e. B symptoms, mediastinal mass greater than 0.45 of the thoracic diameter, two or more extranodal sites, bone marrow involvement, inguinal node involvement, serum lactic dehydrogenase greater than 400 IU/L, or low hematocrit. At the time of transplantation, 19 patients were in complete remission and 10 were in partial remission 50%. Procedure-related mortality in the first 90 days post-graft was 7% overall. Of the 24 evaluable patients, 22 (92%) were assessed as complete responders, and 2 (8%) had progression of disease at 6 months. The actuarial overall survival (OS), disease-free survival (DFS) and event-free survival (EFS) at 5 years were 69%, 79% and 58%, respectively. The Cox proportional hazards model was used to assess prognostic factors. In univariate analysis only one prognostic factor was found to be significantly associated with improved DFS, i.e. low serum lactic dehydrogenase (LDH) (DFS at 5 years : 92% if LDH < 400 IU/L vs 44% if LDH 400 IU/L, P = 0.007). DFS rates between first complete remission and first partial remission groups were not significantly different (DFS at 5 years: 87% vs 66%, p = 0.15). These first results are encouraging but randomized studies are needed.

Antiinflammatory and immunoregulatory action of methotrexate in the treatment of rheumatoid arthritis: Evidence of increased interleukin‐4 and interleukin‐10 gene expression demonstrated in vitro by competitive reverse transcriptase‐polymerase chain reaction

Objective To look for in vitro modulation of the main immunoregulatory and antiinflammatory cytokines by methotrexate (MTX) during the course of rheumatoid arthritis (RA). Methods We quantified interleukin-2 (IL-2), IL-4, IL-10, and interferon-γ (IFNγ) gene expression by peripheral blood mononuclear cells ex vivo under basal conditions and in vitro after stimulation with phytohemagglutinin (PHA) or PHA plus MTX, by competitive reverse transcriptase-polymerase chain reaction (RT-PCR), in 12 patients with untreated active RA (group 1), 10 patients with MTX-treated disease in partial remission (group 2), and 11 healthy control subjects. Simultaneously, under the same experimental conditions, we quantified cytokine production by specific enzymelinked immunosorbent assays (ELISAs). Results Under basal conditions, we found no differences in IL-2, IL-10, and IFNγ gene expression in the 3 groups, while IL-4 gene expression was significantly decreased in RA patient group 1 compared with the control group. In vitro, under the action of MTX, IL-10 gene expression was significantly increased in the 3 groups, IL-4 gene expression was significantly increased in RA group 1 and in the control group, and IL-2 and IFNγ gene expression was significantly decreased in RA group 1. Cytokine gene expression assessed by RT-PCR and cytokine production assessed by specific ELISAs were highly correlated. Conclusion In vitro modulation of the cytokine network by MTX, increasing Th2 cytokines and decreasing Th1 cytokines, could explain its antiinflammatory and immunoregulatory actions in vivo during the treatment of RA.

Anti-Leukemia Chemotherapy of High-Risk Myelodysplastic Syndromes

We evaluated the outcome of anti-leukemia chemotherapy on 42 patients with the high-risk myelodysplastic syndromes (MDS)-refractory anemia with excess of blasts (RAEB), 8 cases; RAEB in transformation (RAEB-T), 18 cases; chronic myelomonocytic leukemia (CMMOL), 6 cases; and leukemic transformation of MDS, 10 cases. The median age was 67 (range 20 to 84). As a remission-induction therapy, 35 patients received low-dose chemotherapy, such as low-dose cytarabine infusion, and seven patients received high-dose combination chemotherapy. The complete remission (CR) rates of the low-dose chemotherapy group and the high-dose combination chemotherapy group were 29% and 57%, respectively, and the overall CR rate was 33%. The median survival durations after induction chemotherapy of the CR group (14 cases), the partial remission (PR) group (11 cases), and non-remission (NR) group (17 cases) were 19 months, 8 months, and 3 months, respectively. As a post-remission consolidation chemotherapy, high-dose combination chemotherapy seemed to be superior to low-dose chemotherapy judging from the median CR duration (16 months versus 4 months), but a long-term disease-free survival is hardly expected, in contrast with results in cases of de novo acute myeloid leukemia.

CA-125 in ovarian cancer: Relation between half-life, doubling time and survival

In a retrospective study of 35 patients with stage III–IV ovarian cancer, the probability to reach a complete (CR) or partial remission (PR) was studied by comparing the initial level, half-life and normalisation time of CA-125 during chemotherapy. In 15 CR patients, pretreatment CA-125 level was lower (70 U/l, range 16–1500 U/l) than in 20 PR patients (800 U/l, range 60–9000 U/l). The median normalisation time (NT) was 6 weeks in CR (range 0.7–5.5 months) and 4 months in PR patients (range 1.2–9 months). Marker half-life was 12 days for the CR group (range 4.5–30 days) and 21 days for the PR group (range 5.5–39 days). Remission duration ( r = 0.56) and log cell kill ( r = 0.72) were correlated with survival. Combining initial tumour diameter, marker level and NT predicted CR in 87.5% and PR in 86%. Estimating log cell kill by combining marker half-life and doubling time gives more insight into tumour cell kinetics and individual survival.

High-dose chemoradiotherapy with bone marrow transplantation as consolidation treatment in neuroblastoma: an unselected group of stage IV patients over 1 year of age.

Since January 1983, 56 consecutive children over 1 year of age with stage IV neuroblastoma entered an aggressive protocol, including chemotherapy, radiation therapy, and bone marrow transplantation. The induction protocol included platinum and epipodophyllotoxin (VM-26), alternating with cyclophosphamide, Adriamycin (Adria Laboratories, Columbus, OH), and vincristine (PE/CADO). Surgery was performed after 2 to 4 months, and consolidation with intensive chemoradiotherapy and bone marrow transplantation (BMT) was performed within 12 months of diagnosis. The combination of vincristine, melphalan and total body irradiation (TBI) was used before BMT, and no further treatment was administered before progression. With the exception of two allografts, autologous BMT (ABMT) was given in all cases and was purged using an immunomagnetic procedure (Kemshead technique) in 32 of 35 cases, and a chemical procedure in three of 35. Of the 56 patients, 45 were evaluable. Of those, 23 were grafted in partial remission (PR), and 14 were grafted in either complete remission (CR) or very good partial remission (VGPR). The acute toxic death rate was 19%, the relapse rate was 32%, and the progressive disease rate was 19%. The progression-free survival in the CR/VGPR group (ie, 44% at 32 months post-diagnosis) and in the PR group (13% at 32 months) was not significantly different (P greater than .05). At 24 months, the overall survival of the 56 unselected patients was 39% compared with 12% for comparable patients previously treated by our group (P less than .005).

Failure of conventional chemotherapy in aggressive lymphomas

Between 1975 and 1982 in 2 centres in Glasgow, 53 previously untreated patients with aggressive non-Hodgkin's lymphomas received chemotherapy consisting of one of the following regimens-CVP, MOPP, CHOP or BACOP. Twenty nine patients (55%) entered complete remission (CR), 20 (38%) had partial remission (PR) and 4 (7%) had progressive disease (PD). Of the 29 patients in CR, 9 have relapsed and died, 5 died of infection, 4 died of non-malignant causes, and 11 (21%) remain alive and disease free. The median survival for the CR group is 40 months. All of the patients in the PR and PD group are dead, median survival 11 months. These chemotherapy regimens will cure only the minority of patients with aggressive lymphomas and the use of more intensive regimens is indicated.

Induction and maintenance of remission in acute leukemia. Effectiveness of combination therapy in 227 patients.

A total of 227 patients—124 with acute lymphoblastic leukemia (ALL) and 103 with acute myeloblastic leukemia (AML)—have been studied in order to evaluate the therapeutic effectiveness of vincristine, daunorubicin, and prednisone for induction followed by consolidation courses every 6 months with these drugs and either 6-mercaptopurine and methotrexate (plan A) or methotrexate alone (plan B) for maintenance of remission. In ALL, complete remission (CR) was achieved in 90.2% of untreated and 71.6% of previously treated patients. In AML, 34.8% untreated and 23.5% previously treated patients obtained CR. There was no statistically significant difference between the two maintenance regimens. Median duration of hematologic remission in ALL was 16 months and that of complete remission terminating in either meningeal, visceral, or bone marrow relapse was 9 months. Median survival was 18.2 months. In AML, the median survival was 11.8% months for those that achieved CR, 4.2 months for the partial remission (PR) group, and 0.9 months for nonresponders.