Phase-2 trial of an intensified conditioning regimen for allogeneic hematopoietic cell transplant for poor-risk leukemia.

Patients with poor-risk leukemia have a high relapse rate despite allogeneic transplant. We report on the phase-2 trial of an intensified allogeneic transplant regimen whose aim was tolerable toxicity and durable remission. Study patients (n=30) had unfavorable first remission cytogenetics, progression from myelodysplasia or active disease due to induction failure or relapse. Conditioning was i.v. BU, targeted to a first-dose plasma area under the curve (AUC) of 700-900 µM min, VP-16 at 30 mg/kg of adjusted ideal body weight and fractionated TBI (FTBI) at 1200 cGy in 10 fractions. GVHD prophylaxis was CsA and mycophenolate mofetil. Regimen-related toxicities (Bearman) included grade II mucositis in 29 patients (97%) and grade III in one patient, grade II-III sinusoidal obstructive syndrome in 2 patients (7%), and grade 2-3 (CTC) skin toxicity in 8 patients (27%). The 30- and 100-day TRMs were 0 and 7% respectively. The median follow-up was 83.7 months (60.7-96.4) for surviving patients. The 5-year overall and disease-free survival was 40% for all patients. Cumulative 5-year relapse incidence (RI) was 23% and TRM was 37%. We have shown promising OS and RI in these poor-risk patients, who typically have few curative options.

Acute leukemia and myelodysplasia after adjuvant chemotherapy for breast cancer: durable remissions after hematopoietic stem cell transplantation.

BACKGROUND: Although secondary acute leukemias and myelodysplasia are the known complications of adjuvant chemotherapy for breast cancer, the treatment outcome of these secondary malignancies is presently unclear. We examined the clinical and pathological features as well as the treatment results of a series of patients with acute leukemia/myelodysplasia arising after adjuvant chemotherapy for breast cancer. PATIENTS AND METHODS: Patients referred to our institution during a 5-year period for treatment of acute leukemia/myelodysplasia and who had received adjuvant chemotherapy for breast cancer are included. Leukemia-free survival for the whole group and for patients who underwent hematopoietic stem cell transplantation (HSCT) was estimated. RESULTS: Fifteen women (14 with acute leukemia and one with myelodysplasia) were identified. Seven of 15 patients had received an anthracycline, cyclophosphamide and a taxane. Ten patients developed acute leukemia/myelodysplasia with a latency period of 2 years or less from initiation of chemotherapy. Although mixed-lineage leukemia (MLL) rearrangement was the commonest chromosomal abnormality (8 of 15 patients), various other chromosomal abnormalities were also detected. Twelve of 15 patients underwent HSCT (11 allogeneic and one autologous). Eleven of these 12 patients who underwent HSCT were in remission at a median follow-up of 20.4 months (range 4.4-53.3 months). CONCLUSION: Durable remissions can be achieved in patients who develop acute leukemia/myelodysplasia secondary to adjuvant chemotherapy for breast cancer and are able to undergo allogeneic HSCT. Our results indicate that HSCT should be an early consideration in the management of such patients who are suitable candidates for the procedure.

Iron overload adversely affects outcome of allogeneic hematopoietic cell transplantation.

Iron overload is common in patients undergoing allogeneic hematopoietic cell transplantation (HCT) for hematologic disorders. Serum ferritin, a marker of tissue iron overload, was measured immediately before transplant in adult patients undergoing myeloablative HCT from matched sibling or unrelated donors. The effect of elevated pretransplant ferritin (defined as ferritin >or=1000 ng/ml) on day 100 mortality, overall survival, acute GVHD and infectious complications was assessed. Data on 190 patients were analyzed. In univariate analysis, the high-ferritin group had increased day 100 mortality (20 vs 9%, P=0.038), decreased overall survival (log-rank test: P-value=0.004), increased acute GVHD/death (63 vs 43%, P=0.009) and increased incidence of blood stream infections (BSIs)/death (60 vs 44%, P=0.042). In a multivariate analysis, high ferritin was associated with increased risk of death (Cox model: hazard ratio=2.28, P=0.004), increased day 100 mortality (generalized linear model (GLM) odds ratio=3.82, P=0.013), increased incidence of acute GVHD/death (GLM odds ratio=3.11, P=0.001) and increased risk of BSI/death (GLM odds ratio=1.99, P=0.032). The results remained similar when serum ferritin was considered a continuous variable. Elevated serum ferritin adversely impacts on overall survival and increases the likelihood of acute GVHD and BSI after allogeneic HCT.

Killer Ig-like receptor (KIR) compatibility plays a role in the prevalence of acute GVHD in unrelated hematopoietic cell transplants for AML.

Killer Ig-like receptor (KIR) is a major cluster of the natural killer cell receptors and may play a role in the outcome of hematopoietic cell transplants. A total of 65 AML cases transplanted with T-replete hematopoietic cells from unrelated donors were retrospectively KIR-genotyped by a multiplex PCR method of our own design. The KIR gene frequency and genotype patterns in these 130 samples were consistent with the data in the literature. Based upon overall inhibitory and activating KIR genes in both donors and patients, we developed an algorithm to calculate a compatibility score for each transplant case as plus, zero or minus. Significantly higher incidence (18/20, 90%) of acute (a) GVHD (grade II-IV) was found in the transplant cases with plus scores than that (25/45, 56%) in the cases with zero or minus scores (P < 0.01). When the scores are sorted in the opposite way, fewer cases (13/26, 50%) of aGVHD were found in the transplants with minus scores than that (30/39, 77%) in the transplants with zero or plus scores (P < 0.05). The difference of aGVHD prevalence between the plus score and minus score groups is highly significant (P < 0.01). KIR genotype compatibility calculated by this algorithm may predict aGVHD incidence and be helpful in choosing donors.

Primary myelodysplasia occurring in adults under 50 years old: a clinicopathologic study of 52 patients.

Although myelodysplastic syndromes (MDSs) are generally thought to be diseases of elderly patients, younger patients also have rarely been diagnosed with MDS. This is a report of the clinical, morphologic and cytogenetic features of 52 cases of primary MDS occurring in adults under the age of 50 years. Cases secondary to chemotherapy or radiotherapy were excluded. There were 31 males and 21 females. The median age at presentation was 39 years (range, 18 to 49 years). The interval between onset of symptoms and diagnosis was brief (median, 4 weeks; range, 1-32 weeks). Of the 49 patients for whom information about duration of symptoms was available, 13 (27%) were asymptomatic. Forty-two (81%) of the patients were classified using FAB criteria for blood and bone marrow morphology: refractory anemia (RA), 11; refractory anemia with ringed sideroblasts (RARS), four; refractory anemia with excess blasts (RAEB), 12; chronic myelomonocytic leukemia (CMML), three; refractory anemia with excess blasts in transformation (RAEB-T), 12 patients. Ten patients could not be categorized. Abnormalities involving chromosome 7 was the most frequent cytogenetic abnormality (31%). Partial chromosomal deletion and chromosome gain were also common abnormalities (22% and 9%, respectively). Translocations accounted for only 9% of the main cytogenetic abnormalities encountered in this patient population. For the 49 patients for whom information regarding AML transformation was available, 23 (47%) progressed to acute myeloid leukemia, with an overall median time to progression of 2 months (range 3 weeks to 3 years). In each category except for RARS, approximately half of the patients progressed, with a slightly less median time to progression in RAEB-T than for the other subtypes of MDS. Thirteen patients underwent bone marrow transplantation at the time of presentation of their disease.

Myeloperoxidase immunoreactivity in adult acute lymphoblastic leukemia.

To evaluate the frequency and significance of myeloperoxidase positivity in adult acute lymphoblastic leukemia (ALL), bone marrow biopsy material from 82 adults with ALL was evaluated with a polyclonal myeloperoxidase (pMPO) antibody. Nineteen cases (23%) demonstrated evidence of pMPO immunoreactivity. Positive cases were precursor B-cell lineage, and CD13 or CD15 expression was more frequent than in the pMPO-negative cases. A subset of pMPO-positive cases studied with a monoclonal MPO antibody was negative. Western blot analysis using the pMPO antibody showed the expected 55-kd band for myeloperoxidase in pMPO-positive and pMPO-negative ALLs, suggesting a lack of specificity of this antibody in ALL. Forty-two percent (8/19) of the pMPO-positive ALL cases demonstrated evidence of t(9;22) by either karyotype or polymerase chain reaction analysis. The pMPO-positive ALLs had a lower frequency of extramedullary disease than the pMPO-negative group and a trend toward improved overall survival compared with the pMPO-negative group. Immunoreactivity with pMPO in adult ALL may lead to an incorrect interpretation of biphenotypic acute leukemia using a recently described scoring system, and a revision to that scoring system is proposed to accommodate pMPO-positive ALL.

High-dose cytosine arabinoside and daunorubicin induction therapy for adult patients with de novo non M3 acute myelogenous leukemia: impact of cytogenetics on achieving a complete remission.

Cytogenetic abnormalities are used to define prognostic subgroups of acute myelogenous leukemia (AML) with respect to achieving complete remission (CR) and remaining disease free. These prognostic groups for obtaining CR were based on an induction regimen mainly using standard dose cytosine arabinoside (Ara-C) + daunorubicin (DNR). We have reviewed our experience with 122 adult patients with de novo non-M3 AML who were treated with high-dose (HD) Ara-C 3 g/m2 given over 3 h every 12 h for a total of eight doses followed by DNR 60 mg/m2 daily for 2 days. CR was obtained in 80% while 16% had refractory disease and 4% died of sepsis during hypoplasia. CR rate for favorable, intermediate and unfavorable cytogenetic groups were 87%, 79% and 62%, respectively (P = 0.32). High white blood cell count, age, FAB subtype and LDH levels did not adversely affect CR rate. Eighty-five percent of patients achieved CR with one course of treatment and 87% of complete responders were able to receive post remission therapy. High-dose Ara-C/DNR appears to offer an excellent chance of achieving remission for patients with AML including those with poor risk cytogenetics, without an increase in early toxic deaths.

Autologous stem-cell transplantation for poor-risk and relapsed intermediate- and high-grade non-Hodgkin's lymphoma.

The primary objective of this study was to evaluate the outcome of patients treated with high-dose chemo-/radiotherapy or high-dose chemotherapy and autologous stem-cell transplant (ASCT) for relapsed, refractory, or poor-risk intermediate-grade (IG) and high-grade (HG) non-Hodgkin's lymphoma (NHL). The secondary objectives were to determine prognostic factors for relapse and survival. Between February 1987 and August 1998, 264 patients, 169 (64%) IG and 95 (36%) HG, underwent high-dose therapy and ASCT at City of Hope National Medical Center (COHNMC). There were 157 (59%) males and 107 (41%) females with a median age of 44 years (range, 5-69 years). The median number of prior chemotherapy regimens was 2 (range, 1-4), and 71 (27%) had received prior radiation as part of induction or as salvage therapy. The median time from diagnosis to ASCT was 10.8 months (range, 3-158 months). Ninety-four patients (36%) underwent transplantation in first complete/partial remission (CR/PR), 40 (15%) in induction failure, and 130 (49%) in relapse or subsequent remission. Two preparative regimens were used: total body irradiation/high-dose etoposide/cyclophosphamide (TBI/VP/CY) in 208 patients (79%) and carmustine/etoposide/cyclophosphamide (BCNU/VP/CY) in 56 patients (21%). One hundred sixty-three patients (62%) received peripheral blood stem cells (PBSC) and 101 (38%) received bone marrow (BM) alone or BM plus PBSC. At a median follow-up of 4.43 years for surviving patients (range, 1-12.8 years), the 5-year Kaplan-Meier estimates of probability of overall survival (OS), progression-free survival (PFS), and relapse for all patients are 55% (95% confidence interval [CI]: 49%-61%), 47% (95% CI: 40%-53%), and 47% (95% CI: 40%-54%), respectively. There were 27 deaths (10%) from nonrelapse mortality, including seven (3%) patients who developed second malignancies (five with myelodysplasia/acute myelogenous leukemia and two with solid tumors). By stepwise Cox regression analysis, disease status at ASCT was the only prognostic factor that predicted for both relapse and survival. The 5-year probability of PFS for patients transplanted in first CR/PR was 73% (95% CI: 62%-81%) as compared to 30% (95% CI: 16%-45%) for induction failure and 34% (95% CI: 26%-42%) for relapsed patients. Our results further support the role of high-dose therapy and ASCT during first CR/PR for patients with poor-risk intermediate- and high-grade NHL. Early transplant is recommended for patients failing initial induction therapy or relapsing after chemotherapy-induced remission. Relapse continues to be the most common cause of treatment failure. An alternative approach to prevent relapse, the incorporation of radioimmunotherapy into the high-dose regimen, is being investigated. The development of a second malignancy is a serious complication of high-dose therapy, which requires close surveillance.

Contralateral prophylactic mastectomy improves the outcome of selected patients undergoing mastectomy for breast cancer.

BACKGROUND: Risk factors for contralateral breast cancer (CBC) may indicate a benefit for contralateral prophylactic mastectomy (CPM) at the time of unilateral mastectomy for breast cancer. The purpose of this study is to evaluate the efficacy of CPM in preventing CBC. METHODS: sixty-four patients undergoing CPM and a control group of 182 patients not undergoing CPM and matched for age, stage, surgery, chemotherapy, and hormonal therapy were retrospectively compared for CBC rate, disease-free survival, and overall survival. RESULTS: Thirty-six CBCs occurred in the control group. In the CPM group, 3 CBCs were found at the time of prophylactic mastectomy, but none occurred subsequently (P = 0.005). Disease-free survival at 15 years in the CPM group was 55% (95% confidence interval [CI] 38% to 69%) versus 28% (95% CI 19% to 36%) in the control group (P = 0.01). Overall survival at 15 years was 64% (95% CI 45% to 78%) CPM versus 48% (95% CI 39% to 58%) in controls (P = 0.26). CONCLUSION: CPM prevented CBC and significantly prolonged disease-free survival. Future studies will need to address risk assessment and contralateral breast cancer prevention in patients treated for early breast cancer.

Long-term follow-up of 23 patients with Philadelphia chromosome-positive acute lymphoblastic leukemia treated with allogeneic bone marrow transplant in first complete remission.

Between 1984 and 1997, 23 consecutive patients with Philadelphia chromosome-positive acute lymphoblastic leukemia in first complete remission were treated with allogeneic bone marrow transplants from HLA-matched siblings. All patients but one were conditioned with fractionated total body irradiation (1320 cGy) and high-dose etoposide (60 mg/kg). One patient received high-dose cyclophosphamide instead of etoposide, and another patient received both drugs. Nine patients died following BMT, two from relapsed leukemia, and seven from transplant-related causes. The 3-year probabilities of disease-free survival and relapse are 65% and 12%, respectively. For patients transplanted after 1992, these probabilities are 81% (48-95%, 95% confidence interval) and 11% (2-50%), respectively. The relatively low relapse rate in this group of patients compared to published reports may reflect the enhanced anti-leukemic activity of etoposide in combination with FTBI compared to other conditioning regimens. The enhancement in overall survival for patients transplanted after 1992 may reflect improvements in supportive care, in particular, the prophylaxis of serious fungal and viral infections.

Cyclosporine, methotrexate, and prednisone compared with cyclosporine and prednisone for prevention of acute graft-vs.-host disease: effect on chronic graft-vs.-host disease and long-term survival.

Graft-vs.-host disease (GVHD) is a major predictor of outcome following allogeneic bone marrow transplantation (BMT). For patients alive at day 100 after BMT, the presence or absence of chronic GVHD is one of the most important determinants of survival and quality of life. We wished to determine the effects on chronic GVHD of two regimens used for the prophylaxis of acute GVHD: cyclosporine, methotrexate, and prednisone (CSA/MTX/PSE) and cyclosporine and prednisone (CSA/PSE). One hundred forty-nine evaluable patients were entered into the acute GVHD study. As of 31 March 1997, 63 months after the last patient underwent BMT, the median survival time was 4.5 years (range 0.09-9.9). The incidence of chronic GVHD was independent of the prophylactic regimen (55 vs. 54%), and extensive chronic GVHD occurred in 25 and 24% of patients receiving CSA/MTX/PSE and CSA/PSE, respectively. Of note, the median Karnofsky performance status of both groups was 100% (range 70-100%), reflecting the low incidence of extensive chronic GVHD. Survival rates free of chronic GVHD were 52 vs. 42% (p = 0.29) for patients receiving CSA/MTX/PSE vs. CSA/PSE. The incidence of relapse was also similar in both groups of patients. These data suggest that the combinations of CSA/MTX/PSE and CSA/PSE result in comparable chronic GVHD-free survival without an increase in leukemic relapse.

High-dose chemo/radiotherapy and autologous bone marrow or stem cell transplantation for poor-risk advanced-stage Hodgkin's disease during first partial or complete remission.

Complete remission rates of 70-90% can be achieved following combination chemotherapy for patients with advanced-stage Hodgkin's disease (HD). Patients who present with unfavorable poor prognostic factors, however, have a 5-year disease-free survival of only 40-50%. In an attempt to improve the prognosis of 20 patients with poor-risk advanced-stage HD, we evaluated the role of early high-dose therapy (HDT) and autologous bone marrow/stem cell transplantation (ASCT) during the first complete or partial remission (CR/PR). Patients were eligible for ASCT if they either achieved a PR (defined as > 50% regression) (six patients), or achieved a CR (14 patients) but had presented with three or more of the following unfavorable features: stage IV disease with bone marrow involvement or > or = 2 extranodal sites of involvement; bulky mass > 10 cm or bulky mediastinal mass > 1/3 of mediastina/thoracic ratio; B symptoms; and elevated serum lactate dehydrogenase (LDH) level. The study included 11 men (55%) and 9 women (45%). The median age was 37 years (range 20-57). Seventeen patients (85%) had stage IV disease; 14 (70%) had B symptoms; 13 (65%) had bulky mass > 10 cm; 14 (70%) had > or = 2 extra nodal sites involvement; and eight patients (40%) had elevated LDH levels. All patients were treated with standard four or 7-8 drug combination chemotherapy regimens until they achieved maximal response prior to ASCT with a median of six cycles (range 4-11). Six patients also received involved field radiotherapy to residual bulky mass > 5 cm or bony lesions before ASCT. The median time from diagnosis to ASCT was 8.6 months (range 5.5-18.9). Preparative regimens consisted of fractionated total body irradiation (FTBI) 1200 cGy in combination with etoposide 60 mg/kg and cyclophosphamide 100 mg/kg in all patients except one who had borderline pulmonary function and received lomustine 15 mg/kg instead of FTBI. All patients engrafted and there was no transplant-related mortality. One patient developed congestive cardiomyopathy at 4 years post-ASCT. All patients remain alive and in remission at a median follow-up of 42.8 months (range, 13.2-149.2). These preliminary results suggest that HDT and ASCT can be performed safely during first CR/PR in selected patients with advanced-stage HD who have an unfavorable prognosis. Further randomized studies comparing HDT and ASCT during first CR with conventional chemotherapy and ASCT at relapse in poor-risk advanced-stage HD should be conducted. The prognostic factors and risk groups described recently by an international prognostic study can be used to identify high-risk patients who may be candidates for more intensive therapy.

Extracorporeal photochemotherapy for treatment of drug-resistant graft-vs.-host disease.

Extracorporeal photochemotherapy (EP) is a therapeutic approach to the treatment of drug-resistant graft-vs.-host disease (GVHD) that uses the known immunosuppressive and immunomodulatory effects of ultraviolet light. In 1990, we initiated a pilot study to evaluate the efficacy and safety of EP in patients with refractory GVHD. Between 1991 and 1996, six patients with acute grade IV liver GVHD, 12 patients with chronic following acute GVHD, and six patients with de novo chronic GVHD were treated with EP. All patients had failed to respond to conventional GVHD immunosuppressive drug therapy of cyclosporine and prednisone. The six patients with acute liver GVHD had also received antithymocyte globulin (ATG); therapy for chronic GVHD included thalidomide in eight patients, psoralen plus ultraviolet A in five patients, and ATG in two patients. All patients with acute liver GVHD had progressive liver failure with short survival despite frequent EP. The response rate with EP treatment was 3 of 6 for patients with de novo chronic GVHD and 3 of 12 for patients with chronic following acute GVHD. Three patients with bronchiolitis obliterans had either no response or no documented disease progression while undergoing EP. Side effects of EP were minor and included gastrointestinal upset frequently, catheter-related sepsis in four patients, increased red blood cell and platelet transfusion requirements in one patient, and leukopenia in two patients. EP was discontinued in three patients because of side effects, including GI upset in one patient and bone marrow suppression in two patients. Side effects were reversible with the discontinuation of EP. We were unable to correlate response to EP with the level of methoxypsoralen, number of lymphocytes treated, or pattern of pre- and posttreatment CD4/CD8 ratio. We concluded that EP has some efficacy in the treatment of drug-resistant chronic GVHD, with minor overall toxicity.

Results of high-dose therapy and autologous bone marrow/stem cell transplantation during remission in poor-risk intermediate- and high-grade lymphoma: international index high and high-intermediate risk group.

We have conducted a pilot study to investigate the role of high-dose therapy and autologous bone marrow/stem cell transplantation (ASCT) during first complete or partial remission in 52 patients with poor-risk aggressive lymphoma. There were 42 patients with intermediate-grade or immunoblastic lymphoma who were considered to be high (60%) and high-intermediate risk (40%) groups at diagnosis based on the age-adjusted International Prognostic Index (IPI) and 10 patients with high-grade, SNCCL (small non-cleaved cell, Burkitt's, and non-Burkitt's), who at presentation had poor-risk features defined as elevated serum lactate dehydrogenase level, stage IV, and bulky mass >/=10 cm. The median age was 34 years (range, 16 to 56 years). Thirty-nine were transplanted in first complete remission and 13 in first partial remission after conventional therapy. Conditioning regimens consisted of total body irradiation (TBI) administered as a single fraction 750 cGy in 3 patients and in fractionated doses for a total of 1,200 cGy in 44 patients, in combination with 60 mg/kg etoposide and 100 mg/kg cyclophosphamide. Five patients with prior radiotherapy received 450 mg/m2 carmustine instead of TBI. Stem cell sources were either bone marrow and/or peripheral blood. No in vitro purging was used. All patients engrafted. Two SNCCL patients died of venoocclusive disease at 25 days and acute leukemia at 27 months posttransplantation. There were six relapses at 1.5 to 12.8 months posttransplantation. At a median follow-up of 44 months (range, 1 to 113 months), the estimated 3-year overall survival (OS) and disease-free survival (DFS) for all patients was 84% (95% confidence interval [CI], 70% to 92%) and 82% (95% CI, 68% to 91%), respectively. In the subset of patients with intermediate-grade and immunoblastic lymphoma, the 3-year DFS was 89% (95% CI, 74% to 96%) for all patients, 87% (95% CI, 67% to 96%) for high-risk patients, and 92% (95 CI, 61% to 99%) for high-intermediate risk patients. The 3-year OS and DFS for SNCCL patients were identical at 60% (95% CI, 30% to 84%). These results suggest that high-dose therapy and ASCT during first remission may improve the survival and prognosis of patients with poor-risk intermediate- and high-grade lymphoma. A prospective randomized study comparing high-dose therapy and ASCT with conventional chemotherapy in IPI high-risk patients with aggressive non-Hodgkin's lymphoma should be undertaken.

Paradoxical effect of thalidomide prophylaxis on chronic graft-vs.-host disease.

Thalidomide has been reported to be an effective agent for the treatment of chronic graft-vs.-host disease (GVHD). To determine its efficacy as a prophylactic agent for the prevention of chronic GVHD, a prospective randomized double-blind study was performed. A total of 59 patients were randomized to receive either placebo or thalidomide (200 mg orally twice a day) beginning 80 days after allogeneic bone marrow transplantation (BMT). Fifty-four evaluable patients were analyzed, 26 received placebo, and 28 received thalidomide. The characteristics of patients were well-balanced between the two groups. Following the first interim analysis conducted by the Data Safety Monitoring Board using an intent-to-treat approach, a statistically significant difference in the incidence of chronic GVHD was found. Patients receiving thalidomide developed chronic GVHD more often than patients receiving placebo (p = 0.06). Moreover, an apparent overall survival advantage was noted for patients receiving placebo compared to those receiving thalidomide (p = 0.006). Adjustment for possible confounding factors did not eliminate these negative effects of thalidomide. These results demonstrate that while thalidomide is an effective agent for the therapy of chronic GVHD, its use at the doses administered for the prophylaxis of chronic GVHD resulted in a paradoxical outcome with a higher incidence of chronic GVHD and a lower overall survival. We conclude that the early use of thalidomide results in a shift in the balance between GVHD and induction of tolerance. These data demonstrate again the importance of phase III double-blind controlled randomized studies.

The outcome of matched unrelated donor bone marrow transplantation in patients with hematologic malignancies using molecular typing for donor selection and graft-versus-host disease prophylaxis regimen of cyclosporine, methotrexate, and prednisone.

Graft-versus-host disease (GVHD) is a major obstacle to successful bone marrow transplantation (BMT) from matched unrelated donor (MUD). Currently available HLA-A, -B, and -DR serologic testing may not be sensitive enough to detect clinically relevant donor/recipient (D/R) nonidentity. Better HLA matching of D/R pairs using molecular typing for class II antigens in combination with intensive GVHD prophylaxis may potentially reduce the incidence of GVHD and lead to an improved outcome of MUD transplantation. Between July 1991 and August 1993, thirty consecutive patients with hematologic malignancies underwent MUD transplantation from donors who were identical for HLA -A, -B, and -DR by serologic typing. Twenty-five D/R pairs were matched for DRB and DQB by molecular typing (restriction fragment-length polymorphism and sequence-specific oligonucleotide probe hybridization analyses), whereas five were allele mismatched at either DRB or DQB. All patients also received GVHD prophylaxis with the combination of cyclosporine (CSA), methotrexate (MTX), and prednisone (PSE). The median age was 35 years (range, 15 to 50). The diagnoses were: chronic myelogenous leukemia (CML) in chronic phase (CP) (16), CML in more than CP (3), acute leukemia in more than first complete remission (CR) (8), acute leukemia in first CR (1), and advanced high-grade lymphoma (2). The preparative regimen consisted of 1,320 cGy fractionated total body irradiation (FTBI) and 60 mg/kg cyclophosphamide (CY) daily for 2 days in 17 good-risk patients (CML/CP and acute leukemia first CR); and 1,320 cGy FTBI in combination with 60 mg/kg etoposide and 20 to 60 mg/kg CY in 13 patients with advanced leukemia and lymphoma. All patients received CSA, PSE, and MTX on days 1, 3, 6 for GVHD prophylaxis, and 10 patients also received day +11 MTX. All patients engrafted except one who died early of regimen-related toxicity. The incidence of grade III or IV acute GVHD was 24% (95% confidence interval [CI], 10% to 44%) and that of extensive chronic GVHD was 65% (95% CI, 43% to 84%). At a median follow-up of 13.6 months, 57% of the patients are alive in remission with a median Karnofsky performance status of 90%. The cumulative probability of 2-year disease-free survival for all patients was 53% (95%) CI, 33% to 71%); for good-risk patients, 71% (95% CI, 46% to 87%) and for the poor-risk group, 34% (95% CI, 13% to 64%).(ABSTRACT TRUNCATED AT 400 WORDS)

High-dose therapy followed by autologous peripheral-blood stem-cell transplantation for patients with Hodgkin's disease and non-Hodgkin's lymphoma using unprimed and granulocyte colony-stimulating factor-mobilized peripheral-blood stem cells.

PURPOSE: To evaluate (1) the effect of granulocyte colony-stimulating factor (G-CSF) on peripheral-blood stem-cell (PBSC) mobilization; (2) the rate of hematopoietic recovery after G-CSF-mobilized PBSC transplantation; and (3) the outcome of high-dose myeloablative therapy and PBSC transplantation in patients with relapsed or refractory lymphoma. PATIENTS AND METHODS: Ninety-five patients with lymphoma underwent high-dose therapy followed by PBSC transplant in three sequentially treated cohorts of patients in a nonrandomized study. The first 30 patients received nonmobilized PBSCs (unprimed) without G-CSF after transplant, the next 26 patients received PBSC that were mobilized with G-CSF 5 micrograms/kg/d (primed-5) plus G-CSF after transplant, and the last 39 patients received PBSC mobilized by G-CSF 10 micrograms/kg/d (primed-10) plus G-CSF after transplant. The conditioning regimen consisted of fractionated total-body irradiation (FTBI) 12 Gy in combination with etoposide 60 mg/kg and cyclophosphamide 100 mg/kg. Patients with prior radiotherapy received carmustine (BCNU) 450 mg/m2 instead of FTBI. RESULTS: The use of G-CSF-mobilized PBSCs in combination with G-CSF posttransplant resulted in a significantly accelerated time to recovery of both granulocyte and platelet when compared with the unprimed group. The median number of days to an absolute granulocyte count (ANC) of greater than 0.5 x 10(9)/L was 10 days for G-CSF primed versus 20 days for the unprimed (P = .0001). The median days to platelet transfusion independence was 16 and 31 days (P = .0001) for the G-CSF primed and unprimed, respectively. There were also significant reductions in the number of platelet (P = .02) and RBC transfusions (P = .006) for the G-CSF primed. Multivariate analysis of prognostic factors identified CD34+ cell dose as the only additional factor predicting engraftment. Sixty-nine patients are alive at a median follow-up of 15.9 months (range, 7.4 to 63.7). The cumulative probability of 2-year disease-free survival is 59% (95% confidence interval [CI], 36% to 79%) and 39% (95% CI 25% to 55%) for patients with Hodgkin's disease and non-Hodgkin's lymphoma, respectively. CONCLUSION: The use of G-CSF-mobilized PBSC after high-dose myeloablative therapy resulted in a rapid, complete, and sustained hematopoietic recovery. Disease-free survival over 2 years can be achieved in some patients with relapsed lymphoma after high-dose therapy and PBSC transplantation. However, longer follow-up is required to confirm the curability of this approach.

Cyclosporine, methotrexate, and prednisone compared with cyclosporine and prednisone for prophylaxis of acute graft-versus-host disease.

BACKGROUND: Acute graft-versus-host disease (GVHD) following allogeneic bone marrow transplantation remains a serious problem. In a clinical trial, we tested the combination of cyclosporine and prednisone with and without methotrexate for the prevention of GVHD. METHODS: One hundred fifty patients with either acute leukemia in first complete remission, chronic myelogenous leukemia in first chronic phase, or lymphoblastic lymphoma in first complete remission were enrolled in the study. All the patients were given fractionated total-body irradiation (1320 cGy) and etoposide (60 mg per kilogram of body weight) in preparation for transplantation, and received bone marrow from genotypically histocompatible donors. To prevent GVHD, they were randomly assigned to prophylactic treatment with either cyclosporine, methotrexate, and prednisone or cyclosporine and prednisone without methotrexate. All the patients received standardized supportive care after transplantation, including intravenous gamma globulin. RESULTS: Patients receiving cyclosporine, methotrexate, and prednisone had a significantly lower incidence of acute GVHD of grades II to IV (9 percent) than those receiving cyclosporine and prednisone (23 percent, P = 0.02). Multivariate regression analysis demonstrated that an increased risk of acute GVHD was associated with an elevated serum creatinine concentration (P = 0.006) and treatment with cyclosporine and prednisone alone (P = 0.02). The lower incidence of acute GVHD was not associated with a higher rate of relapse of leukemia or lymphoma. There was no significant difference in disease-free survival at three years between the two treatment groups (64 percent with the three-drug regimen vs. 59 percent with the two-drug regimen, P = 0.57). CONCLUSIONS: The combination of cyclosporine, methotrexate, and prednisone was more effective in preventing acute GVHD of grades II to IV than was the combination of cyclosporine and prednisone without methotrexate.

Extended follow-up in 212 long-term allogeneic bone marrow transplant survivors. Issues of quality of life.

A group of 235 allogeneic marrow recipients were contacted at least one year following their BMT to obtain information on their quality of life; 212 (90%) agreed to participate in this survey. A total of 162 adults and 50 pediatric survivors were interviewed during clinic visits (5%) or over the telephone (95%). Changes in productive activity and marital status at the time of interview were studied, as well as the presence of physical symptoms and perception of a general sense of well-being. Older transplant recipients were observed to have a significantly higher incidence of chronic graft-versus-host disease, common colds, and skin changes when compared with pediatric transplant recipients (P < 0.01). Older subjects were also more likely to require any type of regular medication. Younger survivors were rated with a higher Karnofsky performance status and global subjective score. There were no significant differences between patients who received TBI as part of the conditioning regimen and those who did not, with the exception of increased cataract development in pediatric patients receiving TBI (P < 0.008). We conclude that most allogeneic marrow transplant survivors, especially those individuals of younger age at the time of their transplants, are doing well in the domains tested.