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Treatment of childhood acute lymphoblastic leukemia in second remission with allogeneic bone marrow transplantation and chemotherapy: ten-year experience of the Italian Bone Marrow Transplantation Group and the Italian Pediatric Hematology Oncology Association.

PURPOSE: To compare the results of allogeneic bone marrow transplantation (AlloBMT) with those obtained with chemotherapy (CHEMO) in children with acute lymphoblastic leukemia (ALL) in second complete remission (CR) after a marrow relapse. The experience of the Italian Bone Marrow Transplantation Group and the Italian Pediatric Hematology Oncology Association is summarized. PATIENTS AND METHODS: All children who had a relapse in the period 1980 to 1989 in 27 centers in Italy were eligible for the study. Of 287 eligible patients, 230 were treated with CHEMO, most of them (93%) according to a standard multiple-drug relapse protocol. The remaining 57 children underwent AlloBMT. Preparative regimens included total-body irradiation and chemotherapy (n = 51) or chemotherapy alone (n = 6). Statistical analysis was performed with a Cox regression model adjusting for waiting time to transplant and prognostic factors. RESULTS: In the whole series, minimum and median follow-up after second CR were 3 and 6.2 years, respectively; at 8 years from second CR, disease-free survival (DFS) was 20.0% (SE 2.5) and survival was 26.4% (SE 2.9). In the group of patients with an early first relapse, DFS was significantly longer after AlloBMT than after CHEMO (relative risk [RR] = 0.45, P = .002). No significant advantage of AlloBMT over CHEMO was found for patients with a late relapse (> 30 months since diagnosis). Duration of first CR significantly influenced prognosis in the CHEMO group (RR = 0.32, P = .0001 for patients with late first relapse versus patients with early first relapse). CONCLUSION: Results suggest an advantage in DFS of AlloBMT over CHEMO in ALL patients who experienced an early first medullary relapse. Prospective trials are needed to address efficacy of AlloBMT versus CHEMO in patients with late bone marrow relapse.

Adolescent↗

Percutaneous autologous bone marrow grafting for simple bone cysts.

Twelve patients with simple bone cysts treated by percutaneous autologous bone marrow grafting were studied prospectively to evaluate the radiographic healing of the cysts, complications, and clinical outcome. The procedure included percutaneous aspiration of the cyst's fluid and the injection of the autologous bone marrow into the cyst cavity, which was aspirated from the posterior iliac crest. The mean volume of the lesions was 51.2 cubic centimeters (27 to 74 cc). The mean follow-up time was 23 months (range: 18 to 38 months). Complete healing occurred in two of the patients. Three cysts had residual cystic defect in which two required curettage and bone chip grafts. Six cases recurred. One patient failed to show any signs healing. We concluded that factors such as the size, multi-loculation, and completeness of the filling of the cyst with bone marrow grafting might influence the postoperative results of the treatment of simple bone cysts with bone marrow injection. We found more favorable result with unilobular, small cysts. Therefore, we believe that this method of treatment should be applied to carefully selected patients.

Adolescent↗

Indications for bone marrow grafting.

Bone marrow transplantation has found during the last decade his major indications which are severe aplastic anemia and acute leukemia in complete remission. For the time being, bone marrow transplant is feasible only if the patient has an HLA identical sibling. Efforts are being made to improve the prognosis of complications such as graft versus host disease and interstitial pneumonitis. The long term survival currently obtained is over 50 per cent.

Acute Disease↗

The incidence of DPB1 differences between serological and mixed lymphocyte culture matched unrelated individuals: implications for selection of bone marrow donors.

Bone marrow transplantation from unrelated donors is being used increasingly for the treatment of patients with leukaemia and other disorders of lymphohaemopoiesis. Selection of histocompatible unrelated bone marrow donors currently relies on serological HLA identity and negative mixed lymphocyte cultures (MLC) between potential donor-recipient pairs. Since serological HLA-DP typing is not feasible, we used the HLA-DPB1 oligonucleotide typing method to test whether the current selection procedure can also guarantee identity for HLA-DP. In 40 consecutive patients, one-third (62/193) of the serologically HLA-A, -B, -C, -DR and -DQ identical donors were judged as MLC negative (relative response below 5%) with the presumptive recipient. HLA-DPB1 oligonucleotide typing of the MLC negative donors revealed that only one-third of these (20/62) were also identical for DP. In the majority of the pairs, we found a DPB1 disparity. A difference in the graft-versus-host direction was seen in 25/62 cases in the host-versus-graft direction in 28/62 cases and in both directions in 29/62 cases. These data indicate that, in spite of the strict MLC criteria used, the current procedure did not guarantee complete MHC class II identity. Therefore oligotyping for DPB1 can improve matching for DP and should be introduced for typing of volunteers. We suspect that DP differences may contribute to the higher incidence of graft-versus-host disease or graft rejection in unrelated donor transplants.

Bone Marrow Transplantation↗

Bone marrow obtained during hip surgery: a novel source for studies of hemopoiesis in human long-term bone marrow culture (LTBMC).

Studies with human bone marrow cells are often impaired by the poor quality of sternal aspirates due to varying numbers of contaminating blood cells before enrichment procedures and insufficient progenitor cell yields. In this study we report on experiments performed with human bone marrow cells isolated from a) spongiose bone fragments collected during hip surgery in patients with osteoarthritis or b) sternal aspirates. After Ficoll-Histopaque density gradient centrifugation absolute cell numbers were always lower in the samples obtained from sternal aspirates. However, both sources proved to yield the same proportions of the respective myeloid cell populations. Human long-term bone marrow cultures (LTBMC), semi-solid agar assays (CFU-GM day 14), and 3H-thymidine incorporation assays proved the comparability of the two bone marrow sources.

Adult↗

Pityriasis rosea-like eruption after bone marrow transplantation.

Bone marrow transplantation is associated with numerous cutaneous complications that may be related to the underlying (preexisting) disease, to pretransplant conditioning, to immunosuppression, to concomitant medication, or to graft-versus-host reaction. We describe four bone marrow transplant recipients with the clinical and histologic features of pityriasis rosea, a hitherto unreported association.

Adult↗

Rehabilitation following bone marrow transplantation.

Bone marrow transplantation and stem cell transplantation are increasingly used to treat hematologic malignancies and some solid tumors. The treatment entails bone marrow-ablative therapies and intensive medical support to sustain the patient through pancytopenia and other complications of the disease, transplantation process, or drug side effects. Patients who develop graft-versus-host disease are the most difficult subset of transplant recipients to manage. Most transplant recipients perform at normal or near-normal functional levels at the inception of the transplantation process but are at high risk for developing functional deficits as a result of cumulative impairments. These impairments arise from their disease, their prior cancer treatment, transplant induction, graft-versus-host disease, immobility, infection, steroid-related side effects, and other sequelae of transplantation. Preventive and preemptive rehabilitation interventions can minimize functional loss and facilitate recovery, but the transplantation team must be sensitive to and regularly assess for early functional declines in these patients. The physiatrist and the other members of the rehabilitation team must be thoroughly acquainted with the unique needs and challenges of the bone marrow transplantation population in order to design and modify treatment programs effectively and safely. Outcome research has shown that some patients have continued limitations in function despite successful transplantation. Few evidence-based data are available that addresses factors correlating with poor functional outcomes other than graft-versus-host disease. However, this disease has not been investigated utilizing objective functional instruments. Future research should more clearly elucidate the functional impact of allogeneic and autologous transplants by using standardized physical performance measures as well as thorough function-based symptomatology questionnaires.

Bone Marrow Transplantation↗

Unrelated bone marrow transplantation as a rescue procedure following inadvertent loss of an autologous bone marrow graft.

We report a 27-year-old male patient with acute myeloid leukaemia who was successfully treated with an unrelated bone marrow graft within 7 days following the loss of his autologous bone marrow graft. Several factors were found to be essential in order to locate an HLA-ABDR (DRB1)DQ(DQB1) identical, sex-matched, CMV-negative and ABO compatible donor within a week. These included a common HLA phenotype of the patient, the presence of an experienced donor registry in close proximity to a blood bank associated with an HLA laboratory, a large donor file with fully HLA-ABDR typed donors and the almost exclusive use of blood bank donors as potential bone marrow donors. The possibility of further streamlining the logistics of finding a suitable unrelated bone marrow donor is discussed.

Adult↗

[Psychological adaptation to bone marrow transplantation].

Bone marrow transplantation, used with increasing success over the past ten years, is recognized as highly stressful. Physiological and psychological rehabilitation after treatment is often difficult. This paper outlines the psychological issues encountered by adult patients with haematological malignancies through a review of the adjustment disorders associated with bone marrow transplantation, their prevalence, symptomatology and predictive factors. Some guidelines are proposed for the prevention of the stresses associated with hospitalization.

Adaptation, Psychological↗

T-cell depletion does not affect long-term human bone marrow culture.

Bone marrow long-term cultures were studied for 8 weeks in four experiments before and after T-cell depletion with a mixture of monoclonal antibodies directed against CD2, CD5 and CD7. No differences in cellularity or granulomonocytic progenitor numbers appeared during the period of culture. We conclude that in vitro treatment in itself is not likely to explain non-take or graft rejection associated with T-depleted bone marrow transplantation.

Animals↗

[Psychological aspects of bone marrow donation in donor brothers and sisters in bone marrow transplantation].

It appears to be necessary to consider, during a bone marrow transplantation, brothers and sisters who are donors. These children face psychological difficulties, which are not always understood by medical staff and families who are mainly concerned with the health of the sick children. Systematic meetings with a hundred donors point out the distress experienced in these situations.

Bone Marrow Transplantation↗

[Bone marrow transplantation].

Bone marrow transplantation (BMT) has evolved from an experimental undertaking to an established therapeutic strategy for hematological neoplasias, severe aplastic anemia, congenital immunological and metabolic disorders and some solid tumors. This report summarizes the main indications for autologous and allogenic transplants, the prerequisites and potential techniques, early and late complications as well as preventive and therapeutic strategies. The results of 397 BMT, 357 allogeneic and 40 autologous transplants, performed in Basel between 1973 and 1995, illustrate the present potential and main prognostic factors: stage of disease, age and histocompatibility. 50% of the patients treated with an allogeneic BMT from an HLA-identical sibling early in the disease are alive 15 years post BMT, 80% free of disease and reintegrated into work and family. New strategies are testing the use of unrelated HLA-compatible volunteer donors and the potential of mobilized peripheral blood precursor cells instead of bone marrow for allogeneic and autologous transplants.

Bone Marrow Transplantation↗

Oral cavity complications of bone marrow transplantation.

Bone marrow transplantation, once regarded as experimental, has evolved into a standard treatment for a variety of malignancies. Considerable advances have been made in histocompatibility typing, pretransplantation chemotherapy, and posttransplantation immunosuppressive therapy as well as prophylaxis and treatment of infections. Oral complications develop in almost all patients, and their early recognition may result in the institution of prompt treatment and prolonged survival. Mucositis, often severe and extremely painful, develops in more than three quarters of bone marrow transplant recipients, and its prevention, unfortunately, remains unsatisfactory. Herpes simplex virus and Candida albicans account for most oral infections, although their incidence has been dramatically reduced by the institution of prophylactic agents. Graft versus host disease continues to be a significant complication of marrow transplantation, and the detection of commonly occurring oral changes may support its diagnosis.

Antineoplastic Agents↗

Production and functional properties of eosinophils from bone marrow cultures.

Bone marrow cultures have been established from mice infected with Mesocestoides corti and undergoing parasitic eosinophilia. In the absence of added conditioned medium, eosinophil differentiation ceases, and eosinophils are undetectable by 7 days, whereas neutrophil production continues over several weeks as with normal bone marrow. Eosinophil production can be induced by adding pokeweed mitogen-stimulated spleen supernatants (MSSS) or specific antigen-stimulated spleen supernatants (ASSS) produced from-spleen cells of M. corti-infected mice. In contrast to the continuous production of neutrophils, eosinophil production is transient, suggesting that there is no continued production of eosinophil progenitor cells in these cultures. More eosinophils are produced when MSSS is added at the initiation of cultures, compared to after a delay of 2 weeks, and establishing the cultures at 33 degrees C does not appear to enhance eosinophil production. The eosinophils produced are shown to express the eosinophil differentiation antigen defined by monoclonal antibody NIMP-R13, they produce eosinophil peroxidase in similar amounts to eosinophils taken from mice. They show normal phagocytic activity of antibody-coated erythrocytes and lyse red cells coated with antibodies of IgG1, IgG2a, IgG2b, but not IgM isotypes.

Animals↗

Assessment of cellularity in bone marrow fragments.

Bone marrow cellularity was measured using the Quantimet 720 Image Analyser in 50 biopsy samples. In haematologically normal subjects the percentage cellularity of the marrow was between 40 and 63%. Subjective assessment of cellularity was an unreliable indicator of the quantitative measure.

Biopsy↗

In vitro purging of bone marrow with mafosfamide synergizes with in vivo chemotherapy to delay the hematological recovery in a murine model of autologous bone marrow transplantation.

Very long-lasting leukopenias and thrombocytopenias have been observed in patients submitted to transplantation of autologous bone marrow incubated in vitro with cyclophosphamide derivatives. With the aim of evaluating the contribution of in vitro exposure of bone marrow to mafosfamide (Asta-Z) and of in vivo chemotherapy given before bone marrow collection in these cytopenias, we designed a murine model of syngeneic bone marrow transplantation including treatment of donor and recipient mice with high doses of cyclophosphamide and in vitro exposure of the bone marrow transplant to Asta-Z. Blood platelets and leukocytes, medullary splenic colony forming unit (CFU-S), committed megacaryocytic (CFU-Meg) and granulomacrophagic (CFU-GM) precursor cell recovery was followed up to 56 days posttransplant. The data indicate that in vitro exposure of bone marrow to Asta-Z before reinfusion increases the delay in platelet recovery already induced by the chemotherapy given to donor mice and is specifically responsible for the prolongation of leukopenia. In recipient bone marrow, a synergy between the ablative effect of the in vitro treatment of bone marrow graft and the chemotherapy given to donors and recipients on CFU-S, CFU-Meg and CFU-GM was found.

Animals↗

Donor immunization with Haemophilus influenzae type b (HIB)-conjugate vaccine in allogeneic bone marrow transplantation.

Bone marrow transplant patients are at increased risk for infections with polysaccharide encapsulated organisms and respond poorly to polysaccharide vaccines. We evaluated the effect of donor immunization with Haemophilus influenzae type b (HIB) polysaccharide-conjugate vaccine on recipient antibody responses following allogeneic bone marrow transplantation. Thirty-two allogeneic transplant patients and their donors were immunized before transplantation with HIB-conjugate, tetanus toxoid and 23-valent pneumococcal vaccines. Following transplantation, patients received HIB-conjugate and tetanus toxoid vaccines at 3, 6, 12, and 24 months and 23-valent pneumococcal vaccine at 12 and 24 months. Thirty-three patients with unimmunized donors were immunized following transplantation in an identical manner. Patients whose donors were immunized had significantly higher total anti-HIB antibody concentrations at 3 months (P = .0001), 6 months (P = .0001), 12 months (P = .0001), and 24 months (P = .002) after transplant compared with patients whose donors were unimmunized. Higher antitetanus toxoid antibody concentrations were also noted in patients with immunized donors, whereas donor immunization with pneumococcal vaccine had no effect on antibody concentrations following transplantation. Donor immunization with HIB-conjugate vaccine resulted in higher antibody concentrations in patients as early as 3 months after allogeneic transplantation and may be an effective strategy to prevent HIB infections.

Adolescent↗