Improvement in outcome for children receiving allogeneic bone marrow transplantation in first remission of acute myeloid leukemia: a report from the Groupe d'Etude des Greffes de Moelle Osseuse.

PURPOSE: We retrospectively analyzed the outcome of children with acute myeloid leukemia (AML) in first complete remission (CR) who received HLA-identical bone marrow transplantation (BMT) in 13 French transplant centers. PATIENTS AND METHODS: Seventy-four children were treated from June 1979 through December 1990. The conditioning regimen included total-body irradiation (TBI) in 54 cases and busulfan in 20. Prophylaxis of graft-versus-host disease (GVHD) consisted of cyclosporine (CycloA) plus methotrexate (MTX) for 38 patients, MTX for 17, CycloA for 18, and T depletion without other prophylaxis for one. The mean value of the interval from diagnosis to transplantation was 167 days. RESULTS: Sixteen patients died of transplant-related complications, 12 relapsed, and 46 are alive in continuous remission with a median follow-up of 46 months. We examined results obtained over three successive periods: 1979 to 1982 (n = 14 children), 1983 to 1986 (n = 29), and 1987 to 1990 (n = 31). Probabilities of event-free survival (EFS) were 43%, 48%, and 82% for the three successive periods, respectively (P < .02). This improvement in EFS was linked to a decreased risk of transplant-related mortality: 36%, 36%, and 3%, respectively (P < .01). Other factors associated with a better EFS in the univariate analysis were a short time interval from diagnosis to transplant (< 120 days), the absence of significant (grade > or = 2) acute GVHD, and the absence of chronic GVHD. In the multivariate analysis, two factors had a favorable impact on long-term survival: the year of transplantation (years 1987 to 1990 v others) and the absence of acute GVHD. CONCLUSION: The outcome for children receiving allogeneic BMT in first CR of AML has improved in France during recent years.

Allogeneic bone marrow transplantation for children with acute myeloblastic leukemia in first complete remission: impact of conditioning regimen without total-body irradiation--a report from the Société Française de Greffe de Moelle.

PURPOSE: To analyze the French experience of chemotherapeutic preparation before human leukocyte antigen (HLA)-identical bone marrow transplantation (BMT) in children with acute myeloblastic leukemia (AML) in first complete remission (CR). PATIENTS AND METHODS: The data base used for this study was a French BMT registry for childhood AML. Twenty-three children were conditioned with busulfan and 120 mg/kg cyclophosphamide (Bu-Cy 120 group). Nineteen received busulfan and 200 mg/kg cyclophosphamide (Bu-Cy200 group). During the same time period, 32 patients were prepared with total-body irradiation (TBI group) most often in combination with 120 mg/kg of cyclophosphamide. RESULTS: The probability of relapse was 54%, 13%, and 10% for the Bu-Cy120, Bu-Cy200, and TBI groups, respectively (P < .05 in the univariate analysis, log-rank test, 2 df). In the multivariate analysis, a conditioning regimen with Bu-Cy120 was significantly associated with a higher risk of relapse (P = .02; relative risk, 3.62). The probability of transplant-related mortality (TRM) was 0% for Bu-Cy120, 5% for Bu-Cy200, and 10% for TBI. Kaplan-Meier estimations of event-free survival (EFS) were 46% +/- 24%, 82% +/- 18%, and 80% +/- 14%, respectively, for the three groups, with median follow-up durations of 28 months (range, 3 to 78), 31 months (4 to 68), and 48 months (2 to 73). In the multivariate analysis, two factors adversely affected EFS: a conditioning regimen with Bu-Cy120 (P = .07) and a long interval from diagnosis to BMT (> or = 120 days, P = .08). CONCLUSION: Bu-Cy120 is a well-tolerated preparation, but results in a high risk of relapse for children with AML in first CR. This high risk of relapse is not observed when the dose of cyclophosphamide is increased to 200 mg/kg.

Use of an anti-interleukin-2 receptor monoclonal antibody for GVHD prophylaxis in unrelated donor BMT.

Severe acute GVHD remains the main complication in unrelated donor BMT (UD-BMT). The previous encouraging reports on the use of anti-IL-2 receptor monoclonal Ab (33B31) for GVHD prophylaxis in genoidentical BMT led us to add this Ab to the standard GVHD prophylaxis regimen (MTX plus CsA). Sixty-four consecutive patients received 33B31, 20 mg on days 1 and 2, then 10 mg per day from day 3 to day 28 in association with CsA and MTX. They were compared with a historical control group of 89 patients who received conventional GVHD prophylaxis. The 33B31 was well tolerated. We did not find any statistical difference in terms of incidence and time of onset of severe GVHD, occurrence of chronic GVHD, engraftment, relapse or survival among the two groups. Immunization occurred but did not influence serum levels of 33B31. No correlation was found between the severity of GVHD and serum Ab levels. We conclude that other approaches for reducing acute GVHD should be developed to improve UD-BMT results.

Allogeneic bone marrow transplantation following a busulfan-based conditioning regimen in young children with acute lymphoblastic leukemia: a Cooperative Study of the Société Française de Greffe de Moelle.

A subgroup of children with ALL remains at high risk of relapse despite the administration of intensive chemotherapeutic protocols and may benefit from allogeneic BMT. The cytoreductive regimen used most often combines TBI with cyclophosphamide. Nevertheless, miscellaneous long-term sequelae have been consequent upon radiotherapy, especially in young children. This retrospective multicentric study analyzes the outcome of children with ALL under 4 years of age receiving an HLA-genoidentical BMT following a radiation-free preparative regimen. A busulfan-based regimen with cyclophosphamide or melphalan +/- etoposide +/- cytarabine was given to 21 children (median age: 28 months, range 6-48). Sixteen patients with initial poor prognostic factors were transplanted in first complete response (CR) and five patients in relapse or second CR. With a median follow-up of 47 months, the results show an overall 4-year DFS of 61.1%. Leukemic recurrence was observed in eight patients. The preparative regimen was well-tolerated and there were no transplant-related deaths. A busulfan-based BMT preparative regimen may be a therapeutic alternative to TBI-containing regimens in young children. Efforts are currently aimed at reducing the relapse rate in these children by optimizing the tumoricidal potential of chemotherapy and the graft-versus-leukemia effect of allogeneic BMT.

Allogeneic bone marrow transplantation in chronic lymphocytic leukemia: 17 cases. Report from the EBMTG.

Allogeneic bone marrow transplantation (BMT) was performed in 17 patients with chronic lymphocytic leukemia (CLL): 15 resistant and two untreated forms. There were 12 males and five females with a mean age of 40 years (32-49). The conditioning regimens and graft-versus-host disease (GVHD) prophylaxis varied. Successful engraftment was obtained in 15 evaluable cases. Lymphocytosis and clinical symptoms subsided in all but one case. All 15 evaluable patients developed acute GVHD. Among the 17 patients grafted, one early death was observed at the 15th day post-BMT, and one refractory patient died 2 months after BMT. Of the remaining 15 patients in complete remission (CR), four died from GVHD, hemorrhage and graft failure, and two relapsed at 7 and 54 months after BMT and died. Nine patients are alive in CR with a mean follow-up of 25.6 months (4-48). Chimerism was complete in eight patients and partial in the two T cell-depleted cases. In one case, an immunoglobulin gene rearrangement study showed no residual disease. These results suggest that allogenic BMT might be an alternative and possible curative therapy for refractory CLL in young patients when performed relatively early in the disease.

Allogeneic bone marrow transplantation for childhood acute lymphoblastic leukemia in second remission: factors predictive of survival, relapse and graft-versus-host disease.

Between 1983 and 1993, 42 patients with acute lymphoblastic leukemia (ALL) in second complete remission (CR) underwent an allogeneic HLA-identical bone marrow transplant (BMT; there was one family mismatched graft). The conditioning regimens varied, consisting of cyclophosphamide (CY) and total body irradiation (TBI; n = 10); CY, TBI, Ara C, VP-16 (n = 11); TBI, Ara C, melphalan (n = 20) (TAM) or other (n = 1). Cyclosporine A (CsA) (n = 15) or CsA and methotrexate (MTX) (n = 24) were the main regimens for prophylaxis of graft-versus-host disease (GVHD). Nineteen of 42 patients are alive in CR ranging from 1 to 72 months after BMT with a median follow-up of 36 months. The 4-year actuarial survival rate was 53%. The actuarial relapse rate was 17%. Twenty three patients died: 4 patients of leukemic relapse, 9 of infection, 2 of acute GVHD, 2 of multiorgan failure after chronic GVHD, 2 of a secondary tumour and 4 patients died of other causes. Several pre- and post-transplant characteristics were analyzed to determine predictive factors for survival, relapse and GVHD. The relapse rate was significantly influenced by the type of conditioning regimen with no relapse in the TBI, Ara C, melphalan group. The analysis of long-term sequelae shows that there are no severe complications in this last group. Our results confirm that allogeneic BMT can lead to long-term survival for children with ALL in second CR and suggest an advantage of using the TAM conditioning regimen in the eradication of the leukemic disease.

Clinical applications of stem cell transfusion from cord blood and rationale for cord blood banking.

Umbilical cord blood collected and cryopreserved at birth contains enough hematopoietic progenitor stem cells for engraftment. HLA identical sibling cord blood transplant has been performed for the first time, in a child with Fanconi anemia. Three years latter, this child is alive with a complete donor type bone marrow. Since this first attempt, several other patients with other diseases have been transplanted successfully. Cord blood banking is a safe and easy procedure. Due to the high proliferative capacity of neonatal hematopoietic progenitors and to the relative immunological functional immaturity of neonatal lymphocytes cord blood cells could be used for matched unrelated or partially mismatched transplants.

Retrospective evaluation of autologous bone marrow transplantation vs allogeneic bone marrow transplantation from an HLA identical related donor in acute myelocytic leukemia. A study of the European Cooperative Group for Blood and Marrow Transplantation (EBMT).

We analyzed retrospectively data from 1696 patients with AML transplanted in Europe from January 1987 to December 1992 and reported to the acute leukemia EBMT registry. Groups of patients were analyzed according to age (adults and children) and status at transplant (first remission = CR1; second remission = CR2). (1) 1114 adult patients were transplanted in CR1; 516 received an allograft; 598 received an autograft. Following alloBMT, the transplant-related mortality (TRM) was significantly higher (27 vs 13%, P < 10(-4)), the relapse incidence (RI) lower (25 vs 52%, P < 10(-4)) and the leukemia-free survival (LFS) better (55 vs 42%, P = 0.006). Favorable prognostic factors for alloBMT were a FAB type other than M4-M5, a donor-recipient combination excluding a female donor to a male recipient, and a younger age. Favorable prognostic factors for ABMT were a younger age of the patients at time of transplant, the AML3 FAB type, and a longer interval from CR1 to ABMT. (2) 288 adult patients were transplanted in CR2: 98 received an allograft; 190 received an autograft. The TRM was higher following allogeneic BMT (32 vs 20%, P = 0.02) and the RI lower (42 vs 63%, P = 0.001). The LFS was not significantly different (alloBMT: 39%; ABMT: 30%, P = 0.22). (3) 242 children were transplanted in CR1; 129 received an allograft; 113 received an autograft. Following alloBMT, the RI was lower (25 + 5 vs 48 + 6%, P < 10(-4)), and the LFS better (68 vs 47%, P = 0.002). The use of TBI was a favorable prognostic factor in allografted patients with a lower RI and a better LFS. (4) The number of children transplanted in CR2 was too small for a comparative analysis. These results confirm that both allogeneic and autologous BMT are suitable curative approaches for AML. They favor the use of an HLA identical related allogeneic transplant when available, especially in younger patients, over ABMT with unpurged marrow. The role of purging in ABMT could not be addressed in this study.

Allogeneic bone marrow transplantation vs aggressive post-remission chemotherapy for children with acute myeloid leukemia in first complete remission. A prospective study from the French Society of Pediatric Hematology and Immunology (SHIP).

The objective of this study was to compare allogeneic bone marrow transplantation (BMT) with high-dose cytarabine containing chemotherapy in children with acute myeloid leukemia (AML) in first complete remission (CR). One hundred and seventy-one children were enrolled on the LAME89/91 protocol. Induction chemotherapy was a combination of cytarabine and mitoxantrone. After achieving CR, patients who had an HLA-identical sibling donor underwent allogeneic BMT. Children not eligible for BMT received post remission chemotherapy which included two consolidation courses, the second consolidation consisting of high-dose cytarabine with amsacrine and asparaginase. CR was achieved in 149 children (87%). Thirty-two had an HLA-identical sibling donor and were eligible for BMT. These 32 patients, as well as an additional child who had a one antigen HLA-mismatched father, received BMT during first CR. Consequently, 33 patients were analyzed in the BMT group and 116 in the chemotherapy group. The 4-year probability of relapse was 26 +/- 15% in the BMT group and 47 +/- 10% in the chemotherapy group (P = 0.04). The risk of therapy-related death was 3% for BMT and 7.7% for chemotherapy. Disease-free survival (DFS) was 72 +/- 15% in the BMT group and 48 +/- 10% in the chemotherapy group (p = 0.02). We conclude that allogeneic BMT from a matched sibling donor is the treatment of choice for reducing the relapse risk and for increasing DFS in children with AML in first CR.

Long-term outcome after allogeneic hematopoietic stem cell transplantation for advanced stage acute myeloblastic leukemia: a retrospective study of 379 patients reported to the Société Française de Greffe de Moelle (SFGM).

To assess the place of allogeneic hematopoietic stem cell transplantation (HSCT) in the advanced stage of acute myeloid leukemia (AML), we retrospectively analyzed 379 consecutive patients who underwent allogeneic HSCT for advanced AML. The median follow-up of the entire cohort was 7.5 years. Sixty-nine patients (18%) were transplanted with primary resistant disease. Three hundred and ten (82%) were relapsed patients, 94 (30%) of whom were in untreated relapse, 67 (22%) in refractory relapse and 149 (48%) in 2nd or 3rd complete remission at time of transplantation. The 5-year probabilities of overall survival (OS), disease-free survival (DFS), and transplant-related mortality (TRM) were 22 +/- 4%, 20 +/- 4%, 45 +/- 6%, respectively. In multivariate analysis, we demonstrated the favorable impact on OS, DFS and TRM of two factors over which we have no control (age <15 years, complete remission achievement) and three factors over which we have some control (female donor, acute and chronic graft-versus-host disease). The results of this study suggest that the graft-versus-leukemia effect is important in advanced AML and that new HSCT modalities are needed for some patients with this indication.

Recent treatments of aplastic anemia. The International Group on SAA.

The treatment of severe aplastic anemia has been modified recently by the demonstration that Cyclosporine A is active alone or in combination leading to more than 50% response rate. Combination or sequential treatments with ATG seem to be better than such drug separately but this must be studied in randomized studies. Long term follow-up is necessary to assess the rate of malignant transformation. Growth factors have been recently introduced. G or GM-CSF seem to be active. IL-3 has not been proven to be effective in very small non randomized study. Allogeneic bone marrow transplantation is the best treatment with a matched related donor, progress must be achieved in methods of conditioning and GVH prophylaxis when a matched unrelated donor is used.

Aplastic anemia associated with "bird-headed" dwarfism (Seckel syndrome).

The Seckel syndrome or "bird-headed" dwarfism associates a severe short stature, mental deficiency and various malformations with characteristic facial appearance. It has been described in these children a moderate or severe marrow hypoplasia. The aplasia is unlikely constitutional and different from the Fanconi disease hypoplasia. We report here 2 cases of a such association. One of them had been cured by bone marrow transplantation.

[Invasive aspergillosis and bone marrow allograft]. / Aspergillose invasive et allogreffe de moelle.

Invasive aspergillosis is the most frequent cause of infectious death after allogeneic bone marrow transplantation. Risk factors include the patient's condition (granulocytopenia, immunosuppression) and his environment (air spores count). Pulmonary infections are prominent. Other infections usually occur in the setting of disseminated disease via hematogenous spread. Cerebral aspergillosis appears to be especially frequent and of very poor prognosis. Infections of the paranasal sinuses occur less often and are associated or not with pneumonitis. Mycologically confirmed diagnosis is difficult to obtain: treatment will often have to be instored on clinical findings alone or even on an empiric basis. However, the prognosis remains extremely poor explaining the actual physicians' concern in finding a better prophylaxis of this infection.

Matched unrelated bone marrow transplants. Results from the French group (GEGMO).

From a bank of 50,000 HLA typed French bone marrow donors, 125 transplants have been performed since 1986, with HLA AB and DR--identical MLC--negative donors. The median age was 25 years and the diagnosis was CGL in 59 cases, ALL in 22 cases, AML in 17 cases, SAA in 7 cases, inborn errors in 7 cases and others in 13 cases. Most of the patients received a standard conditioning regimen according to their diagnosis. The prophylaxis of GVHD was methotrexate and cyclosporine A in 77 cases; in addition to this combination 44 patients received an anti-IL2 receptor monoclonal antibody from day +1 to day +28. There was no difference between the two groups as regards the incidence and severity of GVH or survival. The actuarial survival was 36% with a median follow up of 300 days. Unlike matched sibling grafts, the usual prognostic factors such as stage of disease or age were not found to significantly modify the incidence of GVHD, which was 75%. The results of matched unrelated donor transplants are reasonably good, but must be improved by a better selection of donors and better prevention of GVHD.

Prevention and treatment of CMV infection after allogeneic bone marrow transplant.

CMV infection is the major infectious complication following bone marrow transplantation. It is most often related to reactivation of latent infection in patients who were CMV seropositive before BMT. The incidence and severity have recently been modified by the use of preventive and curative treatments. Prevention of CMV infection with the transfusion of seronegative blood products is useful only when donor and recipient are seronegative. High-dose acyclovir has been shown effective in one randomized study. A multicenter study is currently being performed in Europe to confirm this result. Intravenous gammaglobulins seemed to lower the number of patients who incur interstitial pneumonitis but not the incidence of viremia. They also decreased the incidence of gram-negative sepsis and severe GVH and improved survival. The treatment is based on the use of gancyclovir. Several studies show that gancyclovir is more effective in asymptomatic patients with viral isolation from blood or bronchoalveolar lavage. The addition to gancyclovir of high-dose gammaglobulin improves survival in symptomatic patients with interstitial pneumonitis. This progress in the prevention and treatment of CMV infection has improved the overall results of allogeneic bone marrow transplantation.

Influence of various conditioning regimens on the outcome of bone marrow transplantation for leukemia.

Allogeneic bone marrow transplantation is widely used for the treatment of leukemias. Relapse is one of the main complications. Various types of conditioning have been used. Most teams use a combination of cyclophosphamide and different modalities of total body irradiation. In some regimens, high dose alkylating drugs like Busulfan are substituted for radiation. None of these regimens has modified significantly the long term disease free survival, indicating the need for prospective randomized trials.

Avascular necrosis of bone after allogeneic bone marrow transplantation: clinical findings, incidence and risk factors.

In the present study we describe the incidence, clinical course, and management of avascular necrosis of bone following allogeneic bone marrow transplantation, and identify risk factors related to its development. All patients developing avascular necrosis of bone after allogeneic bone marrow transplantation between January 1974 and September 1992 were included in the analysis and were studied using the Hôpital Saint Louis Bone Marrow Transplant Database and hospital records. 27/727 allogeneic transplant recipients developed avascular necrosis leading to an 8.1% incidence at 5 years, by product limit estimate, ranging from 5% to 11.2%. Symptoms developed 119-1747 d (median 398 d) after transplantation. In these 27 patients a total of 52 joints were affected (mean 1.92 per patient, range 1-7). The hip joint was most often affected (69% of patients). All patients had joint pain that led to diagnosis by means of standard radiographs with or without the help of technetium-99 scans and/or magnetic resonance imaging. All but three patients received steroid therapy for acute graft-versus-host disease. Among 10 factors tested, three were shown to be significantly linked to an increased risk for developing avascular necrosis by multivariate analysis: male gender (relative risk (RR) 4.72, P = 0.002), age older than 16 (RR = 3.87, P = 0.004), and acute graft-versus-host disease requiring steroid therapy (RR = 6.30, P = 0.0002). 10 patients (37%) required joint replacement within 19 months (range 2-42) following diagnosis of avascular necrosis. In conclusion, avascular necrosis of bone is a frequent late complication of allogeneic bone marrow transplantation causing significant morbidity and requiring replacement surgery in one-third of affected patients. In this 18-year single-centre survey, older age, male gender and steroid therapy given for acute graft-versus-host disease were shown to independently increase the risk of avascular necrosis of bone.