Marrow Transplantation For Acute Leukemia Research Articles

Influence of Age on Acute and Chronic GVHD in Children Undergoing HLA-Identical Sibling Bone Marrow Transplantation for Acute Leukemia: Implications for Prophylaxis

Relapse remains the major cause of mortality after hematopoietic cell transplantation (HCT) for pediatric acute leukemia. Previous research has suggested that reducing the intensity of calcineurin inhibitor-based graft-versus-host disease (GVHD) prophylaxis may be an effective strategy for abrogating the risk of relapse in pediatric patients undergoing matched sibling donor (MSD) HCT. We reasoned that the benefits of this strategy could be maximized by selectively applying it to those patients least likely to develop GVHD. We conducted a study of risk factors for GVHD, to risk-stratify patients based on age. Patients age <18 years with leukemia who received myeloablative, T cell-replete MSD bone marrow transplantation and calcineurin inhibitor-based GVHD prophylaxis between 2000 and 2013 and were entered into the Center for International Blood and Marrow Transplant Research registry were included. The cumulative incidence of grade II-IV acute GVHD (aGVHD) was 19%, that of grade II-IV aGVHD 7%, and that of chronic GVHD (cGVHD) was 16%. Compared with age 13 to 18 years, age 2 to 12 years was associated with a lower risk of grade II-IV aGVHD (hazard ratio [HR], .42; 95% confidence interval [CI], .26 to .70; P = .0008), grade II-IV aGVHD (HR, .24; 95% CI, .10 to .56; P = .001), and cGVHD (HR, .32; 95% CI, .19 to .54; P < .001). Compared with 2000-2004, the risk of grade II-IV aGVHD was lower in children undergoing transplantation in 2005-2008 (HR, .36; 95% CI, .20 to .65; P = .0007) and in 2009-2013 (HR, .24; 95% CI. .11 to .53; P = .0004). Similarly, the risk of grade III-IV aGVHD was lower in children undergoing transplantation in 2005-2008 (HR, .23; 95% CI, .08 to .65; P = .0056) and 2009-2013 (HR, .16; 95% CI, .04 to .67; P = .0126) compared with those doing so in 2000-2004. We conclude that aGVHD rates have decreased significantly over time, and that children age 2 to 12 years are at very low risk for aGVHD and cGVHD. These results should be validated in an independent analysis, because these patients with high-risk malignancies may be good candidates for trials of reduced GVHD prophylaxis.

Impact of Donor Epstein-Barr Virus Serostatus on the Incidence of Graft-Versus-Host Disease in Patients With Acute Leukemia After Hematopoietic Stem-Cell Transplantation: A Study From the Acute Leukemia and Infectious Diseases Working Parties of the European Society for Blood and Marrow Transplantation.

We investigated the effect of Epstein-Barr virus (EBV) serostatus on the overall outcome of allogeneic hematopoietic stem-cell transplantation (allo-HSCT). The study included 11,364 patients who underwent allogeneic peripheral-blood or bone marrow transplantation for acute leukemia between 1997 and 2012. We analyzed the impact of donor and recipient EBV serologic status on overall survival, relapse-free survival, relapse incidence, nonrelapse mortality, and incidence of graft-versus-host disease (GVHD) after allo-HSCT. Patients receiving grafts from EBV-seropositive donors had the same overall survival as patients who received grafts from EBV-seronegative donors (hazard ratio [HR], 1.05; 95% CI, 0.97 to 1.12; P = .23). Seropositive donors also had no influence on relapse-free survival (HR, 1.04; 95% CI, 0.97 to 1.11; P = 0.31), relapse incidence (HR, 1.03; 95% CI, 0.94 to 1.12; P = .58), and nonrelapse mortality (HR, 1.05; 95% CI, 0.94 to 1.17; P = .37). However, in univariate analysis, recipients receiving grafts from seropositive donors had a higher risk of chronic GVHD than those with seronegative donors (40.8% v 31.0%, respectively; P < .001; HR, 1.42; 95% CI, 1.30 to 1.56). When adjusting for confounders, higher risk was identified for both acute and chronic GVHD. In seronegative patients with seropositive donors, the HR for chronic GVHD was 1.30 (95% CI, 1.06 to 1.59; P = .039). In seropositive patients with seropositive donors, the HR was 1.24 (95% CI, 1.07 to 1.45; P = .016) for acute GVHD and 1.43 (95% CI, 1.23 to 1.67; P < .001) for chronic GVHD. Seropositive patients with seronegative donors did not have an increased risk of GVHD. Our data suggest that donor EBV status significantly influences development of acute and chronic GVHD after allo-HSCT.

Commentary on Thomas and Epstein: "Bone Marrow Transplantation in Acute Leukemia".

See related article by Thomas and Epstein, [Cancer Res 1965;25:1521–4][1] . Visit the Cancer Research 75th Anniversary [timeline][2]. Fifty years ago, Dr. E.D. Thomas and Dr. R.B. Epstein published the intellectual and scientific basis for the use of high-dose cytotoxic therapy, specifically

The Outcomes of Haploidentical Blood and Marrow Transplantation in Acute Leukemia: A Single-Center Study of 439 Cases

To investigate the outcomes of haploidentical blood and marrow transplantation (haplo-BMT) with our integrated strategies in acute leukemia, all patients with AML or ALL after haplo-BMT were analyzed. Between April 2012 and December 2014, consecutive 439 AML or ALL patients underwent haplo-BMT in our hospital were included. The median age was 18 (2 to 64) years old. AML was 232 (52.8%) and ALL was 207 (47.2%) cases. Transplants at CR1, ≥CR2 or advanced disease were 185 (42.1%), 104 (23.7%), 150 (34.2%), respectively. High-resolution HLA typing for A, B, C, DRB1 and DQB1 were done. Graft, conditioning and GVHD prophylaxis were as previous report. The 3rd party cells with either haploidentical bone marrow or unrelated cord blood were infused right after haplo-BMT. Minimal residual disease (MRD) was monitored routinely by quantitative PCR or flow cytometry. The patients with persistent MRD were interfered by immunosuppressant withdrew, adoptive immunotherapy with cytokine induced killer or NK cells or donor lymphocyte infusion. Children (<18 years old) were 204 (46.5%) and adults (≥18 years old) were 235 (53.5%) cases. All patients but 3 achieved durable engraftment. HLA matching between recipient and donor at 5/10, 6/10, 7/10, 8/10, 9/10 and 10/10 was in 301 (68.6%), 77 (17.5%), 37 (8.4%), 12 (2.7%), 9 (2.1%), 3 (0.7%) cases, respectively. Donors were from sibling (20.5%) or parent (68.6%) or child (10.7%) or other relatives (0.2%). The cumulative incidences of grade II to IV aGVHD and grade III to IV aGVHD were 32.1%, 19.3%, respectively. The cumulative incidences of cGVHD and extensive cGVHD were 49.2%, 18.9%, respectively. 100-day and 2-year transplant-related mortality were 4.1%, 15.7%, respectively. Two-year relapse rate was 13.7%. With the median follow up 17 (6 to 38) months, overall 2-year disease-free survival (DFS) in CR1, ≥CR2 and advanced disease were 76.5%, 69.0%, 45.2%, respectively (CR1 vs.≥CR2, p=0.035; CR1 vs. NR, p=0.000; ≥CR2 vs. NR P=0.01). For AML, two-year DFS rates in CR1, ≥CR2 and advanced disease were 74.1%, 76.9%, 48.2% (CR1 vs.≥CR2, p=0.84; CR vs. advanced disease, p=0.000). For ALL, two-year DFS rates in CR1,≥CR2 and advanced disease were 78.9%, 56.6%, 38%, respectively (CR1 vs.≥CR2, p=0.018; CR1 vs. NR, p=0.000; ≥CR2 vs. NR P=0.02 ). Multivariate analysis indicated that disease status before transplant was the only impact factor on DFS after haplo-BMT in acute leukemia (p<0.001) but not recipient’s age, HLA disparity and recipient-donor relationship. With our strategies, overall outcomes of haplo-BMT in acute leukemia have been improved remarkably and very encouraging. Therefore, haplo-BMT should be an important alternative way to save life for the patients with acute leukemia who need urgent BMT but without matched either sibling or unrelated donor.

EBMT Risk Score Predicts Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Patients Who Have Failed a Previous Transplantation Procedure

Increasing numbers of allogeneic hematopoietic stem cell transplantation (allo-SCT) are being performed for patients who have failed a previous allogeneic or autologous SCT. We investigated whether the EBMT risk score could predict outcome after a subsequent allo-SCT. We analyzed prognostic factors in 124 consecutive patients who underwent a second transplantation using an allogeneic donor at our institution. Patients with either a first autologous (N = 64) or first allogeneic (N = 60) SCT were included. Age, disease stage, time interval from diagnosis to transplantation, donor type, and donor-recipient sex combination were used to establish a score from 0 to 7 points, from which 3 groups were identified. The 5-year survival probability decreased from 51.7% for risk scores 0-3 (low, n = 25), to 29.3% for risk score 4 (intermediate, n = 42), and only 10.4% for risk scores 5-7 (high, n = 57), P = .001. We propose that the EBMT risk score can identify patients most likely to benefit from a second transplantation.

Moyamoya Syndrome after Cranial Irradiation for Bone Marrow Transplantation in a Patient with Acute Leukemia

It is well known that radiation-induced vasculopathy and arteritis are two of the complications of whole brain radiation therapy. Moyamoya syndromes after cranial irradiation among patients with brain tumors were previously reported. However, we could find only three cases of prophylactic cranial irradiation for hematological disorders and no case of cranial irradiation before bone marrow transplantation in patients with acute leukemia. We recently treated a boy who developed moyamoya vessels 1.5 years after cranial irradiation for bone marrow transplantation for acute leukemia. This is the first report of moyamoya syndrome after cranial irradiation for bone marrow transplantation. The mechanism and incidence of vasculopathy after cranial irradiation are unclear. It would be useful to accumulate data and reveal the etiology of moyamoya vessels formation after cranial irradiation.

Effect of Graft Content Outcome of Allogeneic Marrow Transplantation in Acute Leukemia.

Background: Evidence suggests that the outcome of allogeneic hematopoietic transplant in acute leukemia (AL) is, in part related to a graft versus leukemia effect. Recent studies suggest a role for natural killer cell (NK) alloreactivity in this process. We report here baseline findings relevant to the influence of the allograft content of natural killer (NK) cells on the outcome of matched related (MRD) and unrelated donor (MUD) myeloablative allografts for AL during a recent time period.Methods: 19 pts received a 6/6 MRD peripheral blood stem cell (PBSC) allograft and 8 pts received a MUD marrow (BM) graft for high risk or relapsed AL between January, 1998 and September, 2003 (21 AML, 6 ALL). There were 14 males and 13 females; median age 41 (19 – 70); 13 were in 1st CR, 4 in 2nd or greater CR, 3 primary induction failures, 4 in 1st relapse and 3 in 2nd relapse. 21 received TBI conditioning (all but one with Cytoxan), 4 received Busulphan & Cytoxan. 17 MRD pts received PBSC grafts; 1 a CD34 selected graft and 1BM, while all MUD received BM. Graft characteristics, including CD34, CD3, CD16/56, CD4, CD8, and CD19 were measured prior to transplant. Patient outcomes, including relapse and death were obtained from a database maintained by the clinical trials office.Results: After a minimum of 6 months from transplant, 7 MRD and 2 MUD pts are alive, a median of 20 months from transplant (range 6 to 66 months), and 18 died, a median of 4 months after transplant (range 0.5 to 13.2 months). Eight patients relapsed. Five patients died of relapse, 7 of infection, 1 of GVH, 3 of multiorgan failure, and 2 of other causes. MRD pts who relapsed were signficantly older than those who did not (median 49 vs 38; p = 0.04), and pts who relapsed received grafts that had a higher percentage of NK cells (medain 4.2%) than those who did not (median 2.7%, p = 0.04), but the number of NK cells/kg was similar in patients who relapsed versus those who did not, either within or between MRD/MUD groups. There was no difference between patients who relapsed vs those who did not with respect to the graft content of total leukocytes, CD34, CD3, CD4, CD8 or CD19, either within or between MRD/MUD groups. Likewise, there were no differences in graft contents of the in patients who survived vs those who did not. Compared with MRD pts, MUD pts, as expected received significantly fewer CD34/kg, NK and all lymphocyte subsets and had a longer hospital stay and time to ANC>500, but no difference in PD, GVHD, or survival (Table).Conclusion: In this single institution experience there was no relationship between graft content of CD34, NK or CD3 cells and AL relapse or survival after myeloablative MRD or MUD transplant for high risk AL.Patient Characteristics & Median Cells Infused/kg x 10E6Donor groupPatient AgeANC > 500, dLOSCD34NKCD3CD8Related4113.6 *29 *6.9 *26 *286 *98 *+/− 95% CI61.251.38.75626Unrelated4216.6413.75.53819+/− 95% CI102100.92.9116.6LOS=length of stay; * p<.05 vs Unrelated

Treatment with granulocyte colony-stimulating factor after allogeneic bone marrow transplantation for acute leukemia increases the risk of graft-versus-host disease and death

Treatment with granulocyte colony-stimulating factor after allogeneic bone marrow transplantation for acute leukemia increases the risk of graft-versus-host disease and death

Bilateral Cavitary Pulmonary Consolidations in a Patient Undergoing Allogeneic Bone Marrow Transplantation for Acute Leukemia

A 10-year-old boy developed severe dyspnea and respiratory failure during a hospitalization for an allogeneic unrelated bone marrow transplantation for acute myeloid leukemia. He had first presented 23 weeks earlier with acute myeloid leukemia and had not responded to the initial induction chemotherapy. Next, he was successfully treated with another regimen of remission-induction chemotherapy without complications. He received an allogeneic unrelated bone marrow transplant after a conditioning regimen of cyclophosphamide (Endoxan; AstaMedica BV; Diemen, the Netherlands) therapy, total body irradiation, and low-dose antithymocyte globulin. Both donor and recipient were seronegative for cytomegalovirus. Immediately after transplantation, the patient received therapy with cyclosporine A, short-course methotrexate, and total bowel decontamination. During this time, he was nursed in a protective environment. Seven days after undergoing the bone marrow transplantation, he developed a fever. A blood culture revealed a coagulase-negative Staphylococcus infection for which he was treated with IV antibiotics (ceftazidime and teicoplanin). Six days later (13 days after the bone marrow transplantation), a chest radiograph showed bilateral pulmonary infiltrates (Fig 1).

Dose-effect relationship for cataract induction after single-dose total body irradiation and bone marrow transplantation for acute leukemia

Purpose : To determine a dose-effect relationship for cataract induction, the tissue-specific parameter, α/β, and the rate of repair of sublethal damage, μ value, in the linear-quadratic formula have to be known. To obtain these parameters for the human eye lens, a large series of patients treated with different doses and dose rates is required. The data of patients with acute leukemia treated with single-dose total body irradiation (STBI) and bone marrow transplantation (BMT) collected by the European Group for Blood and Marrow Transplantation were analyzed. Methods and Materials : The data of 495 patients who underwent BMT for acute leukemia, who had STBI as part of their conditioning regimen, were analyzed using the linear-quadratic concept. The end point was the incidence of cataract formation after BMT. Of the analyzed patients, 175 were registered as having cataracts. Biologic effective doses (BEDs) for different sets of values for α/β and μ were calculated for each patient. With Cox regression analysis, using the overall chi-square test as the parameter evaluating the goodness of fit, α/β and μ values were found. Risk factors for cataract induction were the BED of the applied TBI regimen, allogeneic BMT, steroid therapy for >14 weeks, and heparin administration. To avoid the influence of steroid therapy and heparin on cataract induction, patients who received steroid or heparin treatment were excluded, leaving only the BED as a risk factor. Next, the most likely set of α/β and μ values was obtained. With this set, the cataract-free survival rates were calculated for specific BED intervals, according to the Kaplan-Meier method. From these calculations, cataract incidences were obtained as function of the BED at 120 months after STBI. Results : The use of BED instead of the TBI dose enabled the incidence of cataract formation to be predicted in a reasonably consistent way. With Cox regression analysis for all STBI data, a maximal chi-square value was obtained for α/β = 1.75 Gy and μ = 0.75 h −1. When Cox regression analysis was applied for patients who had no steroid treatment after BMT, a maximal chi-square value was obtained for α/β = 1 Gy and μ = 0.6 h −1. Cox regression analysis was repeated using the data of patients who had not received posttransplant steroid treatment and also no heparin administration; we found α/β = 0.75 Gy and μ = 0.65 h −1. An increased cataract incidence was observed after steroid treatment of >14 weeks and heparin administration. Conclusion : The α/β value of 0.75 Gy and a μ value of 0.65 h −1 found for the eye lens are characteristic for late-responding tissues. The incidence of cataract formation can now be quantified, taking into account the values calculated for α/β and μ, TBI dose, and dose rate. Also, the reduction in cataract incidence as a result of lens dose reduction by eye shielding can be estimated.

Second allogeneic bone marrow transplantation in acute leukemia: results of a survey by the European Cooperative Group for Blood and Marrow Transplantation.

Leukemic relapse is the most frequent cause of treatment failure after allogeneic hematopoietic stem-cell transplantation (HSCT). To identify prognostic factors affecting the outcome of second HSCT, we performed a retrospective study on patients with acute leukemia (AL) undergoing second HSCT who reported to the Acute Leukemia Working Party of the European Cooperative Group for Blood and Marrow Transplantation registry. One hundred seventy patients who received second HSCTs for AL experienced relapse after first HSCTs were performed from 1978 to 1997. Status at second HSCT, time between first and second HSCT, conditioning regimen, source of stem cells, treatment-related mortality (TRM), acute graft-versus-host disease (aGVHD), leukemia-free survival (LFS), overall survival (OS), and relapse were considered. Engraftment occurred in 97% of patients. Forty-two patients were alive at last follow-up, with a 5-year OS rate of 26%. The 5-year probability for TRM, LFS, and relapse was 46%, 25%, and 59%, respectively. Grade > or = 2 aGVHD occurred in 59% of patients, and chronic GVHD occurred in 32%. In multivariate analysis, diagnosis, interval to relapse after first HSCT > 292 days, aGVHD at first HSCT, complete remission status at second HSCT, use of total-body irradiation at second HSCT, acute GVHD at second HSCT, and use of bone marrow as source of stem cells at second HSCT were associated with better outcome. Second HSCT represents an effective therapeutic option for AL patients relapsed after allogeneic HSCT, with a 3-year LFS rate of 52% for the subset of patients who experienced relapse more than 292 days after receiving the first HSCT and who were in remission before receiving the second HSCT.

Adoptive immunotherapy with haploidentical allogeneic peripheral blood lymphocytes following autologous bone marrow transplantation.

Patients who undergo autologous bone marrow transplantation for acute leukemia are at high risk for relapse. We have evaluated the feasibility of administering cell-mediated immunotherapy with family-related haploidentical lymphocytes following autologous bone marrow transplantation in order to evoke a graft-vs-leukemia effect in the autologous setting.Twenty-six patients aged 1.5-48 years were enrolled in this study. Eighteen suffered from acute myeloid leukemia, seven from acute lymphoblastic leukemia, and one from myelodysplastic syndrome. Eleven patients were transplanted in first remission, six in second remission, one in fourth remission, and eight in relapse. Conditioning consisted of Busulfan/Cyclophosphamide or Busulfan/Thiotepa/Cyclophosphamide. Nineteen patients (Group A) were treated with gradual increments of haploidentical donor T cells, starting on day +1, with an additional course of T cells plus intravenous recombinant human interleukin-2 one month later if no signs of graft-vs-host disease developed in the interim. Seven patients (Group B) were treated with high-dose haploidentical T cells on day +1 in conjunction with intravenous recombinant human interleukin-2. Donor cells were detected in the peripheral blood of both groups 12-48 hours post-cell-mediated immunotherapy, peaking at 48 hours. Three patients in Group A developed transient Grade I graft-vs-host disease. One patient in Group B developed Grade I, and three Grade IV, graft-vs-host disease. Group A patients engrafted normally, but the Group B patients with Grade IV graft-vs-host disease showed no signs of engraftment. Our results show that it is feasible to induce graft-vs-host disease in the autologous stem cell transplantation setting. However, the high-dose regimen of haploidentical T cells in conjunction with interleukin-2 results in severe toxicity and nonengraftment.

Targeted therapy of acute myeloid leukemia with monoclonal antibodies and immunoconjugates.

Traditional chemotherapy for acute leukemia often causes life-threatening toxic effects due to a lack of specificity for hematopoietic cells. Monoclonal antibodies and fusion proteins that target cell surface antigens on leukemic blasts are being evaluated for their cytotoxic effects and as a means of delivering chemotherapeutic agents or radiation directly to malignant cells. It is hoped that this strategy might selectively ablate malignant cells without many of the toxic effects commonly associated with conventional chemotherapy. In acute myeloid leukemia (AML), the cell surface antigens CD33 and CD45 are especially suitable targets. Although CD33 is expressed on AML blast cells from about 90% of patients, normal hematopoietic stem cells lack this antigen, as do essentially all nonhematopoietic tissues. For that reason, anti-CD33 antibodies have been created to target malignant myeloid and immature normal cells selectively while sparing normal stem cells. Anti-CD33 antibodies have also been used to deliver radiation or a cytotoxic agent directly to leukemic cells. Since the vast majority of leukemias and normal stem cells express the cell surface antigen CD45, another targeting approach allows the delivery of myeloablative radiation to bone marrow and spleen, common sites of leukemic involvement. Consequently, 131I-labeled anti-CD45 antibody has been combined with traditional preparative regimens for patients receiving bone marrow transplantation for acute leukemia. Finally, fusion proteins such as those combining diphtheria toxin with granulocyte-macrophage colony-stimulating factor (GM-CSF) to target the GM-CSF receptor are now being evaluated in clinical trials. Both unconjugated and conjugated antibodies have shown promise in early clinical trials, and may represent appealing therapeutic alternatives for patients with AML.

Pediatric marrow transplantation for acute leukemia using unrelated donors and T-replete or -depleted grafts: a case-matched analysis.

A retrospective, case-matched analysis of the short-term toxicity, risk of GVHD and relapse as well as outcome in pediatric unrelated marrow transplantation was conducted by comparing recipients of T-replete and -depleted grafts in a two-center setting. Both groups contained 30 patients with acute leukemia matched by age at transplant, gender, primary diagnosis and disease status. Acute (90% vs 53%) and chronic (48% vs 0%) GVHD were more common among recipients of T-replete grafts. No significant differences in graft rejection/failure or viral infections were encountered between the two groups. Relapses were more prevalent (37% vs 15%) among recipients of T-depleted grafts. Outcome (EFS) was similar in the two groups. Consequently, in the analysis of transplant outcome, the higher risk of procedure-related, toxic complications among pediatric recipients of T-replete marrow grafts appears to be balanced by an increased risk of relapse among the recipients of T-depleted grafts.

Clinical studies of new "biologic" approaches to therapy of acute myeloid leukemia with monoclonal antibodies and immunoconjugates.

Conventional chemotherapeutic treatments of acute leukemias are often associated with life-threatening toxic effects due to a lack of specificity for hematopoietic cells. Monoclonal antibodies and fusion proteins that target antigens on leukemic blasts are being explored for their antileukemic effects and as a means of delivering chemotherapy or radiation directly to malignant cells. This approach might be safer and more effective than current non-specific chemotherapeutic agents. The cell surface antigens CD33 and CD45 are attractive targets. Although CD33 is expressed on acute myelocytic leukemic blast cells from about 90% of patients, normal hematopoietic stem cells lack this antigen, as do essentially all non-hematopoietic tissues. Anti-CD33 antibodies have been engineered to selectively target malignant myeloid and immature normal cells while sparing normal stem cells. Recently, anti-CD33 antibodies have also been used to deliver radiation or a cytotoxic agent directly to leukemic cells. The strategy for using CD45 as a target differs from CD33 in that it is expressed not only by the vast majority of leukemias, but also by normal stem cells. Therefore, 131I-labeled anti-CD45 antibody has been used in combination with conventional preparative regimens for patients receiving marrow transplantation for acute leukemia. Because the receptor for granulocyte-macrophage colony-stimulating factor is expressed by most myeloid leukemias, fusion proteins consisting of granulocyte-macrophage colony-stimulating factor ligand associated with diphtheria toxin have been proposed as a means of delivering a toxic agent directly to leukemic cells. Both unconjugated and conjugated antibodies show significant promise in the treatment of acute myelocytic leukemia.

Improved outcome with T-cell-depleted bone marrow transplantation for acute leukemia.

To eliminate the risk of rejection and lower the risk of relapse after T-cell-depleted bone marrow transplants in acute leukemia patients, we enhanced pretransplant immunosuppression and myeloablation. Antithymocyte globulin and thiotepa were added to standard total-body irradiation/cyclophosphamide conditioning. Donor bone marrows were depleted ex vivo of T lymphocytes by soybean agglutination and E-rosetting. This approach was tested in 54 consecutive patients with acute leukemia who received transplants from HLA-identical sibling donors or, in two cases, from family donors mismatched at D-DR. No posttransplant immunosuppressive treatment was given as graft-versus-host disease (GVHD) prophylaxis. Neither graft rejection nor GVHD occurred. Transplant-related deaths occurred in six (16.6%) of 36 patients in remission and in seven (38.8%) of 18 patients in relapse at the time of transplantation. The probability of relapse was .12 (95% confidence interval [CI], 0 to .19) for patients with acute myeloid leukemia and .28 (95% CI, .05 to .51) for patients with acute lymphoblastic leukemia who received transplants at the first or second remission. At a median follow-up of 6.9 years (minimum follow-up, 4.9 years), event-free survival for patients who received transplants while in remission was .74 (95% CI, .54 to .93) for acute myeloid leukemia patients and .59 (95% CI, .35 to .82) for acute lymphoblastic leukemia patients. All surviving patients have 100% performance status. Adding antithymocyte globulin and thiotepa to the conditioning regimen prevents rejection of extensively T-cell-depleted bone marrow. Even in the complete absence of GVHD, the leukemia relapse rate is not higher than in unmanipulated transplants.

CD6-Depleted Allogeneic Bone Marrow Transplantation for Acute Leukemia in First Complete Remission

AbstractThe appropriate timing of bone marrow transplantation (BMT) for adults with acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL) is controversial. Although allogeneic transplantation results in a lower risk of disease recurrence than intensive chemotherapy alone, overall outcome following BMT may not be improved due to the higher incidence of therapy-related fatal complications, frequently as a result of the development of graft-versus-host disease (GVHD). Selective T-cell depletion of donor marrow can reduce the incidence of GVHD and thereby limit transplant-related toxicity. Herein we report the risk of GVHD, incidence of transplant related mortality (TRM), likelihood of disease relapse, and overall survival in adult patients undergoing BMT with CD6 depleted allogeneic marrow for acute leukemia in first remission. Forty-one consecutive allogeneic transplants were performed on patients with acute leukemia and high-risk features (28 AML, 13 ALL) using T12 monoclonal antibody and complement to remove CD6+ T cells from donor marrow. No pre- or posttransplant immune suppressive medications for GVHD prophylaxis were administered. The actuarial estimated risk of grade 2 to 4 acute GVHD was 15% in patients receiving HLA identical grafts. Chronic GVHD developed in five patients. The estimated risk of TRM for patients in first complete remission was 5% at Day +100 and 16% at 2 years. Fatalities attributable to infection with cytomegalovirus or Epstein-Barr virus occurred in only three patients. Estimated probabilities of relapse, overall survival, and event-free survival at 4 years were 25%, 71%, and 63%, respectively. No significant differences in GVHD, TRM, relapse rate, or survival was observed for patients with AML compared with those with ALL. Allogeneic transplantation with CD6 depleted bone marrow is effective in consolidating remissions of high-risk patients with acute leukemia in first remission without excessive toxicity.

Gonadal function after bone marrow transplantation for acute leukemia during childhood

Objective: To examine the impact of bone marrow transplantation (BMT), using high-dose chemotherapy and hyperfractionated total body irradiation, on gonadal function in survivors of acute leukemia treated during childhood. Study design: We conducted a retrospective study of 33 subjects (17 boys) who underwent a BMT for acute leukemia (acute lymphoblastic leukemia, n = 20; acute myelogenous leukemia, n = 13) at a single institution. All patients were prepubertal at the time of BMT (median age, 7.1 years [3.7 to 11.6 years]); at the time of their last examination the boys were a median of 14 years (10.4 to 17.1 years) of age and the girls were a median of 16.9 years (9.5 to 21.9 years) of age. Results: Of 17 boys, 14 (82%) entered puberty spontaneously and 13 demonstrated age-appropriate plasma concentrations of testosterone. Two boys (aged 10.5 and 11 years) remain clinically and hormonally prepubertal, and one boy has overt Leydig cell failure requiring androgen replacement therapy. Thirty-six percent of pubertal boys have elevated plasma concentrations of luteinizing hormone and 64% have raised levels of follicle-stimulating hormone. Boys with increased levels of luteinizing hormone were significantly younger at BMT (5.4 ± 0.8 vs 7.8 ± 0.8 years; p = 0.024). Of 16 girls, 9 (56%) had spontaneous puberty with onset of menarche at a median age of 13 years (9.5 to 15.8 years). Though six (67%) of these nine girls have had increased plasma concentrations of luteinizing and follicle-stimulating hormones, normalization has occurred in two during a period of 4 to 7 years. The remaining seven subjects required hormone replacement because of clinical and biochemical evidence of ovarian failure. One of these subjects has recovered ovarian function after 5½ years. Female patients with ovarian failure were significantly older at BMT compared with female patients with spontaneous puberty/menarche (8.6 ± 23 years vs 6.1 ± 1.8; p = 0.03). Conclusion: Our results indicate that most prepubertal boys undergoing BMT with chemotherapy and hyperfractionated total body irradiation can expect to enter and progress normally through puberty. For prepubertal girls treated with these regimens, at least 50% retain adequate ovarian function to enter puberty and menstruate regularly. (J Pediatr 1997;130:210-6)

Cancer of the Esophagus Following Allogeneic Bone Marrow Transplantation for Acute Leukemia

The successful development of allogeneic bone marrow transplantation (BMT) has markedly improved the treatment results for acute leukemia and other hematologic diseases. However, significant complications are associated with this procedure including the development of chronic graft versus host disease (GVHD). Treatment for this condition requires chronic immunosuppression which can lead to the development of second cancers. It is well known that immunosuppression is associated with a variety of tumors, most commonly lymphoma. The development of solid tumors appears to be less common but follow-up studies of patients treated for Hodgkin's disease demonstrate a rising incidence of solid tumor development after a delay of 5 to 10 years. We describe a patient recently treated for a squamous cell carcinoma of the esophagus which developed 5 years after an allogeneic BMT for acute myelogenous leukemia (AML). The patient had been treated with immunosuppressants for chronic GVHD. The clinical course is described and the literature is reviewed regarding recent experience with the development of solid tumors following allogeneic BMT. The majority of second tumors following BMT are lymphomas and leukemias. Secondary solid tumors are less common, but the incidence appears to increase over time. Squamous carcinomas are most common and a preparative regimen combining radiation and chemotherapy may increase risk. Careful long-term follow-up of BMT is essential in order to detect second tumors at an early stage.

Growth in Children After Bone Marrow Transplantation for Acute Leukemia

We evaluated the growth of children with acute leukemia who received a bone marrow transplant (BMT) after preparation with hyperfractionated total body irradiation (TBI). Seventy-two patients (27 female and 45 male patients) with acute lymphoblastic leukemia (ALL; n = 39) or acute myelogenous leukemia (AML; n = 33) who were less than 14 years of age at BMT were studied. Before BMT all had received multiagent chemotherapy and 31 had received cranial irradiation (RT). Preparation for BMT included total body irradiation (1,375 cGy [n = 37] or 1,500 cGy [n = 35]). Heights, expressed as standard deviation scores (SDS), were studied up to 4 years post-BMT. The estimated height SDS for the entire group at the time of BMT was -0.28 +/- 0.05 and decreased to -1.11 +/- 0.22 at 4 years post-BMT (P < .0001). Using a growth curve model to compare covariate groups over the period of study, we found that the loss in height SDS was most significant in those patients who received cranial RT before BMT (P = .005). The estimated height SDS for patients treated with cranial RT went from -0.52 +/- 0.20 at transplantation to -1.83 +/- 0.23 4 years later. In contrast, patients who did not receive cranial RT before BMT showed a smaller decrease in height SDS over the 4-year observation period, ie, -0.11 +/- 0.20 decreasing to -0.73 +/- 0.21. Similarly, patients with a diagnosis of ALL had a greater loss of height SDS than those with AML (P = .033). Fifteen of 18 patients tested were found to be growth hormone (GH) deficient; 9 patients were treated with GH and all showed an improvement in growth velocity (P < .0001). We conclude that (1) children with acute leukemia who have received cranial RT and subsequently undergo BMT, primarily those with ALL, are at high risk for growth failure and GH deficiency, and (2) that fractionation of TBI may have a relative sparing effect on growth.