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PubMed1989

Restriction fragment length polymorphism analysis of hematopoietic cells following successful treatment of relapsed acute lymphoblastic leukemia following bone marrow transplantation.

Despite aggressive therapy for leukemia in the form of bone marrow transplantation (BMT) relapse occurs in a significant number of cases. The origin of the leukemic relapse, whether it is of donor or recipient origin, and how best to treat the patients continue to pose problems for the clinician. In this paper we present a case in which the cytogenetics suggested that the relapse was of donor origin; however, molecular analysis revealed that the leukemic population was of host origin. The leukemic relapse following the BMT was treated with a second BMT. This resulted in a remission of 28 months after which leukemic relapse was again diagnosed. Using conventional chemotherapy it was possible to obtain another complete remission. This case illustrates a pitfall to cytogenetic analysis and two contrasting methods of dealing with leukemic relapse following BMT.

Adult↗

PubMed1989

Marrow transplantation for acute lymphoblastic leukemia: factors affecting relapse and survival.

Transplant outcome was analyzed in 690 recipients of bone marrow transplants (BMTs) for acute lymphoblastic leukemia (ALL) in first (n = 299) or second remission (n = 391). Actuarial 5-year leukemia-free survival was 42% +/- 9% (95% confidence interval) and 26% +/- 6%, respectively; relapse rates were 29% +/- 9% and 52% +/- 8%, respectively. Five-year leukemia-free survival was 56% +/- 18% in children and 39% +/- 10% in adults (P less than .02) transplanted in first remission. In first-remission adults, non-T-cell phenotype, male to female donor-recipient sex-match and graft-v-host disease (GVHD) were associated with decreased leukemia-free survival; inclusion of corticosteroids in the regimen to prevent GVHD was associated with increased leukemia-free survival. Variables associated with decreased leukemia-free survival after second-remission transplants were age greater than or equal to 16 years and relapse occurring while on therapy. Variables associated with increased probability of relapse were similar for first- and second-remission transplants and included GVHD prophylaxis without methotrexate and absence of GVHD. In first-remission transplants, leukocyte count greater than or equal to 50 x 10(9)/L at diagnosis was also associated with increased relapse; in second remission, relapse while receiving chemotherapy was also associated with increased posttransplant relapse. These data emphasize the importance of both disease- and transplant-related variables in predicting outcome after BMT. They may be used to explain differences between studies, design future trials, and identify persons most likely to benefit from BMT.

Adolescent↗

PubMed1989

TdT+/nonlymphoid antigen+ acute leukemias: immunologic and karyotypic monitoring during therapy and at relapse suggests the transformation of a bipotential stem cell.

Immunophenotype and karyotype were monitored in 19 adult acute leukemia patients with blast cell populations expressing terminal transferase (TdT) and nonlymphoid antigens either at presentation or at relapse. Three patterns of immunophenotypic course were observed when following the patients through at least one, sometimes two (six patients), or three relapses (one patient). Induction chemotherapy induced predominantly TdT+ leukemias with a minor monoblastic component to become TdT-negative, purely monoblastic without clinical response or change in karyotype in five patients (group 1). In group 2, relapse was associated with the disappearance (four patients) or the appearance of TdT+/nonlymphoid antigen+ features (four patients). In two instances, new nonrandom cytogenetic abnormalities, in one case, evolution of an initial abnormal cytogenetic clone, were found at relapse. Six patients (group 3) presented and relapsed with identical TdT+ myeloblastic, promyeloblastic, monoblastic immunophenotype and karyotype. In general, FAB classification did not reflect expression of TdT in nonlymphocytic leukemias or the presence of nonlymphoid blast features in lymphocytic leukemias. Lymphoid-specific antigens in addition to TdT were not detected in any of the cases at the time of nonlymphoid antigen expression. In 11 of the 19 patients, simultaneous expression of TdT and myeloid or monocytic antigens could be demonstrated at the single cell level using double-fluorescence staining. These follow-up data are best consistent with a drug-induced maturation drive of a TdT+/monocytic (majority of cases) or TdT+/myelocytic leukemic stem cell with its differentiation commitment being influenced by chemotherapy or by other as yet undefined conditions predisposing to proliferation of the leukemic cell at relapse.

Acute Disease↗

PubMed1989

[Tuberculosis relapse in the GDR--causes and development].

In a cooperative study 169 bacteriologically confirmed tuberculosis relapses of the years 1984-1986 were analysed with regard of causes or relapse favouring factors. In 58.5% relapse occurred 3 or more years after cessation of previous treatment. Relapse was presumedly caused in 22.3% by inadequate chemotherapy (considering duration and/or continuation and/or combination), in 25% by alcoholism and in 14.9% by silicosis. Resistance to 2 or more antituberculotic drugs was found only in 5.3%. Advanced age and polymorbidity are relapse favouring factors. Consideration of adequate chemotherapy is the most important factor to avoid relapse.

Age Factors↗

PubMed1987

Molecular analysis of relapse in chronic myeloid leukemia after allogeneic bone marrow transplantation.

Four patients with Philadelphia (Ph') positive chronic myeloid leukemia (CML) were studied before, after, and on relapse following allogeneic bone marrow transplantation (BMT). Southern analysis of DNA from cells collected before and at relapse after BMT was performed in order to investigate the origin of the leukemia at relapse. Using minisatellite probes we showed that the relapse occurred in cells of host origin in all four patients and this was confirmed with a Y chromosome specific probe in two male patients who had a female donor. Furthermore, using two probes for the breakpoint cluster region (bcr) on chromosome 22, we showed that leukemic cells at relapse bore identical rearrangements to those in the disease at time of presentation of each patient. We conclude that relapse in all four patients is due to re-emergence of the original leukemic clone.

Bone Marrow Transplantation↗

PubMed1986

Relapse rates in lepromatous leprosy according to treatment regularity.

In Gudiyatham Taluk, South India, 1008 lepromatous (LL) and borderline lepromatous (BL) patients were studied. They had previously been smear positive, had attained smear negativity, and continued on DDS monotherapy. "Relapse" was defined as the reappearance of Mycobacterium leprae in skin smears. The area is endemic for leprosy. The lower relapse rates in the first three years of smear negativity alone were associated with more-regular treatment during both past smear positivity and smear negativity. From the fourth year of smear negativity onward, only the more-regular treatment during smear negativity was associated with lower relapse rates; whereas patients with more-regular treatment during past smear positivity had no lower risk of relapse than those with less-regular treatment. The finding that regularity of treatment during smear positivity seems to have no effect on relapse rates beyond the third year of smear negativity is discussed. In a leprosy-endemic area, it is argued that beyond the first three years of smear negativity in an LL or BL patient, sources of M. leprae outside the patient may be more responsible for relapse than the patient's own bacilli.

Dapsone↗

PubMed1983

[Relapse in Basedow's disease after treatment with synthetic antithyroid drugs. Prognostic value of analysis of the HLA system].

One hundred and eleven unselected patients with hyperthyroidism due to Graves' disease received decreasing doses of carbimazole for 18 months. Clinical examination and hormonal assays (serum T3, T4, free T4 index) were done at 4, 9 and 18 months of treatment. Patients were typed for 35 HLA antigens and were followed up for 2 years after withdrawal of treatment; 39 patients were excluded for various reasons and 72 were retained for study. Of the 72 patients, 37 relapsed and 35 remained in remission: 40 patients were DR3+ (20 relapsed) and 32 were DR3- (17 relapsed). HLA frequency was not significantly different in patients who relapsed and in those who remained in remission. Thus, under the conditions of this study, HLA frequency could not be used to predict relapse of hyperthyroidism due to Graves' disease. This study brings out an other interesting point: relapse frequency of about 50% focuses our attention on the limits of medical treatment.

Carbimazole↗

PubMed1984

Differentiation in vitro of human myelogenous leukemia cells from patients in relapse.

Leukemia cells from patients with acute myeloid leukemia in relapse were treated with various inducers of differentiation of human myeloid leukemia cell lines. Leukemia cells in primary culture from most, but not all, patients underwent morphological, cytochemical and biochemical changes after treatment with inducers of differentiation such as 12-O-tetradecanoylphorbol-13-acetate (TPA), retinoic acid, actinomycin D, aclarubicin, and alkyl lysophospholipid. The most effective inducer varied from specimen to specimen. Leukemia cells from patients in relapse were compared with those from untreated patients. The responsiveness to TPA of leukemia cells from patients in relapse was similar to that of leukemia cells from untreated patients. However, retinoic acid or actinomycin D resistance was more frequently observed in leukemia cells from patients in relapse than in those from patients before initial therapy. This is the first report to indicate that leukemic cells from relapsed patients who are resistant to cytotoxic chemotherapeutic drugs can be induced to differentiate into mature cells by appropriate inducers. However, the responsiveness to inducers of leukemia cells from patients in relapse is not the same as that of leukemia cells before therapy.

Adolescent↗

PubMed1982

Relapsing idiopathic membranous nephropathy.

In a series of 60 patients with idiopathic membranous nephropathy (IMN), 8 subjects, aged 16-65 years at presentation, suffered spontaneous relapse of proteinuria after remissions of 25 months to 30 years. Renal biopsy was performed at the time of relapse in 5 cases and revealed histopathology identical to that of the original lesion. Eight courses of immunosuppressive therapy given to 6 patients did not affect either the appearance or duration of remission or relapse. No patient had a familial tendency to renal disease. Immunogenetic markers, HLA A, B and DR, did not distinguish those who relapsed from other patients with IMN. At the end of the study, 3 patients were in a second remission, one had died of myocardial infarction during relapse, 3 remained nephrotic and one had mild renal insufficiency but no proteinuria. As compared with the rest of the series the overall prognosis was not influenced by the relapses.

Adolescent↗

PubMed1981

Significance of relapse after adjuvant treatment with combination chemotherapy or 5-fluorouracil alone in high-risk breast cancer. A Western Cancer Study Group Project.

Beginning in 1974, patients undergoing mastectomy at high risk for recurrence (greater than or equal to 4 nodes positive; median, 9.4 positive; range, 4 to 28) were randomized after stratification for menopausal status and radiotherapy to receive either 5-fluorouracil (5-FU, 500 mg/sq m i.v. every week) or cyclophosphamide, 400 mg/sq m; methotrexate, 30 mg/sq m; and 5-FU, 500 mg/sq m (CMF; all given i.v. every 2 weeks) in a 12-month program. All 62 patients remain evaluable with median follow-up now exceeding 70 months (range, 60 to 80 months). CMF significantly prevented early disease recurrence (97% relapse free on CMF versus 75% on 5-FU at 12 months; p less than 0.05) and demonstrated survival advantage during the initial 40-month follow-up. This significance was subsequently lost, and the percentages of relapse free and overall survival after 70 months are: (formula, see text) The apparently paradoxical relationship between relapse and survival on the 5-FU arm was related to survival after recurrence. Survival after recurrence was significantly longer on the 5-FU compared to the CMF arm (median of greater than 38 versus 10 months, respectively; p less than 0.01). These results suggest (a) long-term survival in adjuvant trials cannot be accurately predicted by short-term differences in relapse frequency, (b) survival after relapse may be influenced by the antecedent adjuvant therapy received, and (c) disease relapse does not necessarily preclude long-term survival.

Breast Neoplasms↗

PubMed1995

CD8-depleted donor lymphocyte infusion as treatment for relapsed chronic myelogenous leukemia after allogeneic bone marrow transplantation.

Donor lymphocyte infusions can reinduce complete remission in the majority of patients with chronic myelogenous leukemia (CML) who relapse into chronic phase after allogeneic bone marrow transplantation (BMT). Such infusions are associated with a high incidence of graft-versus-host disease (GVHD) and marrow aplasia. BMT using selective depletion of CD8+ lymphocytes from donor cells reduces the incidence of GVHD without an increase in leukemia relapse. We hypothesized that infusion of CD8-depleted donor peripheral blood lymphocytes could also reinduce complete remissions with a lesser potential to produce symptomatic GVHD in patients with CML who relapsed after allogeneic BMT. Ten patients with Ph(+) CML who relapsed a median of 353 days after BMT (range, 82 to 1,096 days) received donor lymphocyte infusions depleted of CD8+ cells. Nine patients received a single infusion and 1 received two infusions. Four patients were treated while in chronic phase with clonal evolution, 2 during accelerated phase, 3 during blast crisis, and 1 in a cytogenetic relapse. A mean of 0.9 +/- 0.3 x 10(8) mononuclear cells/kg were infused, containing 0.6 +/- 0.4 x 10(6) CD3+CD8+ cells/kg. Six patients achieved hematologic and cytogenetic remission at 4, 8, 11, 15, 39, and 54 weeks after lymphocyte infusion. Two patients developed > or = grade II acute GVHD, and 1 patient developed mild chronic GVHD. We conclude that donor lymphocyte infusions depleted of CD8+ cells can induce remissions with a low rate of severe acute GVHD in patients with CML who relapse after allogeneic BMT, supporting the hypothesis that CD8+ lymphocytes are important effectors of GVHD, but may not be essential for the graft-versus-leukemia effect against this disease. Further controlled studies are required to confirm these preliminary observations.

Acute Disease↗

PubMed1994

Hematopoietic growth factor stimulation and cytarabine cytotoxicity in vitro: effects in untreated and relapsed or primary refractory acute myeloid leukemia cells.

Stimulation of clonogenic acute myeloid leukemia (AML) cells by hematopoietic growth factors (HGF) is capable of enhancing cytosine-arabinoside (Ara-C) cytotoxicity in vitro. Until now it has not been known to what extent in vitro Ara-C cytotoxicity can be restored by HGF stimulation in samples from previously treated AML patients. Therefore, we studied the individual effects of the hematopoietic growth factors (HGF) granulocyte colony-stimulating factor (G-CSF), interleukin-3 (IL-3), and granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulation on the Ara-C sensitivity of clonogenic leukemic cells from six patients with newly diagnosed AML. These results were directly compared with the outcome using AML samples from the same patients at relapse or primary refractory AML. In one patient, a sample of the second relapse was also studied. The results were expressed as IC50 values, and were used to calculate sensitivity ratios, defined as the ratio of the IC50 value with drug exposure alone and with HGF plus Ara-C. In AML samples treated with Ara-C alone and no HGF, IC50 values of Ara-C in relapsed/refractory AML were greater than IC50 values of AML cells at diagnosis. Addition of either HGF enhanced the Ara-C cytotoxicity for the relapsed samples significantly (for G-CSF p = 0.036, IL-3 p = 0.036, and for GM-CSF p = 0.036). The values of Ara-C sensitization of AML samples due to HGF at relapse did not significantly differ from those at diagnosis. However, enhancement of Ara-C cytotoxicity to AML progenitors by IL-3 or GM-CSF stimulation was significantly less in the cell specimens from AML recurrence patients as compared with the original diagnosis samples. In three AML samples at diagnosis and at their relapse, Ara-C incorporation into the DNA was determined. IL-3 stimulation enhanced Ara-C incorporation in all samples tested. Nevertheless, Ara-C incorporation in the relapsed samples was significantly less than that in the diagnosis samples of the same patients. A good correlation between Ara-C incorporation and bromodeoxyuridine (BrdU) incorporation was found. The results indicate that HGF stimulation in relapsed/refractory AML enhances Ara-C cytotoxicity, but not to the level that was observed with AML samples at diagnosis.

Adult↗

PubMed1994

Relapse rates in patients treated with dapsone monotherapy and combinations of dapsone and thiambutosine, thiacetazone, isoniazid and streptomycin in the pre-MDT era.

Relapse rates were studied in patients from northern Thailand who were started on dapsone monotherapy between 1949 and 1976. Included are a group of patients who, for various reasons, also received combinations of dapsone and thiambutosine, thiacetazone, isoniazid and streptomycin. The overall relapse rate in paucibacillary patients on dapsone monotherapy only was 2.7 per 1000 person-years at risk (PYR) (average observation period 13.9 years). In the multibacillary patients who received dapsone monotherapy only, the relapse rate was 10.5 per 1000 PYR (average observation period 12.4 years). In both groups it was found that 50% of the relapses occurred after the seventh year of follow up. The overall relapse rate in those patients whose treatment included thiambutosine, thiacetazone, isoniazid and/or streptomycin for at least 3 months was 17.9 per 1000 PYR (average observation period 11.9 years). The difference with the multibacillary patients treated with dapsone monotherapy only is not significant. It is concluded that alternative antileprosy drugs included in therapy regimens with dapsone in the pre-MDT era did not result in relapses occurring less often.

Dapsone↗

PubMed1994

Effect of graft-versus-host disease prophylaxis on relapse in patients transplanted for acute myeloid leukemia.

Between November 1978 and September 1988, 184 patients with acute myeloid leukemia in first remission received marrow transplants from HLA-identical siblings after conditioning with 120 mg/kg of cyclophosphamide and 12.0 Gy fractionated total body irradiation. Patients received either cyclosporine (CYA, n = 59), methotrexate (MTX, n = 82), or MTX + CYA (n = 43 as graft-versus-host disease (GVHD) prophylaxis. The probabilities of grades II-IV acute GVHD after CYA, MTX or MTX+CYA were 0.43, 0.48 and 0.28, respectively (p = 0.06). The probability of non-relapse mortality was 0.53, 0.50 and 0.42 at 4 years in patients treated with CYA, MTX, or MTX + CYA, respectively. The probability of relapse was 0.24 in patients receiving CYA, 0.24 in patients receiving MTX and 0.44 in patients receiving MTX + CYA (p = 0.02). The probability of survival at 4 years was 0.54 with CYA, 0.51 with MTX and 0.45 with MTX + CYA. A multivariate analysis of risk factors for relapse examined age, WBC at diagnosis, blast count at diagnosis, percentage of marrow blasts, FAB subtype, the number of remission induction courses to achieve a remission, maintenance therapy, consolidation therapy, marrow cell dose, donor-recipient sex, GVHD prophylaxis regimen and isolation and decontamination in laminar airflow rooms. GVHD prophylaxis with MTX + CYA was independently significantly associated with an increased risk of relapse (relative risk 2.25, p = 0.01). Acute GVHD was associated with increased non-relapse mortality (RR = 3.58, p < 0.0001). The administration of MTX + CYA did not adversely affect survival because patients receiving this regimen experienced less mortality from causes other than relapse when compared with patients receiving either CYA or MTX alone.

Adolescent↗

PubMed1994

Hairy cell leukemia. An update on a cohort of 93 patients treated in a single institution. Effects of interferon in patients relapsing after splenectomy and in patients with or without maintenance treatment.

We retrospectively analysed the results of interferon alpha-2 (IFN) treatment in 93 patients with hairy-cell leukaemia, of which 31 had previously undergone splenectomy. Induction treatment (3 x 10(6) U three times weekly for 12 months) was completed in 84 cases (90%). Peripheral hematological response was observed in 76 patients. Two patients had persistent splenomegaly, and response was observed in both cases after splenectomy. Five additional patients were responsive after 18-24 months of induction treatment and 1 was unresponsive. Of 28 patients on maintenance treatment (1 x 10(6) U 3 x per week), no patient relapsed after a median follow-up of 30 months. The toxicity level was acceptable and IFN resistance was not observed. On the other hand, of 56 patients without maintenance treatment, 37 relapsed at a median of 19 months. Thirty of 32 evaluable patients remained responsive to a second course of IFN. Of 19 patients without relapse, 11 had undergone splenectomy compared to 0/37 patients who relapsed (p < 0.001). In conclusion, the study shows the following, (1) IFN, provides excellent palliation without major toxic side effects; (2) long term maintenance was well tolerated and prevented peripheral haematological relapse; (3) lack of maintenance treatment was associated with peripheral haematological relapse requiring a second treatment; and (4) certain previously splenectomized patients may not require maintenance treatment. These long term results must be compared with the effectiveness and toxicity of new drugs, such as pentostatin and 2-chloro-deoxy-adenosine.

Cohort Studies↗

PubMed1994

Autologous bone marrow transplantation for childhood acute lymphoblastic leukemia in remission: first choice for isolated extramedullary relapse?

Between May 1984 and May 1992, 75 children 3-19 (median 9) years of age underwent autologous marrow transplant. Clinical data were obtained from the BMT Registry of the AIEOP (Italian Association of Pediatric Hemato/Oncology). Fifty-six children were transplanted after marrow +/- other site(s) relapse and 19 after an isolated extramedullary relapse. The transplant preparative regimens varied according to the center performing the transplant. Seven patients (9%) died of transplant-related complications. Forty-four (58.6%) of 75 patients relapsed again following autologous BMT. The 5-year DFS was 27.8%. An isolated extramedullary relapse was the only variable that statistically influenced DFS. In this retrospective study, autologous BMT for patients with ALL in second CR following marrow relapse did not offer an encouraging result (13% probability of DFS at 5 years), whereas autologous BMT following an (early) isolated extramedullary relapse resulted in nearly 70% DFS. Autologous BMT may be appropriate for this latter group of patients.

Adolescent↗

PubMed1994

Clinical significance of p53 mutations in relapsed T-cell acute lymphoblastic leukemia.

In T-cell acute lymphoblastic leukemia (T-ALL), p53 gene mutations were found in 12 of 51 patients in first relapse (24%). In a retrospective study, bone marrow samples at diagnosis were obtained from 9 of the 12 relapsed patients with p53 mutation; only one patient was found to harbor a p53 mutation at diagnosis. No further p53 mutations were identified in 18 unpaired diagnosis T-ALL samples. This is the first report of a p53 mutation in T-ALL at diagnosis. p53 mutations in relapsed T-ALL were clinically relevant. Patients with p53 mutations experience a shorter duration of survival than those patients without p53 mutations. Additionally, patients with p53 mutations were significantly less likely to have achieved a complete second remission from reinduction therapy than those patients without p53 mutations and experience a shorter duration of survival from relapse even when a second reinduction is obtained. Though primarily identified only at relapse, p53 mutations were also associated with a decreased duration of first remission and overall decrease in survival from diagnosis. Patients with p53 mutations had a 3.8-fold increase in risk of death than those patients without p53 mutations. These findings suggest that p53 mutation is associated with poor clinical outcome that is characterized by (1) a shortened duration of survival after first relapse; (2) a reduced response to reinduction therapy; (3) a shortened duration of first remission; and, hence, (4) an overall decreased duration of survival and increased risk of death.

Base Sequence↗

PubMed1994

Relapses after a single dose of rifampin in skin-smear negative multibacillary patients after dapsone monotherapy.

Between 1982 and 1985, a single 1500 mg dose of rifampin (RMP) was given to 136 multibacillary leprosy patients who had become clinically inactive and skin-smear negative after various durations of dapsone monotherapy, and then antileprosy chemotherapy was totally stopped. By the end of June 1992, 15 relapses were detected among these patients. The overall relapse rate was 11%; the relapse rate per 100 patient-years was 2.1%, which was the highest among those published to date; the cumulative risk of relapse at year 7 of follow up was 8.8%. All of these figures indicate that the relapse rate among this group was at least the same as in other studies where patients received dapsone monotherapy only. Therefore, the administration of a single large dose of RMP could neither prevent relapse nor reduce its rate among multibacillary patients who had already become clinically and skin-smear negative after dapsone monotherapy.

Adult↗