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PubMed1994

Intensive therapy with cyclophosphamide, carmustine, etoposide +/- cisplatin, and autologous bone marrow transplantation for Hodgkin's disease in first relapse after combination chemotherapy.

The optimal timing in which to use intensive chemotherapy and autologous bone marrow transplantation (BMT) in Hodgkin's disease (HD) is uncertain. In 1985, we initiated a program in which this modality was used as the initial salvage therapy in patients relapsing after combination chemotherapy. Fifty-eight patients with HD in first relapse after primary chemotherapy received conditioning with high-dose cyclophosphamide, carmustine, etoposide (VP16-213) +/- cisplatin (CBV +/- P) followed by autologous BMT. All but six of these patients were given a median of two cycles of conventional chemotherapy +/- involved field radiation therapy before CBV +/- P and autologous BMT. These measures were not used as a means for patients selection; all patients receiving such therapy ultimately were transplanted. The probability of nonrelapse mortality, progression of HD, and progression-free survival post-BMT were calculated, and prognostic factors for progression-free survival were evaluated using the Cox proportional hazards method. Treatment-related deaths occurred in only three patients. Thirteen patients have relapsed at a median 0.7 years (range 0.1 to 3.5) post-BMT. At a median follow-up of 2.3 years (range 0.4 to 7.2), the actuarial progression-free survival is 64% (95% confidence interval, 46% to 78%). In the statistical analysis, three similarly weighted but independent prognostic factors were identified: "B" symptoms at relapse, extranodal disease at relapse, and initial remission duration of less than 1 year. Patients with no risk factors had a 3-year progression-free survival of 100%, compared with 81% in patients with one factor, 40% in those with two factors, and 0% in patients with all three factors. CBV +/- P and autologous BMT is highly effective salvage therapy for HD patients in a first relapse, particularly in the subset of patients with less than two adverse factors. Therapy must be improved in the future for patients with > or = 2 adverse factors.

Adolescent↗

PubMed1994

[Relapse of acute leukemia after allogeneic bone marrow transplantation].

The relapses of 45 acute leukemia patients who underwent allogeneic bone marrow transplantation between April 1976 and February 1992 were analyzed clinically. The relapse rates of acute nonlymphocytic leukemia (ANLL) and acute lymphocytic leukemia (ALL) were 4/26 (15%) and 9/19 (47%), respectively. Although multivariate analysis could not be done, a high frequency of leukemia relapse was significantly associated with ALL, a younger age, history of extramedullary leukemia and blood-type identity. Chromosomal abnormalities at diagnosis, interval from diagnosis to bone marrow transplantation (BMT) and graft-versus-host disease (GVHD) prophylaxis were likely to be predictive of relapse. On the other hand, neither stage of leukemia at BMT, acute GVHD, sex, nor WBC count at diagnosis was a predictive factor. Eight of 10 relapsed patients achieved complete remission posttransplant, but the duration of remission was only 138 days on average. Four second BMT procedures for relapsed leukemia were carried out but were associated with many complications. However, one is alive well over 6 years after the second transplantation. There is a high treatment-related mortality following second BMT, but there is some possibility of long survival in some patients.

Adolescent↗

PubMed1993

Cyclosporin versus cyclophosphamide for patients with steroid-dependent and frequently relapsing idiopathic nephrotic syndrome: a multicentre randomized controlled trial.

OBJECTIVE: To compare the efficacy (maintenance of remission), safety and tolerability of cyclosporin (CsA) with those of cyclophosphamide in patients with steroid-dependent or frequently relapsing nephrotic syndrome (NS). DESIGN: Open, prospective, randomized, multicentre, controlled study for parallel groups, stratified for adults and children. The setting was in nephrological departments in Italy. SUBJECTS AND INTERVENTIONS: Seventy-three patients with steroid-sensitive idiopathic NS admitted to the study were randomly assigned to cyclophosphamide (2.5 mg/kg/day) for 8 weeks or CsA (5 mg/kg/day in adults, 6 mg/kg/day in children) for 9 months, tapered off by 25% every month until complete discontinuation at month 12. Seven patients lost to follow up were not considered in the analysis. The remaining 66 patients were followed up for 3-24 months after randomization. MAIN OUTCOME MEASURES: Relapse-free survival; number of N.S. relapses/patient/year; cumulative dose of prednisone/patient; laboratory investigations (kidney and liver functions, haematological parameters); incidence of adverse events. RESULTS: At month 9, 26 of 35 CsA-treated patients were still in complete remission and a further five patients were in partial remission; 18 of 28 cyclophosphamide-treated patients were in complete remission, and one in partial remission (P = NS). No difference between adults and children was seen with either treatment. The risk of relapse was similar between frequent relapsers (19 of 22) and steroid-dependent patients (8 of 14) given CsA, and those given cyclophosphamide (5 of 15 and 6 of 15). The mean number of relapses per year and the mean dose of prednisone per year were significantly less (P < 0.001) in both groups for the experimental year than for the year before randomization. At 2 years, 25% of the patients given CsA (50% adults and 20% children) and 63% of those given cyclophosphamide (40% adults and 68% children) had not had any relapse of NS. Tolerance to the two drugs was generally good. The CsA-related side-effects were mild and disappeared after drug discontinuation. CONCLUSIONS: This study shows that both treatments are effective and well tolerated; more patients given cyclophosphamide had stable remissions.

Adolescent↗

PubMed1979

Alternate-day versus intermittent prednisone in frequently relapsing nephrotic syndrome. A report of "Arbetsgemeinschaft für Pädiatrische Nephrologie".

23 children with frequently relapsing minimal-change nephrotic syndrome were treated with alternate-day prednisone (35 mg/m2/48 h) and 25 other patients were treated with intermittent prednisone (40 mg/m2 on three consecutive days out of seven) for six months. This was followed by six months without any maintenance steroid treatment except when relapse required a short period of prednisone therapy until remission. The number of relapsers was significantly lower on alternate-day than on intermittent treatment. In the alternate-day group, the number of relapsers and the rate of relapse was significantly less before treatment withdrawal; in the intermittent group, only the number of relapsers was reduced. An alternate-day regiment is therefore preferable to the intermittent regimen in the interrupted steroid treatment of children with nephrotic syndrome.

Adolescent↗

PubMed1993

Treatment of late bone marrow relapse in children with acute lymphoblastic leukemia: a Pediatric Oncology Group study.

Children with acute lymphoblastic leukemia (ALL) who have completed 2.5 to 3 years of initial chemotherapy have an off-therapy relapse rate of approximately 20%. In an attempt to improve the survival of children with a late bone marrow (BM) relapse (ie, occurring greater than 6 months after cessation of primary therapy), the Pediatric Oncology Group designed a randomized study to compare the efficacy of doxorubicin/prednisone and cytarabine/teniposide in a multidrug retreatment chemotherapy program. Treatment consisted of remission reinduction with vincristine, prednisone, and doxorubicin, central nervous system prophylaxis with triple intrathecal chemotherapy, and continuation therapy (for 132 weeks) with alternating cycles of oral 6-mercaptopurine/methotrexate and intravenous vincristine/cyclophosphamide. Patients received intermittent courses of either prednisone/doxorubicin (regimen 1) or teniposide/cytarabine (regimen 2) during continuation therapy and a late intensification phase with either vincristine, prednisone, and doxorubicin (regimen 1) or teniposide and cytarabine (regimen 2). One hundred two of 105 evaluable patients (97%) achieved a second complete remission. Twenty-eight of 50 patients on regimen 1 have failed compared with 28 or 52 patients on regimen 2 (log-rank analysis, P = .68), indicating that this trial was inconclusive as to which treatment regimen was superior. The overall 4-year event-free survival for children with a late BM relapse was 37% +/- 6%. Age less than 10 years at initial diagnosis (P < or = .001), white blood cell count less than 5,000/microL at relapse (P = .036) and duration of first remission greater than 54 months (P = .039) were independently associated with a more favorable outcome. While the randomized trial was inconclusive, prolonged second complete remissions were secured in more than one-third of children with a late BM relapse of ALL. The prognostic factors identified may help select children with a late BM relapse who can be successfully retreated with chemotherapy alone.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1993

[Testicular relapse, with Ph-positive chromosome after bone marrow transplantation for acute lymphocytic leukemia].

A 25-year-old man with acute lymphocytic leukemia (ALL) had received bone marrow transplantation (BMT). Testicular relapse occurred 6 months after BMT as the first relapse, and couple of weeks later, bone marrow relapse developed. At that time, karyotypic analysis showed Ph-chromosome which was not observed before the first remission and DNA analysis revealed rearrangements of minor BCR, IgL, IgH, TCR and TCR genes. Testicular relapse often develops in ALL of children after BMT. However, some reports, including this report, indicate that testicular relapse following BMT can also occur in adults, so that the incidence of testicular relapse could be reduced either by total body irradiation (TBI) or testicular irradiation before transplantation. Incidence of Ph-positive chromosome following BMT is a key to illuminate the mechanism of the Philadelphia chromosome. Rearrangements of Ig and TCR gene can be considered as an abnormal gene rearrangement occurring at an early stage of B cell proliferation.

Adult↗

PubMed1993

Detection by polymerase chain reaction of residual cells with the bcl-2 translocation is associated with increased risk of relapse after autologous bone marrow transplantation for B-cell lymphoma.

Although molecular biologic techniques can now detect minimal numbers of residual cancer cells in patients in complete clinical remission, the clinical significance of minimal residual disease has never been conclusively established. If the detection of minimal residual disease predicts which patients will relapse, then therapy could be altered based upon the detection of these cells. The t(14;18) can be detected by polymerase chain reaction (PCR) amplification in 50% of patients with B-cell non-Hodgkin's lymphoma and allows detection of one lymphoma cell in up to 1 million normal cells. To determine the clinical significance of the detection of minimal residual lymphoma cells in the bone marrow (BM) PCR amplification was used to detect the presence of residual lymphoma cells after autologous BM transplantation (ABMT) in serial BM samples from 134 patients with B-cell lymphoma in whom a bcl-2 translocation could be detected. PCR analysis was performed on a total of 542 BM samples obtained while these patients were in complete remission. Disease-free survival was markedly increased in patients with no PCR-detectable lymphoma cells in the marrow compared with those in whom residual lymphoma cells were detected (P < .00001), and the presence of detectable lymphoma cells was associated with a 48-fold increase in the risk of relapse. Of the 77 patients (57%) with no PCR-detectable lymphoma cells in their most recent BM sample, none have relapsed. In contrast, all 33 patients (25%) who have relapsed had PCR-detectable lymphoma cells detected in their BM before clinical relapse occurred. In 19 patients (14%), residual lymphoma cells in the BM were detected early following transplantation and subsequently were no longer detectable, although these patients received no further therapy. In these patients, residual lymphoma cells may already have been irreversibly damaged by the high-dose therapy or an endogenous immune mechanism may be capable of eliminating residual lymphoma cells in some patients. Therefore, although the detection of minimal residual disease by PCR following ABMT in patients with lymphoma identifies those patients at high risk of relapse, the presence of residual minimal disease early after transplantation may not be associated with poor prognosis in a small subset of patients. Confirmatory studies will be required to determine more definitively the role of minimal disease detection to identify which patients require additional therapy.

Bone Marrow Purging↗

PubMed1995

Treatment of relapsing experimental autoimmune encephalomyelitis in rats with allogeneic bone marrow transplantation from a resistant strain.

We previously showed that relapsing experimental autoimmune encephalomyelitis (R-EAE) in BUF rats, a model for multiple sclerosis, responds favorably to treatment with TBI and syngeneic BMT. Relapses of paresis occurred less frequently than in untreated controls, but were not completely prevented. Therefore, we investigated the effect of allogeneic BMT from the resistant WAG rat strain. BUF rats were treated with either high-dose TBI or CY and Bu followed by allogeneic BMT. This treatment induced complete remission, and reduced both the spontaneous and induced relapse rate more efficaciously than syngeneic BMT. Evidence is provided that a subclinical GVHR contributes to the prevention of spontaneous relapses. The almost complete absence of induced relapses likely results from the repopulation by the resistant immune system of the donor, which proved to be functional by responding to immunization with type II collagen. It is thus unlikely that a BMT-related immunodepression contributed to the lower incidence of induced relapses. We propose that allogeneic BMT should be considered for the treatment of severe progressive MS with a poor prognosis.

Animals↗

PubMed1996

Minimal residual disease may predict bone marrow relapse in patients with hairy cell leukemia treated with 2-chlorodeoxyadenosine.

Minimal residual disease (MRD) can be detected in bone marrow core biopsies of patients with hairy cell leukemia (HCL) after treatment with 2-chlorodeoxyadenosine (2-CdA) using immunohistochemical (IHC) techniques. The purpose of this study was to determine whether the presence of MRD predicts bone marrow relapse. We studied paraffin-embedded bone marrow core biopsies from 39 patients with HCL in complete remission (CR) 3 months after a single cycle of 2-CdA. Biopsies performed 3 months posttherapy and annually thereafter were examined by routine hematoxylin and eosin (H&E) staining and IHC using the monoclonal antibodies (MoAbs) anti-CD45RO, anti-CD20, and DBA.44. At 3 months after therapy, 5 of 39 (13%) patients had MRD detectable by IHC that was not evident by routine H&E staining. Two of the five patients (40%) with MRD at 3 months have relapsed, whereas only 2 of 27 (7%) patients with no MRD and at least 1 year of follow up relapsed (P = .11). Over the 3-year follow-up period, two additional patients developed MRD. Overall, three of six (50%) patients with MRD detected at any time after therapy have relapsed, whereas only 1 of 25 (4%) patients without MRD has relapsed (P = .016). These data suggest that the presence of MRD after treatment with 2-CdA may predict relapse.

Antibodies, Monoclonal↗

PubMed1996

Remission with carbimazole therapy & assessment of T4 suppression test as an index of relapse in patients with Graves' disease in India.

This study determined the relapse rate following the use of antithyroid drugs (ATD) in patients with Graves' disease and assessed T4 suppression test as a follow up index for predicting relapse after carbimazole treatment in 21 patients who had taken 9-12 months of ATD treatment continuously with good compliance. T4 suppression test was done before stopping ATD treatment. During one year of follow up after stopping ATD therapy, 12 (57%) patients relapsed and 9 (43%) remained in remission. Six of the 12 relapses occurred in the first 3 months of stopping ATD therapy. The response following the use of carbimazole therapy was comparable to that reported from iodine sufficient western countries and may be because of the salt iodination programme in our country. T4 suppression test was normal in 14 (66%) and abnormal in 7 (34%) patients. All the patients with abnormal T4 suppression test relapsed after stopping ATD. The overall accuracy of the T4 suppression test (76%) also favourably compared with reported values of other useful but less readily available markers such as thyrotropin releasing hormone (TRH) stimulation test and thyroid receptor antibodies. Thus, in our experience antithyroid drugs were able to induce long term remission in 43 per cent patients with Graves' disease and abnormal T4 suppression test can be used as a reliable parameter for predicting relapse.

Adult↗

PubMed1996

Clinical and laboratory studies of 2-chlorodeoxyadenosine +/- cytosine arabinoside for relapsed or refractory acute myelogenous leukemia in adults.

Previous studies in pediatric patients with acute myelogenous leukemia (AML) have suggested that 2-chlorodeoxyadenosine (2CdA) is an effective therapeutic agent. Santana et al (J Clin Oncol 1992; 10: 364-370) reported a CR rate of 8/17 (95% Cl 23-72%) in children with relapsed AML and a median first CR of 21 months. The activity of 2CdA in adults with relapsed or refractory leukemia was therefore investigated in a phase I study. In the phase II study, based on biochemical modulation rationale, 2CdA was combined with Ara-C for adults with relapsed AML to test the effectiveness of this combination therapy. In the phase I study 27 patients (25 AML and two MDS) with a median first CR duration of 21 weeks, received 2CdA at doses ranging from 5 to 13 mg/m2/day by continuous infusion (CI) for 7 days. In vitro and ex vivo pharmacologic studies performed to determine the effect of pretreatment with 2CdA on Ara-CTP accumulation in leukemic blasts demonstrated a 50-65% increase in the rate of Ara-CTP accumulation. Based on this biochemical modulation, 2CdA (12 mg/m2/day x 5 days by CI) was combined with Ara-C (1 g/m2/day over 2 h) in a phase II study. Seventeen patients (15 AML, two MDS) with relapsed AML (median 1st CR of 19 weeks) were treated. In the phase I study two patients died before the day 14 marrow (ED). Marrow hypoplasia developed in 16 of the remaining 25. Leukemic regrowth occurred in nine after a median hypoplastic period of 2 weeks (range 1-3 weeks). The other seven patients died with aplastic marrows, median duration of hypoplasia was 2 weeks, range 1-4 weeks. None achieved CR and the median survival was 10.5 weeks. Toxicity generally was mild except for three late occurring cases of grade III or IV renal dysfunction and two cases of tumor lysis syndrome. The MTD was 10.8 mg/m2/day x 7 days. In the phase II study two patients, both with AML, achieved CR (95% CI 1-33%). In both cases leukemia relapsed after 10 weeks and 17 weeks. There was one ED. Most (11/16) cleared their marrow although leukemic infiltrate regrew in six cases. Toxicity was generally mild, with two episodes of grade 2 GI bleeding, one episode of severe renal dysfunction and one case of grade 2 CNS toxicity. We conclude that as a single agent 2CdA at the MTD is a cytoreductive agent but is not sufficient to achieve CR in adults with relapsed AML. While combination of Ara-C with 2CdA increases the Ara-CTP uptake in these heavily treated patients this regimen does not appear to be an improvement over existing modalities.

Adult↗

PubMed1996

The reliability of Marlatt's taxonomy for classifying relapses.

Marlatt's focus on the relapse situation has had a major impact upon research and clinical practice in treating addictions. One component of his work was the development of a taxonomy for classifying precipitants of relapse. This taxonomy has been incorporated into the nomenclature of clinicians and clinical researchers as part of an explanatory framework for understanding relapses. Despite the taxonomy's influence it has never been examined for the reliability of its use across research studies. The present study compared the reliability of independent classifications of 149 relapse episodes by trained raters at three research laboratories. Despite considerable across-laboratory training, reliability was found to be inconsistent for research purposes. It is concluded that comparability of results based on Marlatt's relapse taxonomy across independent studies must be subject to question, and assumptions necessary for the aggregation of a knowledge base are not supported. Recommendations are offered for improving the reliability of the taxonomy and the methods used to collect taxonomy data. More generally, questions regarding the value of the specific relapse categories, as well as the overall taxonomy, are raised.

Adult↗

PubMed1998

TEL-AML1 fusion transcript in relapsed childhood acute lymphoblastic leukemia. The Berlin-Frankfurt-Münster Study Group.

The cryptic translocation t(12;21)(p13;q22) has been recently recognized as the most common genetic rearrangement in B-lineage childhood acute lymphoblastic leukemia (ALL). The resulting fusion transcript, termed TEL-AML1, has been associated with an excellent prognosis at initial ALL diagnosis. Hence, we postulated that the incidence of TEL-AML1 fusion should be lower in patients with ALL relapse. To address this assumption and to investigate the prognostic significance of TEL-AML1 expression in relapsed childhood ALL, bone marrow samples of 146 children were analyzed by reverse-transcriptase (RT)-polymerase chain reaction (PCR). All children were treated according to Berlin-Frankfurt-Münster (BFM) ALL relapse trial protocols (ALL-REZ BFM 90-96). Their clinical features and outcome were compared with those of 262 patients who could not be tested due to lack of bone marrow samples. Thirty-two of 146 children with relapsed ALL were TEL-AML1-positive. Four of the negative patients had T-lineage and nine Philadelphia chromosome (Ph)-positive leukemia. Thus, the incidence of TEL-AML1 in relapsed Ph1-negative, B-cell precursor ALL is 32 of 133 (24%). The 32 TEL-AML1-positive and 101 negative patients differed significantly with respect to duration of last remission (42.5 v 27 months; P = . 0001) and age at initial diagnosis (53.5 v 74 months; P = .0269). At a median follow-up time of 21.5 months, children positive for TEL-AML1 had a significantly (P = .0011) higher probability of event-free survival (EFS; 0.79 v 0.33). The predominant majority of patients had been treated for initial ALL according to German multicenter BFM (108 of 133) or Cooperative ALL study group (CoALL) (19 of 133) frontline protocols. The comparison of tested and not-tested (N = 262) patients showed no significant difference. TEL-AML1 positivity predicted a favorable short-term outcome; long-term results are unknown. Screening for TEL-AML1 should become routine at relapse diagnosis and might be used for therapy stratification in future trials.

Adolescent↗

PubMed1997

[Analysis of in-field and marginal relapse in stage I/II non-Hodgkin's lymphoma treated with radiotherapy].

One hundred sixty-three patients with previously untreated stage I/II non-Hodgkin's lymphoma were analyzed as to their in-field and marginal relapse of the irradiated field following treatment with more than 30 Gy of radiotherapy between 1981 and 1995 at Hyogo Medical Center for Adults. Local regrowth in case of partial response was counted as in-field relapse. Complete response was obtained in 94.5% of the cases at the termination of radiotherapy and in 98.8% finally. The ten-year cumulative in-field relapse and marginal relapse rates were 5% and 8.7%, respectively. The cumulative in-field relapse rate (CIFRR) in cases of bulky disease (more than 5 cm in largest diameter of the tumor) was significantly higher than in those of non-bulky disease (26.1% in 8 years vs 2.4% in 10 years, P < 0.01). The radiation dosage delivered (40 Gy = < and 50 Gy > vs 50 Gy < =) a great much difference in cases of bulky disease (23.8% for 8-year CIFRR vs 0% for 1-year CIFRR, respectively), but less difference with non-bulky disease (2.6% vs 2.2%). High LDH and suboptimal dose chemotherapy (three courses and less chemotherapy containing ADM or its derivatives, chemotherapy without ADM or no chemotherapy) had a negative impact on marginal control in aggressive lymphoma. Extended field setting in aggressive lymphoma was not proven to be beneficial in comparison with involved field setting as to marginal field relapse. Thus, it is concluded that (1) higher doses should be given to bulky disease, (2) careful field coverage with enough margin is recommended for aggressive lymphoma with high LDH or treated without optimal dose chemotherapy, and (3) extended field setting is not necessary.

Adolescent↗

PubMed1998

A new combination of carboplatin, high-dose cytarabine and cross-over mitoxantrone or idarubicin for refractory and relapsed acute myeloid leukemia.

BACKGROUND AND OBJECTIVE: High-dose cytarabine (HIDAC) and new anthracycline-type drugs (mitoxantrone, idarubicin) are the mainstay of several active regimens against relapsed and refractory acute myeloid leukemia (AML). The present study was undertaken to assess the feasibility, toxicity, and antileukemic activity of carboplatin (CBDCA) added to a combination of the two former agents. DESIGN AND METHODS: Two regimens (R) of CBDCA plus HIDAC and either mitoxantrone or idarubicin (crossover) were sequentially evaluated. R-1 consisted of CBDCA 300 mg/m2/d (24-hour infusion) on days 1-4, HIDAC 1 g/m2/bd on days 1-5, and mitoxantrone/idarubicin 12/6 mg/m2/d on days 1-3, followed by granulocyte colony-stimulating factor (G-CSF). R-2, an attenuated-toxicity regimen, consisted of CBDCA and G-CSF as above, HIDAC on alternate days (1, 3, 5), and mitoxantrone/idarubicin 8/5 mg/m2/dose. Intended post-remission therapy included a similar, lower intensity course and a myeloablative phase supported by an allogeneic or autologous blood cell transplant. RESULTS: Twenty-nine patients (median age 53 years, one child) formed the study group: 10 (34%) had a primary refractory disease (8 to idarubicin-cytarabine-etoposide, ICE), 6 (21%) were at second or subsequent relapse, and 5 (17%) had a first remission lasting < 12 months. In addition, 4 patients (14%) had received prior HIDAC and 10 (34%) were relapsing after a bone marrow/blood cell transplant. Twelve patients were treated with R-1 and 17 with R-2. The complete response rate was 25% with R-1 and 53% with R-2, due to a significantly lower death rate by pancytopenic complications (p = 0.023). The probability of response by risk class was: primary refractory 30% (43% with R-2), > 2nd relapse 33% (50% with R-2), 1st relapse < 12 months 40% (50% with R-2), 1st relapse > 12 months 50% (75% with R-2), prior HIDAC 75%, and prior transplant 30% (33% with R-2). Seven patients could undergo an autologous (n = 5) or allogeneic (n = 2) bone marrow/peripheral blood cell transplant after one consolidation cycle. Overall survival was 4.2 months, significantly longer in responders (complete and partial: median 11 months) than non-responders (p < 0.001). Median duration of complete remission was 10 months and 2-year probability 0.31, but no patient remained disease-free at 3 years. INTERPRETATION AND CONCLUSIONS: R-2 was well tolerated, exerted a significant activity in high-risk AML, and is amenable to further improvements. However, the lack of long-term disease-free survivors indicates the need for innovative post-remission strategies.

Acute Disease↗

PubMed1998

Clonal diversity of Ig and T-cell-receptor gene rearrangements identifies a subset of childhood B-precursor acute lymphoblastic leukemia with increased risk of relapse.

Current prognostic indicators such as age, sex, and white blood cell count (WBC) fail to identify all children with more aggressive forms of B-precursor acute lymphoblastic leukemia (ALL), and a proportion of patients without poor prognostic indicators still relapse. Results obtained from an analysis of 65 pediatic B-precursor ALL patients indicated that subclone formation leading to clonal diversity, as detected by Ig and T-cell receptor (TCR) gene rearrangements, may represent a very useful prognostic indicator, independent of age, sex, and WBC. Disease-free survival was significantly shorter in those patients showing clonal diversity at presentation. Furthermore, clonal diversity was detected not only in the majority of high-risk patients who relapsed but was also associated with a high probability of relapse in standard-risk patients. Sixty-five percent (13/20) of standard-risk patients who also showed clonal diversity subsequently relapsed, whereas the percentage of relapses among standard-risk patients without clonal diversity was much lower at 19% (7/36). Continued clonal evolution during disease progression is an important feature of aggressive B-precursor ALL. All 5 patients with clonal diversity who were followed up in our study showed a change in the pattern of clonality between presentation and relapse. This implies an important role for clonal diversity as a mechanism of disease progression through the process of clonal variation and clonal selection.

Adolescent↗

PubMed1998

Leukemic cellular retinoic acid resistance and missense mutations in the PML-RARalpha fusion gene after relapse of acute promyelocytic leukemia from treatment with all-trans retinoic acid and intensive chemotherapy.

This study evaluated whether relapse of acute promyelocytic leukemia (APL) patients from clinical remissions achieved and/or maintained with all-trans retinoic acid (RA) in combination with intensive chemotherapy is associated with leukemic cellular resistance to RA and with alterations in the PML-RARalpha fusion gene. We studied matched pretreatment and relapse specimens from 12 patients who received variable amounts of RA, primarily in nonconcurrent combination with daunorubicin and cytarabine (DA) on Eastern Cooperative Oncology Group (ECOG) protocol E2491, and from 8 patients who received DA only on protocol E2491. Of 10 RA-treated patients evaluable for a change in APL cell sensitivity to RA-induced differentiation in vitro, 8 showed diminished sensitivity at relapse, whereas, of 6 evaluable patients treated with DA alone, only 1 had marginally reduced sensitivity. From analysis of sequences encoding the principal functional domains of the PML and RARalpha portions of PML-RARalpha, we found missense mutations in relapse specimens from 3 of 12 RA-treated patients and 0 of 8 DA-treated patients. All 3 mutations were located in the ligand binding domain (LBD) of the RARalpha region of PML-RARalpha. Relative to normal RARalpha1, the mutations were Leu290Val, Arg394Trp, and Met413Thr. All pretreatment analyses were normal except for a C to T base change in the 3'-untranslated (UT) region of 1 patient that was also present after relapse from DA therapy. No mutations were detected in the corresponding sequences of the normal RARalpha or PML (partial) alleles. Minor additional PML-RARalpha isoforms encoding truncated PML proteins were detected in 2 cases. We conclude that APL cellular resistance occurs with high incidence after relapse from RA + DA therapy administered in a nonconcurrent manner and that mutations in the RARalpha region of the PML-RARalpha gene are present in and likely mechanistically involved in RA resistance in a subset of these cases.

Adolescent↗

PubMed1998

Single agent paclitaxel in resistant and relapsed epithelial ovarian cancer after first-line platinum-based chemotherapy--experience in an Asian population.

The efficacy and toxicity profile of paclitaxel (Taxol) was studied in 33 Singaporean women with epithelial ovarian carcinoma who had either failed to respond or relapsed after an initial response to first-line chemotherapy with combined platinum and cyclophosphamide. Paclitaxel was given intravenously as a single agent at a dose of 200 mg/m2 over 3 hours, with standard pre-medication, at 4 weekly intervals. A total of 102 cycles were administered. The median number of cycles was 3 (range 1 to 8) per patient. Twenty-six patients were eligible for response evaluation. Six (23.2%) patients showed a complete response and 4 (15.4%) showed a partial response. Two (7.7%) patients had stable disease and 14 (53.8%) patients had progressive disease. The response rate was 22.2% (2 of 9 patients) for patients with progressive disease while on the first-line platinum-based chemotherapy, 37.5% (3 of 8 patients) for patients with response-relapse interval of less than 6 months, 40.0% (2 of 5 patients) for patients with response-relapse interval of 6 to 12 months, and 75% (3 of 4 patients) for patients with response-relapse interval of more than 12 months. The median duration of survival was 10 months for the entire cohort of patients, but all complete responders and 75% of partial responders survived the duration of the study period of 24 months, compared to 50% of patients with stable disease and 7% of patients with progressive disease. Toxicity of paclitaxel treatment was evaluated in 102 cycles. Grade 3 or 4 alopecia, grade 1 or 2 sensory peripheral neuropathy and mild facial flush occurred in all patients. Haematological toxicity was mild, with 9.8% of the cycles complicated by grade 3 or 4 neutropenia. Bone marrow suppression was of short duration. No treatment delay or dose modification was needed. It is concluded that the effectiveness of paclitaxel for salvage treatment of patients with resistant or relapsed epithelial ovarian carcinoma after first-line platinum-based chemotherapy among Asian patients is comparable to that reported in Western populations. The treatment was well tolerated by our patients. It should be considered the chemotherapy of choice for patients with relapsed ovarian cancer after prior platinum-based chemotherapy.

Antineoplastic Agents, Phytogenic↗