F. E. Zwaan

HERPES-VIRUS IMMUNITY AND ACUTE GRAFT-VERSUS-HOST DISEASE

The influence of pretransplant herpes-virus antibodies in 126 marrow-graft recipients and their HLA-identical (A, B, C, DR) sibling donors on the incidence of grades II-IV acute graft-versus-host disease (GVHD) was studied in relation to previously reported risk factors for GVHD. Logistic regression procedures were used to control for confounding factors. Increasing donor age (odds ratio 3.7 per decade; p = 0.02) and donor seronegativity for Epstein-Barr virus (EBV; odds ratio 10.1; p = 0.005) were associated with a high incidence of GVHD. Total rather than selective gastrointestinal decontamination (odds ratio 0.1; p = 0.004), donor seronegativity for herpes simplex virus (HSV; odds ratio 0.1; p = 0.003), and recipient EBV-seronegativity (odds ratio 0.05; p = 0.002) were associated with a low incidence of GVHD. Pretransplant EBV and HSV serology may thus contribute substantially to the estimation of the risk for GVHD.

Chemotherapy compared with bone marrow transplantation for adults with acute lymphoblastic leukemia in first remission.

OBJECTIVEnTo compare efficacy of intensive postremission chemotherapy with allogeneic bone marrow transplantation in adults with acute lymphoblastic leukemia (ALL) in first remission.nnnDESIGNnRetrospective comparison of two cohorts of patients.nnnSETTINGnChemotherapy recipients were treated in 44 hospitals in West Germany in two cooperative group trials; transplants were done in 98 hospitals worldwide.nnnPATIENTSnPatients (484) receiving intensive postremission chemotherapy and 251 recipients of HLA-identical sibling bone marrow transplants for ALL in first remission. Patients ranged from 15 to 45 years of age and were treated between 1980 and 1987.nnnMAIN RESULTSnSimilar prognostic factors predicted treatment failure (non-T-cell phenotype, high leukocyte count at diagnosis, and 8 or more weeks to achieve first remission) of both therapies. After statistical adjustments were made for differences in disease characteristics and time-to-treatment, survival was similar in the chemotherapy and transplant cohorts: Five-year leukemia-free survival probability was 38% (95% CI, 33% to 43%) with chemotherapy and 44% (CI, 37% to 52%) with transplant. No specific prognostic group had a significantly better outcome with one treatment compared with the other (6% for the difference; CI, -3% to 15%). Causes of treatment failure differed: With chemotherapy, 268 (96%) failures were from relapse and 11 (4%) were treatment-related; with transplants, 43 (32%) failures were from relapse and 92 (68%) were treatment-related.nnnCONCLUSIONSnThese results suggest that bone marrow transplants currently offer no special advantage over chemotherapy for adults with acute lymphoblastic leukemia in first remission.

Bone marrow transplantation for acute nonlymphoblastic leukaemia: a survey of the European Group for Bone Marrow Transplantation (E.G.B.M.T.).

Summary. Between 1979 and 1982, 229 patients with acute nonlymphoblastic leukaemia in remission were given allogeneic bone marrow transplants from HLA‐identical siblings. Data on 183 patients transplanted in first complete remission were compared with results of 46 patients transplanted in second or subsequent remission. The 2‐year actuarial survival rate was 53% for patients transplanted in first remission and 36% for patients transplanted in second or subsequent remission (P= 0·02). The probability of survival was related to the age of the patient (P=0·02) and of the donor (P= 0·0002). The 2‐year actuarial leukaemia recurrence rate was 12% for patients transplanted in first remission and 44% for patients in a subsequent remission (P= 0·10). Other factors correlating with a higher probability of relapse after transplantation were the leukaemia subtypes M4 and M5 (P=0·007), cyclosporin A used as prophylaxis of graft‐versus‐host disease (P= 0·008), and the absence of chronic (but not of acute) graft‐versus‐host disease (P= 0·003). These data indicate that prolonged survival can be achieved in approximately 50% of patients with acute nonlymphoblastic leukaemia who receive bone marrow transplants during their first complete remission. But modifications of pre‐ and post‐transplant treatment should be considered to reduce the rate of relapse.

Bone marrow transplantation for acute myeloblastic leukaemia: an EBMT Leukaemia Working Party prospective analysis from HLA-typing.

Summary. The optimal post‐remission therapy for patients with acute myeloblastic leukaemia remains controversial. Allogeneic bone marrow transplantation, autologous bone marrow transplantation, and consolidation chemotherapy are the major options. In order to evaluate their respective value the European Group for Bone Marrow Transplantation conducted a prospective registration study. Patients with newly diagnosed acute myeloblastic leukaemia were registered at the time of HLA‐typing and intention to treat in case of presence or absence of an HLA‐identical donor was recorded. 27/79 (34%) patients HLA‐typed at diagnosis had an identical donor identified. The estimated survivals at 3 years from HLA‐typing were 44% and 21% among patients with or without HLA‐identical donor, respectively (P= 0·02). 22/26 (85%) patients for whom allogeneic bone marrow transplantation was intended were transplanted but only 15/47 (32%) patients for whom autologous bone marrow transplantation was intended were indeed transplanted (P < 0·001). The survival was 50%. 29% and 17% (P= 0·004) for patients treated with allogeneic bone marrow transplantation, autologous bone marrow transplantation, or chemotherapy, respectively. 40/68 patients HLA‐typed in first complete remission had an HLA‐identical donor. The estimated 3‐year survival among patients typed in first remission with and without HLA‐identical donors was 42% and 35% (n.s.), respectively. This technique of early patient registration illustrates the problems of patient selection during the course of the disease and might be used as a complement to randomized trials when comparing bone marrow transplantation and other treatment options.

Bone marrow transplantation for acute lymphoblastic leukaemia: a survey of the European Group for Bone Marrow Transplantation (E.G.B.M.T.)

Between 1979 and 1982, 192 patients with acute lymphoblastic leukaemia were given allogenic bone marrow transplants from HLA‐identical siblings. Data on 5 7 patients transplanted in first remission were compared with the results in 96 patients transplanted in second remission, and 39 in third or subsequent remission. The majority of these patients were of the non‐B non‐T‐ALL and T‐ALL subtypes. The 2‐year actuarial survival for non‐B non‐T‐ALL was 58% for patients transplanted in first remission, 34% for second remission patients and 33% for patients transplanted in third or subsequent remission (P= O60). For patients with T‐ALL, the survivals at 2 years for first and second remission transplant patients were 61% and 10%, respectively (P=0‐04). Multifactorial analysis demonstrated a significantly higher probability of survival for patients grafted in first remission (compared with more advanced remission states) and with bone marrow from young (age ≤ 20 years) donors. The 2‐year actuarial risk of relapse for patients with non‐B non‐T‐ALL transplanted in first remission was 0%, 32% and 69% for second and third or subsequent remission patients, respectively (P= 0‐04). For T‐ALL the actuarial risk of relapse at 2 years is 10% for first remission grafts and 48% for second remission grafts (P= 0‐07). Only patients (with both non‐B non‐T‐/and T‐ALL) transplanted in first remission have a high and stable probability of remaining in remission.

The influence of T cell depletion on recovery of T cell proliferation to herpesviruses and Candida after allogeneic bone marrow transplantation.

To test the influence of T cell depletion of the marrow in allogeneic bone marrow transplantation on functional T cell recovery, in vitro lymphocyte proliferation tests (LPTs) to microbial antigens were regularly performed in 23 recipients of normal BM and in 25 patients receiving BM with a fixed low number of T cells (1×105 T cells/kg body weight; recipients of T-depleted BM). The long-term recovery of positive LPT to at least 1 of the 4 tested microbial antigens—Candida, herpes simplex virus (HSV), varicella-zoster virus (VZV), and cytomegalovirus—was nearly similar in both groups: 16/23 versus 18/25. Recovery of LPT to Candida and HSV in the first 3 months appeared to be greatly influenced by prophylactic measures; only 2/23 recipients of normal BM, receiving amphotericin B, showed a positive LPT to Candida versus 13/25 recipients of T-depleted BM (P < 0.01). In contrast, only 1/23 seropositive recipients of T-depleted BM, receiving acyclovir, showed a positive LPT to HSV versus 9/22 recipients of normal BM (P < 0.05). A positive LPT to CMV in the first 3 months was found in 9/9 seropositive recipients of normal BM, versus in 5/11 seropositive recipients of T-depleted BM (P < 0.05). Five of the 6 patients with a negative LPT died of CMV-interstitial pneumonia versus 1/14 with positive LPT (P < 0.01). We conclude that in CMV-seropositive recipients of allogeneic BM, T cell depletion of the graft affects the early recovery of T cell proliferation to CMV, which is associated with a higher risk of fatal CMV-interstitial pneumonia.

Reduction and repopulation of recipient T4+ and T8+ T-lymphocytes in allogeneic bone marrow transplantation

In eight recipients of allogeneic bone marrow grafts who had sex-mismatched donors, the reduction and subsequent repopulation of T4+ and T8+ T-lymphocytes of recipient origin were studied. The origin of the donor-recipient T4+ and T8+ T cells was studied using quinacrine staining of Y chromatin combined with T-cell typing for T4 and T8. Following chemoradiotherapy and bone marrow transplantation (BMT), T cells reached their nadir at a median of five (range 1-8) days after BMT. T8+ T cells decreased at a faster rate from the peripheral blood than T4+ T cells. The first T cells that appeared in the circulation at day 12 were predominantly T4+, and a large number of them were of recipient origin. Thereafter, they gradually decreased, and the numbers of T cells of donor origin increased. In the patients who had no or only minor complications, T4+ and T8+ T cells of donor origin repopulated the blood at similar rates. This pattern, however, was modified by severe graft-versus-host disease or by cytomegalovirus infection.

Survival of patients with chronic myelogenous leukaemia relapsing after bone marrow transplantation: Comparison with patients receiving conventional chemotherapy

Treatment with busulphan and/or hydroxyurea rarely produces remission in patients with chronic myelogenous leukaemia (CML) in chronic phase. HLA‐identical sibling transplants almost always produce remission, and only about 20% of patients relapse post‐transplant. The increased anti‐leukaemic efficacy of transplants results from intensive pretransplant treatment and immune‐mediated anti‐leukaemia effects. We studied 433 patients survivingu2003u20032 years after diagnosis of CML to determine if patients who have relapsed after a transplant in chronic phase have longer survival from diagnosis than comparable subjects receiving chemotherapy. The chemotherapy cohort included 344 adults <u200350 years of age treated on consecutive trials of the Italian Cooperative Study Group on CML between 1973 and 1986. The transplant cohort included 89 patients reported to the International Bone Marrow Transplant Registry who relapsed after an HLA‐identical sibling bone marrow transplant carried out between 1978 and 1992. Survivals in the two groups were compared using Cox proportional hazards regression to adjust for prognostic variables. Median survival was 65 months in the chemotherapy cohort and 86 months in the transplant cohort. The 7‐year probability (95% confidence interval) of survival was 34% (28–39%) in the chemotherapy cohort and 57% (43–70%) in the transplant cohort (P=0.003). There was no difference in survival of patients relapsing after T‐cell depleted and non‐T‐cell‐depleted transplants. We conclude that patients who relapse after an HLA‐identical sibling bone marrow transplant for CML in chronic phase have longer survival from diagnosis than comparable patients receiving chemotherapy. This effect is most likely to be the result of intensive chemotherapy and/or radiation given for pretransplant conditioning.

Splenic Irradiation before Bone Marrow Transplantation for Chronic Myeloid Leukemia: Update of a Prospective Randomized Study

Two hundred and twenty-nine patients with chronic myeloid leukaemia in chronic phase awaiting bone marrow transplantation from an HLA-identical sibling donor were randomized as part of their conditioning, to receive splenic irradiation (SI+, 115 patients), or not (SI-, 114 patients). Both groups were identical in regard to age, sex, donor/recipient sex combination and disease activity. Survival, leukaemia-free survival, incidence of transplant-related mortality, acute and chronic graft versus host disease, incidence of rejection and probability of relapse were not different in either groups at a median follow-up time of 4.5 years (minimum follow-up 2 years). Recovery of peripheral white blood cell counts to 1 x 10(9)/l but not of platelet counts to 50 x 10(9)/l was significantly faster in patients with SI+ (21 vs 24 days). This small benefit does not justify routine splenic irradiation prior to BMT, in CML.

Is Aciclovir Prophylaxis Necessary After Bone Marrow Transplantation

SummaryTo assess the cost-effect relationship of aciclovir prophylaxis versus early treatment, we performed a retrospective study in 44 allogeneic bone marrow transplant recipients, who had only received aciclovir for therapeutic purposes. After bone marrow transplantation 18 herpes simplex infections occurred in 15 of the 33 patients who were seropositive for herpes simplex virus. In ten patients without clinical signs, routine viral cultures yielded herpes simplex virus. Aciclovir was given intravenously to the patients with mucocutaneous herpes infection. All infections responded rapidly. It can be calculated that restricting the drug to therapeutic use reduced the amount of aciclovir used, which in turn diminished the cost of treatment and the risk of aciclovir resistance.ZusammenfassungBei 44 Empfängern von allogenen Knochenmarkstransplantaten, die Aciclovir ausschließlich therapeutisch erhalten hatten, wurde eine retrospektive Studie durchgeführt, um die Kosten-Nutzen-Beziehung für die Prophylaxe im Vergleich zur Frühtherapie zu bestimmen. Bei 15 der 33 Herpes-simplex-Virus-seropositiven Patienten traten nach Knochenmarkstransplantation 18 Herpes-simplex-Virus-Infektionen auf. Bei zehn klinisch symptomfreien Patienten wurde in Routinekulturen Herpes-simplex-Virus nachgewiesen. Patienten mit mukokutaner Herpesinfektion erhielten Aciclovir intravenös appliziert. Alle Infektionen sprachen rasch auf die Therapie an. Es läßt sich errechnen, daß eine Beschränkung auf den therapeutischen Einsatz des Medikamentes den Verbrauch von Aciclovir vermindert und somit die Behandlungskosten und das Risiko der Resistenzentwicklung gegen Aciclovir erniedrigt.