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.

Bone marrow donors other than HLA genotypically identical siblings for patients with thalassemia.

This report describes the successful bone marrow transplantation of three children with thalassemia who received bone marrow, one from an HLA identical but mixed lymphocyte culture-reactive sibling, the other two from an HLA phenotypically identical parent. Evidence of engraftment was detected early (19-21 days) in all three children and only grade II acute GvHD was observed in one patient. Our report indicates that thalassemic patients can be cured by bone marrow transplantation from selected donors other than HLA genotypically identical siblings.

Allogeneic marrow transplantation for thalassemia.

Thirteen patients with homozygous beta thalassemia underwent allogeneic marrow transplantation from sibling donors, 12 of whom were heterozygous for beta thalassemia. Six patients were transplanted in an advanced stage of their disease while seven were transplanted early in their disease course. Donors and recipients were genotypically identical for the HLA-A, -B and -D loci in 11 cases and mismatched for the D locus in two. A variety of preparative regimens was utilized involving high doses of busulphan (Bu) and/or cyclophosphamide (CY) and/or total body irradiation (TBI). Failure of engraftment or autologous hematologic recovery after transient engraftment was seen after intensive preparative regimens including: CY 200 mg/kg and 800 rad of TBI; Bu 8 mg/kg and CY 200 mg/kg; and Bu 8 mg/kg, CY 200 mg/kg, and 300 rad of TBI. A regimen of Bu 16 mg/kg, CY 200 mg/kg, and 400 rad of TBI resulted in deaths from transplant-related causes in the three patients treated with this regimen. Seven of the 13 patients are surviving 363-665 days after transplant. Five of the seven failed to achieve engraftment or had autologous reconstitution after transient engraftment. Five of the six deaths were transplant related, and one patient died of cardiac failure one year after an unsuccessful transplant attempt. Two patients are surviving with engraftment and without thalassemia major 363 and 491 days after transplantation. Both of these patients were transplanted early in their disease course.

A comparative trial of posttransplant immunosuppression in patients transplanted for thalassemia. Cyclosporine alone versus cyclosporine, cyclophosphamide, and methotrexate.

This study compares the efficacy of 2 posttransplant immunosuppressive regimens for prevention of graft-versus-host disease (GVHD). Forty-four patients, ages 8-15 years, with homozygous beta thalassemia received marrow allografts from HLA-identical siblings following an ablative regimen of busulfan and cyclophosphamide. Twenty-two patients received cyclosporine (CsA) alone and 22 received cyclosporine, cyclophosphamide, and methotrexate for prophylaxis against GVHD. Two who received CsA alone have died (1 of graft rejection and 1 of acute GVHD) as did 4 patients who received 3 drugs (1 of rejection, 1 of acute GVHD, 1 of infection and cardiac failure before engraftment, and 1 of acute respiratory failure before engraftment). One patient in each group rejected the transplant and survives with thalassemia. The probability of developing acute GVHD was 41% for the CsA group and 15% for the 3-drug group (P = less than 0.05). Patients receiving CsA alone had a probability of event-free survival of 86% compared to 77% in the group receiving 3 drugs (P = 0.40) with a followup of 209-706 days. Although the study showed a decrease in the incidence of GVHD in recipients of the more intensive prophylactic regimen, this study was terminated since it was apparent that even if larger numbers of patients were studied it would be difficult to demonstrate a significant survival advantage with the use of this drug regimen.

Graft-versus-host disease after bone marrow transplantation for thalassemia: an analysis of incidence and risk factors.

We analyzed risk factors in 724 patients evaluable for acute graft-versus-host disease (GVHD) and in 614 patients evaluable for chronic GVHD who had received bone marrow transplantation (BMT) from HLA-identical siblings and/or parents for thalassemia and/or microdrepanocytosis, in a single institution. The overall incidence of grade II-IV and III-IV acute GVHD (aGVHD) was 26.9% and 13.5%, respectively. The cumulative incidence of grade II-IV aGVHD in patients treated with cyclosporine (CsA)/methylprednisolone (MP) or CsA/methotrexate (MTX)/MP was 32% and 17%, respectively (P=0.001). In logistic regression analysis, the risk factors associated with the onset of grade II-IV aGVHD in the entire group of patients were: patient age < or = 4 years (P=0.009), male patient sex (P=0.023), GVHD prophylaxis with CsA/MP or MTX/MP (P=0.000), more than twofold elevated alanine aminotransferase (P=0.001), and patient seropositivity for two to three herpes viruses (P=0.007). In patients treated with CsA/MP, splenomegaly > 2 cm (P=0.042) and donor age > or = 17 years (P=0.034) predicted aGVHD. Risk factors for grade III-IV aGVHD were similar to the risk factors identified for grade II-IV aGVHD. Moreover, moderate and severe liver fibrosis or cirrhosis predicted grade III-IV aGVHD (P=0.018). The incidence of chronic GVHD (cGVHD) was 27.3%. The probability of cGVHD at 2 years after BMT in patients with grade 0, I, II, and III-IV aGVHD was 15%, 32%, 53%, and 54%, respectively. Among patients with absent or grade I-IV aGVHD, prior aGVHD (P=0.000), female donor sex (P=0.000), use of alloimmune female donors for male patients (0.009), and GVHD prophylaxis with CsA/MP or MTX/MP (P=0.003) predicted cGVHD. This data should be considered in clinical management and in future investigations for improvement of immunosuppressive prophylaxis in BMT patients with thalassemia.

Immunologic recovery in thalassemic marrow graft recipients following high-dose busulfan and cyclophosphamide.

T lymphocyte subsets, mitogenic response, and immunoglobulin levels were studied in peripheral blood from 95 thalassemic patients before and at different times after bone marrow transplantation. With the exception of patients receiving more than 100 transfusion units before transplant, who showed an increased percentage of CD8-positive cells, thalassemic patients were essentially immunologically normal. Depressed lymphocyte proliferative response to phytohemagglutinin, concanavalin-A, and pokeweed mitogen; decreased IgG, IgM and IgA levels; and abnormal T subpopulation distribution were observed early after transplant. Long-term transplanted patients showed complete recovery of the immunological profile with the exception of the IgA levels, which were significantly decreased up to 2 years after transplant.

Chronic graft-versus-host disease: is there an alternative to the conventional treatment?

Despite conventional and new therapies for the treatment of chronic GVHD (cGVHD), this syndrome continues to account for significant morbidity and mortality after allogeneic hematopoietic stem cell transplantation. With the expanded use of allogeneic peripheral blood stem cell transplantation, matched unrelated as well as mismatched related donors there is an increased incidence of cGVHD that poses a new clinical challenge. Over the past 10 years some new agents have been used, particularly, as a salvage therapy for the treatment of cGVHD. Many of the new agents discussed in this paper may have a role in the future as a therapy for cGVHD. Randomized clinical trials must be performed earlier in the course of cGVHD to establish the efficacy of these new drugs.

Long-term complete remission after allogeneic bone marrow transplantation in multiple myeloma.

We report a case of IgG lambda type multiple myeloma treated by allogeneic bone marrow transplantation. After transplant the monoclonal protein persisted for 2 years with no other sign of disease. Thereafter the monoclonal protein was no longer detectable and the patient was considered to be in complete remission for the next 4 years.

Cytomegalovirus infections in thalassemic patients after bone marrow transplantation.

We report the incidence of cytomegalovirus (CMV) seroconversion, infections and mortality in 169 consecutive thalassemic patients transplanted in Pesaro. We observed a 44% incidence of early seroconversion and a 52% incidence of late seroconversion. No relationship was found between seroconversion and acute or chronic graft-versus-host disease (GVHD) or rejection. The donor status did not influence the incidence of seroconversion, GVHD and rejection. Only three patients died of CMV infection (1.7%); in each case CMV disease was the final cause of death in patients with severe acute GVHD.

Haploidentical bone marrow transplantation from mother to child with advanced leukemia.

Use of the mother as mismatched marrow donor was assessed in 19 children with advanced leukemia. Patients were homogeneous for HLA incompatibility, age, donor, and conditioning regimen, and stage of disease. All received busulfan and cytoxan, combined with unmodified donor marrow, ALG given before and after transplant, and short MTX and cyclosporine as GVHD prophylaxis. Survival, LFS, and relapse respectively were 26, 26, and 33%. Incidence of overall and severe acute GVHD was 58 and 32%, respectively. Four patients had failure of engraftment, and two of these are alive with autologous reconstitution in complete remission. Probability of rejection was 21%. Results of haploidentical transplants were compared with those of children with advanced leukemia treated at the same institution, who received marrow from HLA-identical siblings. The probability of long-term leukemia-free survival was similar in the two groups. We thus propose using the mother as an alternative marrow donor in children with advanced leukemia.

Suprapubic cystotomy as treatment for severe hemorrhagic cystitis after bone marrow transplantation.

We analyzed the success of suprapubic cystotomy in patients with severe hemorrhagic cystitis after bone marrow transplantation. Seventy-three out of 963 patients developed severe hemorrhagic cystitis which resulted in urinary tract obstruction after high-dose cytoreductive therapy. Eleven patients (15%) failed medical treatment and required emergency suprapubic cystotomy. Three of these patients died of other complications prior to resolution of HC. Of the remaining 8 patients who underwent surgery, 4 are alive. The mortality rate was significantly higher in patients who required surgery than in those who responded to medical therapy. Patients whose HC required surgery also had a greater transfusion requirement than those who responded to medical therapy. We conclude that surgical treatment of severe HC should be undertaken only after failure of medical therapy.

CsA-associated neurotoxicity and ineffective prophylaxis with clonazepam in patients transplanted for thalassemia major: analysis of risk factors.

Cyclosporin A (CsA) has been shown to be useful in the prophylaxis of acute graft-versus-host-disease (GVHD). However, this immunosuppressive agent produces multiple side-effects including nephrotoxicity, hypertension, hypertricosis, gum hyperplasia, infections, and neurotoxicity. We report a retrospective analysis of neurotoxicity in 625 recipients transplanted for thalassemia and given CsA as part of GVHD prophylaxis. Neurotoxicity consisted in mental status changes, tremor, headache (grade 1), visual disturbance and cortical blindness (grade 2) and seizures and coma (grade 3). The overall toxicity was 28.8% and the incidence of convulsions was 10.1%. Neurological findings were reversible after temporary reduction or discontinuation of CsA. Class 3 patients, when prepared with protocol 6 (Bu 14 + Cy 200 and CsA for GVHD) or when they developed acute GVHD, had the highest risk of convulsions. Age, sex, different conditioning regimens, different anticonvulsive prophylaxis, liver damage due to iron-overload and/or to chronic inflammation did not influence the occurrence of CsA-related CNS toxicity. The occurrence of acute GVHD with concomitant use of high-dose corticosteroids is the single significant predisposing factor in the occurrence of convulsions. Grades 1 and 2 of neurotoxicity occurred earlier and were not influenced even by acute GVHD.

Trichosporon beigelii: a life-threatening pathogen in immunocompromised hosts.

Patients undergoing bone marrow transplantation are profoundly immunosuppressed as a result of their intensive myeloablative chemotherapy and are at high risk for opportunistic fungal infections mainly caused by Candida spp and Aspergillus spp. Trichosporon beigelii (T beigelii) has emerged as a life-threatening opportunistic pathogen in granulocytopenic and immunocompromised hosts and there is a marked increase in cases reported in the literature. Response to antifungal agents is poor, mortality is high and immunological recovery is the most important factor for a favorable outcome in patients with trichosporonosis. We present three cases of T. beigelii infection in patients undergoing allogeneic bone marrow transplantation in our center and we review cases described in the literature.

Hepatitis C virus infection in thalassemia patients undergoing allogeneic bone marrow transplantation.

Ninety-eight patients with homozygous-beta thalassemia who had undergone allogeneic bone marrow transplantation (BMT) between May 1990 and March 1992 were tested for hepatitis C antibodies (anti-HCV) before and after BMT. Anti-HCV positivity was detected in 50 of the 98 patients (51%) before BMT. Seroconversion was demonstrated in seven of the 40 evaluable seronegative patients. In four cases it was probably due to the different sensitivity of first and second generation ELISA. Of the 46 evaluable seropositive patients 4 had transient and 5 persistent negativity for HCV antibodies after BMT. The high prevalence of anti-HCV positivity in thalassemic patients is related to the continuous requirement for blood transfusions. We found a strong correlation between biochemical and histological evidence of liver damage and anti-HCV positive status in multi-transfused patients. In our experience HCV hepatitis does not influence the outcome of BMT.

Allogeneic bone marrow transplantation in children with acute myelogenous leukemia in first remission. Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP) and the Gruppo Italiano per il Trapianto di Midollo Osseo (GITMO).

Fifty-nine children, aged 1-15 years, with acute myelogenous leukemia (AML) received a bone marrow transplant (BMT) from an HLA-identical sibling (n = 57) or from an identical twin (n = 2), while in first remission (CR). These children represent, to the best of our knowledge, all children grafted in first CR in 11 Italian centers between 1980 and 1990. Patients were prepared with total body irradiation (TBI) plus cyclophosphamide (CY) (n = 50) or melphalan (n = 2) or with busulfan plus CY (n = 7). GVHD prophylaxis consisted of cyclosporin A (n = 48), methotrexate (n = 7) or cyclosporin and methotrexate (n = 2). Survivors have been followed for 21-137 months (median 59 months). Actuarial relapse-free survival was 58% at 66-137 months (95% confidence interval (CI) 44-72). Actuarial risk of relapse was 23% at 48 months (95% CI 10.9-34.8). Risk of non-relapse deaths was 33% in the period 1980-87 and 4% in the period 1988-90 (p = 0.02). In multivariate analysis patients with a blood cell count > 14 x 10(9)/l at diagnosis showed a lower relapse-free survival compared with patients with counts < 14 x 10(9)/l (p = 0.006). We could not detect an effect of FAB subtype, patient age, time to achieve remission or transplant-related variables, including year of BMT, on relapse-free survival. In conclusion, allogeneic marrow transplantation can achieve long-term relapse-free survival in over 50% of children with AML and should be considered as consolidation therapy if a matched sibling is available.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac tamponade in thalassemia.

We report a case of acute cardiac tamponade without concurrent myocardial disease occurring in a thalassemia patient early after bone marrow transplantation. The pericardial effusion was preceded by an episode of junctional tachycardia. Repeated evaluation by echocardiography was done shortly after the patient developed the arrhythmia and permitted a detailed, timed observation of the event and description of the symptoms.

Bone marrow transplantation for transfused patients with severe aplastic anemia using cyclophosphamide and total lymphoid irradiation as conditioning therapy: long-term follow-up from a single center.

In transfused patients with aplastic anemia, incidence of graft rejection remains significant. Seventeen transfused patients with severe aplastic anemia received BMT from HLA-identical sibling donors after conditioning with cyclophosphamide (CY, 50 mg/kg/day for 4 days) plus total lymphoid irradiation (TLI, 750 cGy in a single dose). For graft-versus-host disease (GVHD) prophylaxis one patient received methotrexate, five patients received CsA and 11 received CsA in association with methylprednisolone. All patients had sustained engraftment. The actuarial survival of patients was 76% with a median follow-up for surviving patients of 11 years (range 0.3-14.5 years). The incidence of grade II-III acute GVHD was 24%, and chronic GVHD 35%. Median Karnofsky score of surviving patients is 100 (range 90-100). Only one patient developed interstitial pneumonia. None of the patients has developed a malignancy after BMT. The role of limited field irradiation in development of malignant neoplasms after BMT for aplastic anemia is discussed. We conclude that a conditioning regimen using CY + TLI in sensitized aplastic anemia patients results in a high survival rate on long-term follow-up.

An unusual marrow transplant complication: cardiac myxoma.

We report a right atrial myxoma which suddenly developed in a thalassemic patient after allogeneic bone marrow transplantation. The tumor was first detected by echocardiography on day +47 after transplant and the patient underwent surgical removal of the myxoma on day +103. The post-operative course was uneventful, and at more than 3 years from the event, he is alive and well, cured from his congenital disease, with no detectable intra-cardiac tumor. The onset of the myxoma in the early post-transplant period and the extremely high velocity of growth suggest a possible relationship of this condition with the immunosuppressive status.

Second marrow transplants for graft failure in patients with thalassemia.

Thirty-two thalassemic patients with a median age of 7.7 years (range 3.4-26 years) were given a second HLA-identical related marrow transplant (BMT2) for graft failure. Four patients were in class 1 and 28 patients in classes 2 and 3. Twenty-one patients had full thalassemia recurrence (first group) and 11 patients had aplastic marrows (second group) either with or without residual donor marrow cells after the first BMT (BMT1). As conditioning regimen for BMT2 all but five patients received BUCY or CY in association with total lymphoid irradiation (TLI) and/or anti-lymphocyte globulin (ALG), whereas nine patients received a new preparative regimen with hydroxyurea, azathioprine, fludarabine before conditioning with BUCY. Twenty one of 31 evaluable patients (67.7%) had initial, and 16 (51.6%) had sustained engraftment. Ten patients (32.3%) failed to engraft. Overall and event-free survival for the entire group of patients were 49% and 33%, respectively, with a median follow-up of 4 years (range 0.6-14 years) for surviving patients. Event-free survival was higher in the second group of patients compared with the first group (41% vs 29%). The second group of patients appeared to have less graft failure compared with the first group (30% vs 63%; P = 0.1). Transplant-related mortality was 28%. A linear stepwise regression analysis revealed that occurrence of graft failure within 60 days after BMT1 (P = 0.04) and absence of residual donor marrow cells (P = 0.009) predicted for graft failure following BMT2, whereas the occurrence of graft failure after 60 days (P = 0.03) had a positive influence on survival following BMT2. The incidence of grade >/=2 acute GVHD was low (14%). Eight of nine patients who received the new preparative regimen are alive, four without thalassemia. This study shows that BMT2 can be an effective therapy for a proportion of patients with poor survival expectancies despite conventional treatment.

A three or more drug combination as effective therapy for moderate or severe chronic graft-versus-host disease.

We analyzed the results of a three or more drug combination as treatment for moderate or severe cGVHD developing after transplantation for thalassemia, in 45 patients with median age of 11 (range 2-26) years. Eighteen patients received a three drug regimen with cyclosporine (CsA), methylprednisolone (MP) and azathioprine (AZ) as first line therapy, 16 patients received this regimen as salvage therapy and 11 patients were given a four or five drug regimen with CsA, MP, AZ, cyclophosphamide (CY) and/or methotrexate (MTX) mainly as salvage therapy. The overall complete response (CR) rate was 77.3%, with 94% of CR in patients receiving the three drug regimen as first line, 88% in patients receiving it as salvage therapy and 36.6% in patients given the four or five drug regimen. The probability of CR in patients given the three drug regimen as first or salvage therapy or the four/five drug regimen was 89%, 53% and 30%, while the probability of survival was 89%, 65% and 58%, respectively. The incidence of treatment failure was low in our patients. Patients treated with the three drug regimen as first line therapy had less treatment-related complications than patients receiving this regimen as salvage therapy or patients given the four or five drug regimen. The main causes of treatment-related mortality (20%) were infectious complications. This retrospective study showed that a three or more drug combination is safe and effective for treatment of moderate or severe cGVHD at least in younger patients.