Biomedical subjects

Frederick R Appelbaum

Publications and source records attributed to Frederick R Appelbaum.

At least 55 records · Page 3Linked to original sources

PubMed2003

Female donors contribute to a selective graft-versus-leukemia effect in male recipients of HLA-matched, related hematopoietic stem cell transplants.

Male recipients of transplants from female (F-->M) hematopoietic stem cell donors represent a special group in whom donor T cells that are specific for recipient minor histocompatibility antigens encoded by Y-chromosome genes may contribute to a graft-versus-leukemia (GVL) effect and to graft-versus-host disease (GVHD). We examined the contribution of donor/patient sex to the risk for relapse and GVHD in 3238 patients who underwent HLA-identical sibling hematopoietic stem cell transplantation (HSCT) for hematopoietic malignancies at a single institution. Compared with other sex combinations, male recipients of female transplants had the lowest risk for relapse and the greatest odds for GVHD. Remarkably, after controlling for GVHD as a time-dependent covariate, F-->M HSCT still exhibited a lower risk for relapse than other sex combinations, demonstrating a selective GVL effect distinct from that contributed by GVHD. A reduction in relapse after F-->M HSCT was observed in patients with chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), and acute lymphoblastic leukemia (ALL). Taken together, these data suggest that minor H antigens encoded or regulated by genes on the Y chromosome contribute to a selective GVL effect against myeloid and lymphoid leukemias after F-->M HSCT.

Acute Disease↗

PubMed2003

Allogeneic hematopoietic stem cell transplantation for myelofibrosis.

Fifty-six patients, 10 to 66 years of age, with idiopathic myelofibrosis (IMF) or end-stage polycythemia vera or essential thrombocythemia received allogeneic hematopoietic cell transplants from related (n = 36) or unrelated (n = 20) donors. Forty-four patients were prepared with busulfan plus cyclophosphamide and 12 with total body irradiation plus chemotherapy. The source of stem cells was marrow in 33 and peripheral blood in 23 patients. All but 3 patients achieved engraftment. While 50 patients showed complete donor chimerism, 3 patients were found to be mixed chimeras at 26, 48, and 86 months after transplantation, respectively. Two patients died from relapse/progressive disease, and 18 died from other causes. There are 36 patients surviving at 0.5 to 11.6 (median, 2.8) years, for a 3-year Kaplan-Meier estimate of 58% (CI, 43%-73%). Dupriez score, cytogenetic abnormalities, and degree of marrow fibrosis were the most significant risk factors for posttransplantation mortality. Patients conditioned with a regimen of busulfan targeted to plasma levels of 800 to 900 ng/mL plus cyclophosphamide had a higher probability of survival (76% [CI, 62%-91%]) than other patients. Results with unrelated donors were comparable with those with HLA-identical sibling transplants. Thus, allogeneic hematopoietic cell transplantation offers long-term relapse-free survival for patients with myelofibrosis.

Adolescent↗

PubMed2003

Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma.

The full potential of a graft-versus-myeloma effect after allogeneic hematopoietic cell transplantation (HCT) for patients with multiple myeloma (MM) has not been realized because of excessive early transplantation-related mortality (TRM) with conventional HCT. Autologous HCTs have been characterized by almost universal disease recurrences. The current trial combined autologous HCT with subsequent nonmyeloablative allogeneic HCT to maintain the benefits of both approaches with acceptable toxicity. Fifty-four patients, 52 years of age (median; range, 29-71 years), with previously treated stage II or III MM (52% refractory or relapsed disease) were given melphalan 200 mg/m2 and autologous HC transplants. Regimen-related toxicities after autologous HCT were moderate with a median of 6 days of neutropenia, 7 days of hospitalization, and 1 death from infection. Forty to 229 days later (median, 62 days), 52 patients received a single fraction dose of 2 Gy total body irradiation and HC transplants from HLA-identical siblings with postgrafting immunosuppression with mycophenolate mofetil (MMF) and cyclosporine (CSP). Patients experienced medians of 0 days of hospitalization, neutropenia, and thrombocytopenia. Sustained engraftment was uniform. With a median follow-up of 552 days after allografting, overall survival is 78%. One patient (2%) died before day 100 from disease progression. Thirty-eight percent of patients developed acute graft-versus-host disease (GVHD; grade II in all but 4 cases) and 46% chronic GVHD requiring therapy. Tumor responses occurred slowly. Thus far, 57% of patients have achieved complete remissions and 26% have achieved partial remissions for an overall response of 83%. Despite being evaluated in elderly patients with MM, this 2-step approach has reduced the acute toxicities of allogeneic HCT while achieving potent antitumor activities.

Adult↗

PubMed2003

High-dose radioimmunotherapy versus conventional high-dose therapy and autologous hematopoietic stem cell transplantation for relapsed follicular non-Hodgkin lymphoma: a multivariable cohort analysis.

We performed a multivariable comparison of 125 consecutive patients with follicular lymphoma (FL) treated at our centers with either high-dose radioimmunotherapy (HD-RIT) using 131I-anti-CD20 (n = 27) or conventional high-dose therapy (C-HDT) (n = 98) and autologous hematopoietic stem cell transplantation. The groups were similar, although more patients treated with HD-RIT had an elevated pretransplantation level of lactate dehydrogenase (41% versus 20%, P =.03) and elevated international prognostic score (41% versus 19%, P =.02). Patients treated with HD-RIT received individualized therapeutic doses of 131I-tositumomab (median, 19.7 GBq [531 mCi]) to deliver 17 to 31 Gy (median, 27 Gy) to critical organs. Patients treated with C-HDT received total body irradiation plus chemotherapy (70%) or chemotherapy alone (30%). Patients treated with HD-RIT experienced improved overall survival (OS) (unadjusted hazard ratio [HR] for death = 0.4 [95% confidence interval (95% CI), 0.2-0.9], P =.02; adjusted HR, 0.3, P =.004) and progression-free survival (PFS) (unadjusted HR =.6 [95% C.I., 0.3-1.0], P =.06; adjusted HR, 0.5, P =.03) versus patients treated with C-HDT. The estimated 5-year OS and PFS were 67% and 48%, respectively, for HD-RIT and 53% and 29%, respectively, for C-HDT. One hundred-day treatment-related mortality was 3.7% in the HD-RIT group and 11% in the C-HDT group. The probability of secondary myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) was estimated to be.076 at 8 years in the HD-RIT group and.086 at 7 years in the C-HDT group. HD-RIT may improve outcomes versus C-HDT in patients with relapsed FL.

Adult↗

PubMed2003

Conditioning with fludarabine and targeted busulfan for transplantation of allogeneic hematopoietic stem cells.

A regimen of busulfan and cyclophosphamide is standard therapy before transplantation of allogeneic hematopoietic stem cells in patients with chronic myelogenous leukemia (CML) or myelodysplastic syndrome (MDS). The clinical trial reported here was undertaken to test the hypothesis that fludarabine can replace cyclophosphamide in this regimen and facilitate donor engraftment with reduced toxicity. The conditioning regimen consisted of 30 mg/m2 intravenous fludarabine daily from day -9 to day -6, and oral busulfan given at 1 mg/kg 4 times a day every 6 hours from day -5 to day -2, with doses adjusted to target plasma levels of 900 +/- 100 ng/mL at steady state. Cyclosporine and methotrexate were used for prophylaxis for graft-versus-host disease. Enrolled were 42 patients with high-risk CML (n = 4) or MDS (n = 38). The median patient age was 52 years (range, 12-65 years). Mobilized blood stem cells were obtained from HLA-compatible siblings (n = 16) or unrelated donors (n = 26). Engraftment was achieved in all patients, and the day-100 regimen-related mortality was 7%. With a median follow-up of 18 months (range, 13-27 months), the probabilities of overall survival, disease-free survival, and nonrelapse mortality were 42.4%, 34.9%, and 24%, respectively. These data indicate that the combination of fludarabine and targeted busulfan is sufficiently immunosuppressive to facilitate engraftment of blood stem cells from HLA-matched siblings and unrelated donors. Based on these encouraging results, further studies of fludarabine and targeted busulfan are warranted in standard-risk patients.

Adolescent↗

PubMed2003

HLA-matched related hematopoietic cell transplantation for chronic-phase CML using a targeted busulfan and cyclophosphamide preparative regimen.

Allogeneic blood or marrow transplantation (BMT) is a curative therapy for chronic myeloid leukemia (CML). We have previously reported that the pharmacologic targeting of busulfan combined with cyclophosphamide (TBU/CY) can minimize regimen-related toxicity while preserving antileukemic effects. We report here on 131 consecutive chronic-phase CML patients treated with allogeneic related BMT using a TBU/CY preparative regimen, where the busulfan dose was targeted to achieve a steady-state plasma concentration of at least 900 ng/mL. The median age of the patients was 43 years (range, 14-66 years). Estimates of the probabilities of nonrelapse mortality, relapse, survival, and disease-free survival 3 years after transplantation were 14%, 8%, 86%, and 78%, respectively. Age had no statistically significant effect on survival. Although approximately 60% of the patients developed clinically extensive chronic graft-versus-host disease, the median Karnofsky score at last contact date among survivors was 95%. Of surviving patients, 11% were molecularly positive for the bcr-abl mRNA at last contact, with a median level of bcr-abl transcripts of 4.6 copies/microg RNA. These data suggest that TBU/CY is a very effective preparative regimen for CML in chronic phase, associated with an expected survival at 3 years of approximately 85%, with most patients being in molecular remission.

Adolescent↗

PubMed2003

Predictive factors for outcome of allogeneic hematopoietic cell transplantation for adult acute lymphoblastic leukemia.

Between January 1990 and December 1997, 182 adults with acute lymphoblastic leukemia (ALL) received allogeneic hematopoietic cell transplants according to Fred Hutchinson Cancer Research Center protocols. Patients eligible for transplantation included those in first remission, especially those at high risk of relapse (n = 41), and any patient in second or later remissions (n = 46) or in relapse (n = 95). The median patient age was 29.4 years (range, 18.0-57.6 years), and the median duration of disease was 13.3 months (range, 2.4-221.9 months). Fifty-six patients had Philadelphia chromosome-positive ALL. Most patients (n = 169) received a conditioning regimen of cyclophosphamide 120 mg/kg plus 12.0 to 15.75 Gy of total body irradiation and a combination of cyclosporine and methotrexate as graft-versus-host disease (GVHD) prophylaxis. One hundred twenty-one patients received stem cells from HLA-identical donors (88 related donors and 33 unrelated donors), and 61 received stem cells from HLA-mismatched donors (26 related donors and 35 unrelated donors). Actuarial disease-free survival at 5 years was 21% for all patients, 43% for patients in first remission, 24% for patients in second or later remissions, and 9% for patients in relapse. Univariate and multivariate Cox regression analyses were performed to identify factors associated with survival, relapse, nonrelapse mortality, and disease-free survival. Factors significantly associated (P <.01) with improved survival and disease-free survival included younger age and being in first remission. Lower disease-free survival was associated with receiving cyclosporine alone as GVHD prophylaxis (P <.01). Risk of relapse correlated only with disease status at transplantation: patients who underwent transplantation in relapse had a 9-fold increased risk compared with patients who underwent transplantation in first remission. Acute or chronic GVHD had no significant effect on relapse. Increased nonrelapse mortality was associated with HLA-mismatched donors, a positive cytomegalovirus serology before transplantation, and GVHD prophylaxis with only cyclosporine. Patients with Philadelphia chromosome-positive ALL had survival and relapse rates similar to patients with normal cytogenetics.

Adult↗

PubMed2003

Non-myeloablative allografting from human leucocyte antigen-identical sibling donors for treatment of acute myeloid leukaemia in first complete remission.

Many patients with acute myeloid leukaemia (AML) in first complete remission (CR1) are ineligible for allogeneic transplantation as a result of age or medical problems other than leukaemia. Eighteen patients (median age 59 years, range 36-73 years) with de novo (n = 13) and secondary (n = 5) AML in morphological CR1, who were not candidates for conventional allografting, received non-myeloablative peripheral blood stem cell transplants from human leucocyte antigen identical sibling donors after conditioning with 2 Gy total body irradiation (TBI; n = 10) or 2 Gy TBI and 90 mg/m2 of fludarabine (n = 8). Postgrafting immunosuppression was with cyclosporine and mycophenolate mofetil. Two rejections were observed in patients not given fludarabine and one died with relapse. Overall, 10 patients died between 77 and 841 d, seven from relapse and three from non-relapse mortality (NRM). Day +100 NRM was 0% with a 1-year estimated NRM of 17%[95% confidence interval (CI) 0-35%]. The median follow-up among the eight survivors was 766 d (range, 188-1141 d). Seven of these eight survivors remain in complete remission (CR). One-year estimates of overall and progression-free survivals were 54% (95% CI 31-78%) and 42% (95% CI 19-66%) respectively. While follow-up is short, this analysis demonstrates that the procedure is sufficiently safe to be studied in a wider group of patients.

Acute Disease↗

PubMed2003

Prognostic significance of CD38 and CD20 expression as assessed by quantitative flow cytometry in chronic lymphocytic leukaemia.

CD38 expression on chronic lymphocytic leukaemia (CLL) cells is a poor prognostic factor, however, methods for measuring this vary. The QuantiBRITETM flow cytometry (FC) system yields an absolute antigen expression value (antibodies bound/cell, ABC) and may be useful in standardizing CD38 expression analysis. We evaluated cryopreserved pretreatment CLL cells for CD20 ABC, CD38 ABC, and percentage of CD38+ B cells from 131 patients requiring therapy. The 92 patients (70%) with >/= 100 CD38 ABC had worse overall survival (OS; 34% at 5 years) compared with those with < 100 CD38 ABC (70% at 5 years, mortality hazard ratio 2.30, 95% confidence interval 1.28-4.12; two-tailed P = 0.003). Among the 64 patients with < 30% CD38+ cells, OS of the 25 with >/= 100 ABC was worse than that of the 39 with < 100 ABC (P = 0.018). OS of patients with < 30% CD38+ cells and >/= 100 ABC was actually similar to that of patients with >/= 30% CD38+ cells. BrightCD20 expression (>/= 20 000 ABC) was not associated with a worse OS (P = 0.10). The presence of >/= 100 CD38 ABC in CLL patients requiring therapy is an unfavourable prognostic factor for OS and quantitative FC may be superior to percentage CD38+ cell assessment. Prospective trials are required to determine more precisely the prognostic significance of absolute expression levels in fresh CLL cells.

ADP-ribosyl Cyclase↗

PubMed2003

Predictors of relapse and overall survival in Philadelphia chromosome-positive acute lymphoblastic leukemia after transplantation.

Allogeneic transplantation offers a potential cure for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). We performed a retrospective analysis examining pretransplantation and posttransplantation prognostic factors in 90 patients with Ph+ ALL. The median age of the patients was 33 years, with slightly more than half of the patients (58%) in clinical remission at the time of transplantation. Overall, patients had a nonrelapse mortality rate of 30%, a relapse percentage of 34%, and an estimated 5-year disease-free survival rate of 30%. Pretransplantation risk factors for relapse included the expression of the p190 transcript (relative risk [RR] = 5.1; P =.037), evidence of morphologic disease at the time of transplantation (RR = 3.9; P <.001), and type of donor (RR = 2.5; P =.015), with patients receiving autologous or matched related transplants having the highest risk of relapse. The detection of minimal residual disease by reverse transcription polymerase chain reaction for bcr-abl transcripts was a significant posttransplantation risk factor for relapse (RR = 4.4; P =.001), with posttransplantation patients expressing the p190 transcript having the highest risk of relapse (RR = 8.7; P =.0001). In addition, patients with chronic extensive graft-versus-host disease showed a significantly lower risk of relapse (RR = 0.33; P =.038). Thus, these findings indicate that several pretransplantation and posttransplantation risk factors exist for patients with Ph+ ALL. Together, these factors can be used to improve our risk stratification of patients with Ph+ ALL who undergo transplantation, which will greatly enhance our ability to counsel these patients and potentially lead to the development of more specific treatment plans for them.

Adolescent↗

PubMed2002

Cholesterol-modulating agents kill acute myeloid leukemia cells and sensitize them to therapeutics by blocking adaptive cholesterol responses.

The mevalonate pathway produces many critical substances in cells, including sterols essential for membrane structure and isoprenoids vital to the function of many membrane proteins. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase is a rate-limiting enzyme in the mevalonate pathway. Because cholesterol is a product of this pathway, HMG-CoA reductase inhibitors (statins) are used to treat hypercholesterolemia. Statins are also toxic to several malignancies, including acute myeloid leukemia (AML). Although this toxicity has been attributed to the inhibition of Ras/Rho isoprenylation, we have previously shown that statin toxicity in primary AML cells (AMLs) does not correlate with Ras isoprenylation or with activating Ras mutations. In other studies, we have shown that hypoxic and oxidant injuries induce cholesterol increments in renal tubule cells and that statins sensitize these cells to injury by blocking protective cholesterol responses. We now demonstrate that exposing particular AMLs to radiochemotherapy induces much greater cellular cholesterol increments than those seen in similarly treated normal bone marrow. Treatment of these AMLs with mevastatin or zaragozic acid (which inhibits cholesterol synthesis but not isoprenoid synthesis) attenuates the cholesterol increments and sensitizes cells to radiochemotherapy. The extent of toxicity is affected by the availability of extracellular lipoproteins, further suggesting that cellular cholesterol is critical to cell survival in particular AMLs. Because zaragozic acid does not inhibit isoprenoid synthesis, these data suggest that cholesterol modulation is an important mechanism whereby statins exert toxic effects on some AMLs and that cholesterol modulators may improve therapeutic ratios in AML by impacting cholesterol-dependent cytoresistance.

Acute Disease↗

PubMed2002

Quantitative real-time RT-PCR analysis of PML-RAR alpha mRNA in acute promyelocytic leukemia: assessment of prognostic significance in adult patients from intergroup protocol 0129.

The potential prognostic value of quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR [qrtPCR]) measurements of PML-RAR alpha mRNA in acute promyelocytic leukemia was retrospectively assessed before treatment and at 3 posttreatment intervals in 123 patients on intergroup protocol 0129. The primary measure was the PML-RAR alpha(GAPDH) normalized quotient (NQ), that is, PML-RAR alpha mRNA copies divided by glyceraldehyde-3'-phosphate dehydrogenase (GAPDH) mRNA copies. Only samples with more than 2.5 x 10(5) copies of the housekeeping gene GAPDH mRNA (detection sensitivity exceeding 10(4)) were considered NQ evaluable. With RNA from low-density selected cells, paired peripheral blood (PB) and bone marrow samples (n = 140) had comparable NQs (P <.001). Before treatment, high NQ was associated with short-form PML-RAR alpha (P <.001), but not with white blood cell count or clinical outcome. Following treatment, NQ was lower in all-trans retinoic acid-induced complete remission (CR) than chemotherapy-induced CR (P =.018) and at first test after consolidation chemotherapy (P =.037). After consolidation chemotherapy, patients with NQ exceeding 10(-5) had 4.1-fold increased relapse risk (P =.008); however, 73% of patients who experienced relapse had NQ lower than 10(-5). In the follow-up period (FUP), any NQ exceeding 10(-5) and 10(-6) had 17.5-fold and 7.6-fold increased relapse risk, respectively (P <.001), while no gradation of relapse risk (approximately 18%) could be identified at NQ lower than 10(-6), including NQ(-). These results indicate that qrtPCR monitoring of PML-RAR alpha NQ can identify patients at high risk of relapse and suggest that clinically practical PB NQ monitoring at more frequent FUP intervals may improve predictive accuracy for relapse or continuing CR in patients with persistent, fluctuating minimal residual disease levels.

Adolescent↗

PubMed2002

Therapy-related myeloid leukemias are observed in patients with chronic lymphocytic leukemia after treatment with fludarabine and chlorambucil: results of an intergroup study, cancer and leukemia group B 9011.

PURPOSE: Patients with chronic lymphocytic leukemia (CLL) may have disease transformation to non-Hodgkin's lymphoma or prolymphocytic leukemia; however, development of therapy-related acute myeloid leukemia (t-AML) is unusual. A series of patients enrolled onto an intergroup CLL trial were examined for this complication. PATIENTS AND METHODS: A total of 544 previously untreated B-cell CLL patients were enrolled onto a randomized intergroup study comparing treatment with chlorambucil, fludarabine, or fludarabine plus chlorambucil. Case report forms from 521 patients were reviewed for t-AML. RESULTS: With a median follow-up of 4.2 years, six patients (1.2%) to date have developed therapy-related myelodysplastic syndrome (t-MDS; n = 3), t-AML (n = 2), or t-MDS evolving to t-AML (n = 1), from 27 to 53 months (median, 34 months) after study entry. This included five (3.5%) of 142 patients treated with fludarabine plus chlorambucil and one (0.5%) of 188 receiving fludarabine; no chlorambucil-treated patients developed t-MDS or t-AML (P =.007). At study entry, the median age among these six patients was 56 years (range, 44 to 72 years); three were male; the CLL Rai stage was I/II (n = 4) or III/IV (n = 2). Response to CLL therapy was complete (n = 4) or partial remission (n = 1) and stable disease (n = 1). Marrow cytogenetics, obtained in three of six cases at diagnosis of t-MDS or t-AML, were complex, with abnormalities in either or both chromosomes 5 and 7. Other abnormalities involved chromosomes X, 1, 8, 12, 17, and 19. Median survival after diagnosis of t-MDS/AML was 3.5 months (range, 0.5 to 10.1 months). CONCLUSION: Our findings raise the possibility that alkylator-purine analog combination therapy may increase the risk of therapy-related myeloid malignancies, which is of particular relevance with regard to ongoing trials using these combination therapies.

Acute Disease↗

PubMed2002

Cyclosporine inhibition of P-glycoprotein in chronic myeloid leukemia blast phase.

Chronic myeloid leukemia blast phase (CML-BP) cells commonly express the multidrug transporter, P-glycoprotein (Pgp). To determine whether Pgp inhibition improves treatment outcome in CML-BP, the Southwest Oncology Group performed a randomized, controlled trial testing the benefit of the Pgp modulator, cyclosporin A (CsA). Seventy-three eligible patients were assigned to treatment with cytarabine and infusional daunorubicin with or without intravenous CsA. Treatment with CsA yielded no improvement in treatment outcome as measured by the frequency of induction resistance (68% vs 53%), rate of complete remission or restored chronic phase (CR/CP, 8% vs 30%), and survival (3 vs 5 months). Blast expression of Pgp (63%) and LRP (71%) was common, whereas only Pgp adversely impacted the rate of CR/CP (P =.025). We conclude that Pgp has prognostic relevance in CML-BP but that the modulation of Pgp function with CsA as applied in this trial is ineffective.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2002

Conditioning with targeted busulfan and cyclophosphamide for hemopoietic stem cell transplantation from related and unrelated donors in patients with myelodysplastic syndrome.

A total of 109 patients (aged 6-66 years; median, 46 years) with myelodysplastic syndrome (MDS) were treated with busulfan (BU) targeted to plasma concentrations of 800 to 900 ng/mL plus cyclophosphamide (CY), 2 x 60 mg/kg, and hemopoietic stem cell (HSC) transplantation from related (n = 45) or unrelated donors (n = 64). At the time of transplantation, 69 patients had less than 5% myeloblasts in the marrow, and 40 patients had more advanced disease. All but 2 evaluable patients had engraftment. The Kaplan-Meier estimates of 3-year relapse-free survival (RFS) were 56% for related and 59% for unrelated recipients. The cumulative incidences of relapse were 16% for related and 11% for unrelated recipients. Nonrelapse mortality (NRM) at 100 days (3 years) was 12% (28%) for related and 13% (30%) for unrelated recipients. The only factor significant for RFS was the etiology of MDS (de novo better than treatment related; P =.03). Factors significantly correlated with relapse were advanced French-American-British classification (P =.002) and International Prognostic Scoring System score (P =.009), poor-risk cytogenetics (P =.03), and treatment-related etiology (P =.03). None of the factors examined was statistically significant for NRM. Patient age and donor type had no significant impact on outcome. RFS tended to be superior in patients receiving transplants with peripheral blood rather than marrow stem cells. Thus, a targeted BUCY regimen provided effective transplant conditioning for patients with MDS receiving transplants from HLA-identical siblings or alternative donors. Although there was still considerable nonrelapse morbidity and mortality, the present regimen was used successfully even in patients older than 60 years of age.

Adolescent↗

PubMed2002

All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol.

We previously reported a benefit for all-trans retinoic acid (ATRA) in both induction and maintenance therapy in patients with acute promyelocytic leukemia (APL). To determine the durability of this benefit and identify important prognostic factors, long-term follow-up of the North American Intergroup APL trial is reported. A total of 350 patients with newly diagnosed APL were randomized to either daunorubicin and cytarabine (DA) or ATRA for induction and then either ATRA maintenance or observation following consolidation chemotherapy. The complete remission (CR) rates were not significantly different between the ATRA and DA groups (70% and 73%, respectively). However, the 5-year disease-free survival (DFS) and overall survival (OS) were longer with ATRA than with DA for induction (69% vs 29% and 69% vs 45%, respectively). Based on both induction and maintenance randomizations, the 5-year DFS was 16% for patients randomized to DA and observation, 47% for DA and ATRA, 55% for ATRA and observation, and 74% for ATRA and ATRA. There was no advantage of either induction regimen among any subgroups when CR alone was considered. However, female sex, classical M3 morphology (vs the microgranular variant [M3v]), and treatment-white blood cell count (WBC) interaction (ATRA/WBC below 2 x 10(9)/L [2000/microL] best, DA/WBC above 2 x 10(9)/L worst) were each significantly associated with improved DFS (P <.05). Treatment with ATRA, WBC below 2 x 10(9)/L, and absence of bleeding disorder were each significantly associated with improved OS. Age more than 15 years, female sex, and treatment-morphology interaction (DA/M3v worst, ATRA best regardless of morphology) were each significantly associated with improved DFS based on maintenance randomization. The improvement in outcome with ATRA in APL was maintained with long-term follow-up.

Adolescent↗

PubMed2002

Outcome after induction chemotherapy for older patients with acute myeloid leukemia is not improved with mitoxantrone and etoposide compared to cytarabine and daunorubicin: a Southwest Oncology Group study.

Complete remission and long-term survival rates are low for older adults treated for acute myeloid leukemia (AML). Because of favorable phase 2 data using mitoxantrone and etoposide, we conducted a phase 3 study (SWOG-9333) in which patients over 55 years of age with previously untreated AML were randomized to receive mitoxantrone (10 mg/m(2) per day x 5) and etoposide (100 mg/m(2) per day x 5) [ME], or cytarabine (200 mg/m(2) per day x 7) and daunorubicin (45 mg/m(2) per day x 3) [AD] as induction therapy. The randomization was stratified by age, onset of leukemia, and multidrug resistance phenotype. Over a 4-year period, 328 eligible patients from 66 institutions were enrolled. The complete remission rate was 34% (95% confidence interval [CI] 26%-41%) for patients in the ME and 43% (CI 35%-51%) for patients in the AD treatment arm (one-tailed P value.96). The rates of resistant disease were 43% (CI 35%-51%) and 34% (CI 27%-42%), respectively, for the 2 treatment arms (one-tailed P value.95). The estimated overall survival at 2 years was 11% (CI 6%-15%) and 19% (CI 12%-25%) for patients randomized to ME and to AD induction therapy, respectively (one-tailed P value.99). After accounting for the independent prognostic factors associated with survival (karyotype, performance status, age, white blood cell count), exploratory analysis suggested there was a worse survival for patients who received ME compared with AD induction therapy (2-tailed P value.0066). We conclude that the results of our study do not demonstrate any benefit to the use of ME induction chemotherapy instead of AD in older patients with AML.

Acute Disease↗

PubMed2002

Comparison of chronic graft-versus-host disease after transplantation of peripheral blood stem cells versus bone marrow in allogeneic recipients: long-term follow-up of a randomized trial.

In a previous multicenter phase III trial comparing peripheral blood stem cell transplantation (PBSCT) to bone marrow transplantation (BMT) from HLA-matched related donors, we found no statistically significant difference in the cumulative incidence of clinical extensive chronic graft-versus-host disease (GVHD) in the 2 groups. We have analyzed the results in more detail to determine whether the clinical characteristics of chronic GVHD after PBSCT might be distinct from those that occur after BMT. Clinical extensive chronic GVHD developed in 39 of 63 recipients of PBSCs and in 32 of 63 BM recipients who were alive and free of malignancy at day 100 after the transplantation. No significant differences were found in the time and type of onset of clinical extensive chronic GVHD or in the frequency of complications associated with severe morbidity. Involvement of skin and female genital tract was more frequent in PBSC recipients than in BM recipients. The cumulative incidence of chronic GVHD at 3 years was similar in the 2 groups, but the number of successive treatments needed to control chronic GVHD was higher after PBSCT than after BMT (P =.03), and the duration of glucocorticoid treatment was longer after PBSCT compared to BMT (P =.03). These results suggest that chronic GVHD after PBSCT may be more protracted and less responsive to current treatment than chronic GVHD after BMT. Assessment of the overall benefits of PBSCT compared to BMT will require continued long-term follow up of morbidity associated with chronic GVHD.

Adolescent↗