Casticin Promotes Immune Responses, Enhances Macrophage and NK Cell Activities, and Increases Survival Rates of Leukemia BALB/c Mice.

Casticin, derived from Fructus Viticis, has anticancer properties in many human cancer cells, however, there is no report to show that casticin promotes immune responses and affects the survival rate of leukemia mice in vivo. The aim of this study is to evaluate the effects of casticin on immune responses and the survival rate of WEHI-3 cells generated in leukemia mice in vivo. Animals were divided into six groups: normal control mice, leukemia control mice, mice treated with ATRA (all-trans retinoic acid), and casticin (0.1, 0.2, and 0.4 mg/kg) treated mice. All animals were treated for 14 days and then measured for body weights, total survival rate, cell markers, the weights of liver and spleen, phagocytosis of spleen cells, NK cell activities and cell proliferation. Results show that casticin did not affect animal appearances, however, it increased body weights and decreased the weights of liver at 0.2 mg/kg and 0.4 mg/kg treatment. Casticin also decreased spleen weight at 0.2 mg/kg and 0.4 mg/kg treatment, increased CD3 at 0.1, 0.2 and 0.4 mg/kg doses and increased CD19 at 0.2 mg/kg treatment but decreased CD11b and Mac-3 at 0.1, 0.2 and 0.4 mg/kg treatment. Casticin (0.1, 0.2 and 0.4 mg/kg) increased macrophage phagocytosis from PBMC (peripheral blood mononuclear cell) and peritoneal cavity. Furthermore, casticin increased NK cells' cytotoxic activity and promoted T cell proliferation at 0.1-0.4 mg/kg treatment with or without concanavalin A (Con A) stimulation, but only increased B cell proliferation at 0.1 mg/kg treatment. Based on these observations, casticin could be used as promoted immune responses in leukemia mice in vivo.

Multilineage dysplasia is associated with a poorer prognosis in patients with de novo acute myeloid leukemia with intermediate-risk cytogenetics and wild-type NPM1.

Acute myeloid leukemia (AML) with myelodysplasia-related changes is characterized by the presence of multilineage dysplasia (MLD), frequently related to high-risk cytogenetics and poor outcome. However, the presence of MLD does not modify the favorable prognostic impact of NPM1 mutation. The prognosis of patients with AML presenting marked dysplasia lacking high-risk cytogenetics and NPM1 mutation is uncertain. We evaluated the prognostic impact of MLD in 177 patients with intermediate-risk cytogenetics AML (IR-AML) and wild-type NPM1. Patients were categorized as MLD-WHO (WHO myelodysplasia criteria; n = 43, 24 %), MLD-NRW (significant MLD non-reaching WHO criteria; n = 16, 9 %), absent MLD (n = 80, 45 %), or non-evaluable MLD (n = 38, 22 %). No differences concerning the main characteristics were observed between patients with or without MLD. Outcome of patients with MLD-WHO and MLD-NRW was similar, and significantly worse than patients lacking MLD. The presence of MLD (66 vs. 80 %, p = 0.03; HR, 95 % CI = 2.3, 1.08-4.08) and higher leukocyte count at diagnosis was the only variable associated with lower probability of complete remission after frontline therapy. Concerning survival, age and leukocytes showed an independent prognostic value, whereas MLD showed a trend to a negative impact (p = 0.087, HR, 95 % CI = 1.426, 0.95-2.142). Moreover, after excluding patients receiving an allogeneic stem cell transplantation in first CR, MLD was associated with a shorter survival (HR, 95 % CI = 1.599, 1.026-2.492; p = 0.038). In conclusion, MLD identifies a subgroup of patients with poorer outcome among patients with IR-AML and wild-type NPM1.

Lack of noncanonical RAS mutations in cytogenetically normal acute myeloid leukemia.

Transforming mutations in RAS genes are commonly found in human malignancies, including myeloid leukemias. To investigate the incidence, spectrum, and distribution of activating K- and N-RAS mutations in cytogenetically normal acute myeloid leukemia (CN-AML) patients, 204 CN-AML patients were screened. Activating K- and N-RAS mutations were detected in 3 of 204 (1.5 %) and 22 of 204 (10.8 %) CN-AML samples, respectively. RAS mutated patients presented with a lower percentage of bone marrow blasts (65 vs 80 %, P = 0.022). RAS mutations tended to occur with nucleophosmin-1 (NPM1) mutations (P = 0.079), and all three samples containing K-RAS mutations had concomitant NPM1 mutations. There was no significant overlap between K-RAS mutations and N-RAS, FLT3, CEBPA, IDH1/2, WT1 or MLL mutations. RAS mutation status did not impact relapse-free or overall survival of CN-AML patients. In contrast to reports of noncanonical RAS mutations in other cancers, including some leukemia subtypes, we only observed K- and N-RAS mutations in codons 12, 13, or 61 in CN-AML samples. Our findings suggest that while K-RAS mutations are infrequent in CN-AML, activating K-RAS mutations may cooperate with mutated NPM1 to induce leukemia.

Acute myeloid leukemia with t(9;11)(p21-22;q23): common properties of dysregulated ras pathway signaling and genomic progression characterize de novo and therapy-related cases.

We compared pathogenetic features of 32 de novo and 29 therapy-related (t) t(9;11)(p21-22;q23)/MLLT3-MLL acute myeloid leukemia (AML) cases to identify progression factors and to assess whether distinction between these manifestations is warranted. MLLT3-MLL rearrangement was commonly the sole karyotypic abnormality at diagnosis, with many secondary chromosomal changes emerging at relapse in both subgroups. Ras point mutations were common in both groups (overall, 18/50 [36%]) and associated with monocytic phenotype and aneuploid progression. Expression patterns of 675 microRNAs profiled in 7 cases were also similar, with let-7 species linked to Ras down-modulation expressed at low levels. Outcome for both groups was poor (relapsed or refractory in 49/61 [80%] cases); however, patients with t-AML were generally older and female, with worse outcome (P = .03), likely secondary to t-AML mostly arising in patients with breast cancer following topoisomerase inhibitor-containing chemotherapy. Ras activation seems to complement the MLLT3-MLL oncogene in transformation with features of de novo and t-AML with MLLT3-MLL being similar.

High-dose daunorubicin in older patients with acute myeloid leukemia.

BACKGROUND: A complete remission is essential for prolonging survival in patients with acute myeloid leukemia (AML). Daunorubicin is a cornerstone of the induction regimen, but the optimal dose is unknown. In older patients, it is usual to give daunorubicin at a dose of 45 to 50 mg per square meter of body-surface area. METHODS: Patients in whom AML or high-risk refractory anemia had been newly diagnosed and who were 60 to 83 years of age (median, 67) were randomly assigned to receive cytarabine, at a dose of 200 mg per square meter by continuous infusion for 7 days, plus daunorubicin for 3 days, either at the conventional dose of 45 mg per square meter (411 patients) or at an escalated dose of 90 mg per square meter (402 patients); this treatment was followed by a second cycle of cytarabine at a dose of 1000 mg per square meter every 12 hours [DOSAGE ERROR CORRECTED] for 6 days. The primary end point was event-free survival. RESULTS: The complete remission rates were 64% in the group that received the escalated dose of daunorubicin and 54% in the group that received the conventional dose (P=0.002); the rates of remission after the first cycle of induction treatment were 52% and 35%, respectively (P<0.001). There was no significant difference between the two groups in the incidence of hematologic toxic effects, 30-day mortality (11% and 12% in the two groups, respectively), or the incidence of moderate, severe, or life-threatening adverse events (P=0.08). Survival end points in the two groups did not differ significantly overall, but patients in the escalated-treatment group who were 60 to 65 years of age, as compared with the patients in the same age group who received the conventional dose, had higher rates of complete remission (73% vs. 51%), event-free survival (29% vs. 14%), and overall survival (38% vs. 23%). CONCLUSIONS: In patients with AML who are older than 60 years of age, escalation of the dose of daunorubicin to twice the conventional dose, with the entire dose administered in the first induction cycle, effects a more rapid response and a higher response rate than does the conventional dose, without additional toxic effects. (Current Controlled Trials number, ISRCTN77039377; and Netherlands National Trial Register number, NTR212.)

Anthracycline dose intensification in acute myeloid leukemia.

BACKGROUND: In young adults with acute myeloid leukemia (AML), intensification of the anthracycline dose during induction therapy has improved the rate of complete remission but not of overall survival. We evaluated the use of cytarabine plus either standard-dose or high-dose daunorubicin as induction therapy, followed by intensive consolidation therapy, in inducing complete remission to improve overall survival. METHODS: In this phase 3 randomized trial, we assigned 657 patients between the ages of 17 and 60 years who had untreated AML to receive three once-daily doses of daunorubicin at either the standard dose (45 mg per square meter of body-surface area) or a high dose (90 mg per square meter), combined with seven daily doses of cytarabine (100 mg per square meter) by continuous intravenous infusion. Patients who had a complete remission were offered either allogeneic hematopoietic stem-cell transplantation or high-dose cytarabine, with or without a single dose of the monoclonal antibody gemtuzumab ozogamicin, followed by autologous stem-cell transplantation. The primary end point was overall survival. RESULTS: In the intention-to-treat analysis, high-dose daunorubicin, as compared with a standard dose of the drug, resulted in a higher rate of complete remission (70.6% vs. 57.3%, P<0.001) and improved overall survival (median, 23.7 vs. 15.7 months; P=0.003). The rates of serious adverse events were similar in the two groups. Median follow-up was 25.2 months. CONCLUSIONS: In young adults with AML, intensifying induction therapy with a high daily dose of daunorubicin improved the rate of complete remission and the duration of overall survival, as compared with the standard dose. (ClinicalTrials.gov number, NCT00049517.)

Different clinical importance of FLT3 internal tandem duplications in AML according to FAB classification: possible existence of distinct leukemogenesis involving monocyte differentiation pathway.

Impact of FLT3 receptor tyrosine kinase activation via internal tandem duplication (ITD) of the juxtamembrane region on outcome of acute myeloid leukemia (AML) is still controversial. Recent researches reveal a role of FLT3 in monocyte differentiation in hematopoiesis. We analyzed the clinical impact of FLT3 alterations in adult AML patients excluding acute promyelocytic leukemia (APL) who received induction chemotherapy according to morphologic classification. Retrospective review of medical records from three centers in Korea between 1997 and 2007 was performed. Polymerase chain reaction was performed on genomic DNA derived from blood samples of patients before induction chemotherapy for FLT3-ITD detection. We assessed overall survival (OS), first disease-free survival (1-DFS), and response to induction chemotherapy. One hundred eighty-four patients (median age 49.1 years, range 16.0-76.5) with AML excluding APL received induction chemotherapy from three centers. FLT3-ITD was detected in 22 patients. One hundred forty-one patients were below age 60. One hundred seventy-nine patients received induction chemotherapy with cytarabine and idarubicin (AId) regimen. One hundred nineteen patients achieved complete remission (CR) after first induction chemotherapy. FLT3-ITD was not related to achievement of CR. 1-DFS was longer in patients without FLT3-ITD (median 1-DFS 16.5 vs. 8.5 months, p = 0.025). 1-DFS was not different according to FLT3-ITD status in nonmonocyte lineage leukemia (p = 0.355), while 1-DFS was shorter in monocyte lineage leukemia for FLT3-ITD positive patients (20.9 vs. 2.4 months, p < 0.001). FLT3-ITD had no impact on OS except for monocyte lineage, where OS was significantly shorter in FLT3-ITD positive group (39.4 vs. 6.0 months, p = 0.026). Moreover FLT3-ITD was stronger prognostic factors in monocyte lineage AML than risk stratification based on cytogenetics. Status of FLT3-ITD should be analyzed differently in AML patients according to morphologic profile. FLT3-ITD is a predictive and prognostic marker only in monocyte lineage patients. This result suggests an existence of distinct subset of monocyte lineage AML with leukemogenesis involving FLT3 activating pathway.

Long-term follow-up of allogeneic hematopoietic stem cell transplantation for de novo acute myelogenous leukemia with a conditioning regimen of total body irradiation and granulocyte colony-stimulating factor-combined high-dose cytarabine.

We retrospectively evaluated the efficacy and safety of total body irradiation (TBI) and granulocyte colony-stimulating factor (G-CSF)-combined high-dose cytarabine as a conditioning regimen for allogeneic hematopoietic stem cell transplantation (HSCT) in patients with de novo acute myelogenous leukemia (AML). The conditioning regimen consisted of 12 Gy of TBI followed by high-dose cytarabine (3 g/m(2)) every 12 hours for 4 days in combination with the continuous administration of G-CSF. Stem cell sources included bone marrow or peripheral blood stem cells (PBSC) from human leukocyte antigen (HLA)-identical siblings (n = 24), or bone marrow from HLA serologically matched unrelated donors (n = 26). Fifty patients (median age, 38 years) were evaluated. At HSCT, 35 patients were in the first or second complete remission (CR1/2), and 15 patients were not in remission (n = 14) or in the third CR (n = 1). Thirty-six of 50 patients are currently alive, with a median follow-up period of 5.6 years (range: 1.1-12.1 years). The 5-year estimated overall survival (OS) and disease-free survival (DFS) rates were 85.5% (95% confidence interval [CI], 73.7%-97.3%) and 82.1% (95% CI, 69.0%-95.2%) in patients with AML in the first or second CR, 46.7% (95% CI, 21.4%-72.0%), and 40.0% (95% CI, 15.3%-64.7%) in patients with AML in other stages. The 2-year cumulative incidence of treatment-related mortality (TRM) of all patients was 10.4% (95% CI, 1.8%-18.6%). The only factors affecting the OS and DFS were disease status at transplant and cytogenetics by multivariate analysis. These results suggest that G-CSF-combined high-dose cytarabine could be a promising component of the conditioning regimen for allogeneic HSCT for AML, providing a high DFS and low TRM.

[Clinical significance of quantitation of WT1 gene expression for minimal residual disease monitoring of acute myelogenous leukemia].

BACKGROUND: Following induction chemotherapy for AML, a sensitive determination of minimal residual disease (MRD) in patients achieving complete remission (CR) should enable the detection of early relapse. This study was designed to verify if quantitative assessment of the Wilms' tumor (WT1) gene by real time polymerase chain reaction (RQ-PCR) can be used as a marker for MRD detection during the monitoring of AML. METHODS: WT1 gene expression was quantified by RQ-PCR in 31 patients with AML at diagnosis (27 patients) and during follow-up (29 patients) relative to ABL control gene. In four patients, the WT1 gene expression was analyzed in comparison to a second PCR marker, PML-RARA fusion transcript. Prognostic significance of WT1 gene expression was analyzed at diagnosis and at the primary CR evaluation. Longitudinal WT1 gene analysis was performed in 17 AML patients. RESULTS: At diagnosis, WT1 gene expression exceeded the control level in all of the patients. Higher levels of WT1 gene expression were not associated with shorter event free survival or overall survival at diagnosis. Higher levels of WT1 gene expression were associated with shorter event free survival after induction chemotherapy. Relapse was observed in eight of 17 patients analysed longitudinally, and an increase of WT1 gene expression preceded morphologic relapse in four patients with the fusion transcript negative. Concomitant monitoring of PML-RARA fusion transcript reveals the lack of a significant correlation withWT1 gene expression. CONCLUSIONS: Quantitation of WT1 gene expression could be used for MRD monitoring of AML and for the early detection of relapse, especially in patients lacking specific molecular markers.

[What to improve in approach to diagnose and treat pediatric myelodysplastic syndromes and juvenile myelomonocytic leukemia in Poland?]. / Jak poprawic diagnostyke i leczenie dzieciecych zespolów mielodysplastycznych i mlodzienczej bialaczki mielomonocytowej w Polsce?

Group of heterogeneous clonal hematopoietic disorders usually associated with other genetic disorders called for myelodysplastic syndromes (MDS) are occurring less common in children. The WHO classification based on French-American-British (FAB) MDS morphology is widely accepted in adults but does substantially differe from the one applicable in children. The differencies have recently been published. In our national retrospective study we analyzed 99 children with MDS and JMML diagnosed between 1989 and 2003 in Poland. Chemotherapy is generally, not useful in childhood MDS. With a few exceptions hematopoieitic stem cell transplantation (HSCT) is the only curative treatment for children with MDS. In this nationalexperience use of a relative or an unrelated donor results are almost comparable to the internationally published ones. Successful management of the disease needs to be run on a basis of cooperative efforts between clinicians and scientists involved in pediatric MDS. This includes need for centralized update and morphologic re-evaluation of all patients in the country as well as appointments on a regular basis for all individuals involved in treatment of MDS for quality control.

Expression of beta-catenin by acute myeloid leukemia cells predicts enhanced clonogenic capacities and poor prognosis.

Activation of the Wnt/beta-catenin pathway has recently been shown to be crucial to the establishment of leukemic stem cells in chronic myeloid leukemia. We sought to determine whether beta-catenin was correlated to clonogenic capacity also in the acute myeloid leukemia (AML) setting. Eighty-two patients were retrospectively evaluated for beta-catenin expression by Western blot. beta-Catenin was expressed (although at various protein levels) in 61% of patients, and was undetectable in the remaining cases. In our cohort, beta-catenin expression was correlated with the clonogenic proliferation of AML-colony forming cells (AML-CFC or CFU-L) in methylcellulose in the presence of 5637-conditioned medium, and more strikingly with self-renewing of leukemic cells, as assessed in vitro by a re-plating assay. In survival analyses, beta-catenin appeared as a new independent prognostic factor predicting poor event-free survival and shortened overall survival (both with P<0.05). Furthermore, variations in beta-catenin protein levels were dependent on post-transcriptional mechanisms involving the Wnt/beta-catenin pathway only in leukemic cells. Indeed, beta-catenin negative leukemic cells were found to increase beta-catenin in response to Wnt3a agonist in contrast to normal counterparts. Altogether, our data pave the way to the evaluation of Wnt pathway inhibition as a new rationale for eradicating the clonogenic pool of AML cells.

Correlation between expression of CD56/NCAM and severe leukostasis in hyperleukocytic acute myelomonocytic leukaemia.

OBJECTIVE: The possible contribution of surface molecules to the development of leukostasis syndrome in hyperleukocytic acute myeloid leukaemia (AML) was assessed by routine immunophenotyping and grading of the probability of clinical leukostasis. METHODS: Fifty-three patients (23 women, 30 men, median age 59 yr) with hyperleukocytic AML [white blood count (WBC) above 50 x 10(9)/L] were graded for the probability of clinical leukostasis according to the severity of neurologic, pulmonary and other symptoms possibly caused by leukostasis using a recently published scoring system. Age, WBC, absolute blast count, haemoglobin, cytogenetic risk group, infection, relative CD56 expression and absolute count of CD56 positive blasts were analyzed in multivariate stepwise backward logistic regression analysis. RESULTS: In patients with acute monocytic leukaemia (AML M4/M5) the absolute count of leukaemic blasts expressing CD56/NCAM was highly associated with the development of symptoms graded as highly probable leukostasis and all three patients succumbing to early death were CD56 positive. Only the absolute count of CD56 positive blasts was a significant predictor of risk of severe leukostasis (P = 0.020). This was not found in AML without monocytic involvement (AML M1, M2, M3v). CONCLUSIONS: The expression of CD56/NCAM, a surface marker used in routine immunophenotyping of AML, may help to predict severe and potentially fatal leukostasis in hyperleukocytic acute myelomonocytic leukaemia. These results emphasize the usefulness of this four-stage clinical grading scale for analysing the factors, which lead to severe leukostasis in hyperleukocytic patients. We extend previous findings that the mechanisms of leukostasis are different depending on the involvement of the monocytic lineage.

Clinical importance of bone marrow monocytic nodules in patients with myelodysplasia: retrospective analysis of 21 cases.

Bone marrow monocytic nodules (MNs) can occur in various myeloid disorders. This retrospective review identified 21 patients with myelodysplasia who had unusual and distinct MNs. Eight patients had chronic myelomonocytic leukemia (CMML); 4 had acute myeloid leukemia (AML); and 9 had myelodysplastic/myeloproliferative diseases. In each case, the cells forming MNs expressed strong CD68. MNs appeared to persist even after aggressive chemotherapy, including conventional chemotherapy for 2 AML patients and high-dose chemotherapy preceding allogeneic bone marrow transplantation for 1 CMML patient. Thirteen of 21 patients (62%) died, and acute leukemic transformation was the main cause of death in 3 of 8 patients with CMML. The median survival of the 20 patients with appropriate follow-up was 9.8 months. Our findings demonstrate that MNs are associated with CMML, AML, myelodysplastic syndromes, and myeloproliferative diseases and suggest that MNs are resistant to intensive chemotherapy and patients with bone marrow MNs have a poor prognosis.

Allogeneic bone marrow transplantation in juvenile myelomonocytic leukemia without total body irradiation.

Allogeneic bone marrow transplantation (BMT) without a total body irradiation (TBI) conditioning regimen was investigated in children with juvenile myelomonocytic leukemia (JMML). Eight consecutive patients with JMML (n = 6) or monosomy 7 (n = 2) underwent BMT at a median age of 20 months. Donor source included fully matched related (n = 3), mismatched related (n = 2), or fully matched unrelated (n = 3). The conditioning regimen included busulfan, cyclophosphamide, and etoposide (VP16) (melphalan was substituted for VP16 in one patient). The first patient in the series underwent TBI. Graft-versus-host disease prophylaxis was with cyclosporin and methotrexate and in vivo T-cell depletion (Campath 1 g) for mismatched and unrelated transplants. Seven and two patients, respectively, received chemotherapy and splenectomy before BMT. At a median follow-up of 48 months after BMT, five patients remained in remission. The overall survival rate was 63% at 5 years. All deaths occurred in patients with refractory disease at the time of BMT. Allogeneic BMT without TBI appears to be effective therapy for JMML and avoids some of the potential late sequelae of TBI in preschool children.

Treatment with granulocyte colony-stimulating factor after allogeneic bone marrow transplantation for acute leukemia increases the risk of graft-versus-host disease and death: a study from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation.

PURPOSE: Granulocyte colony-stimulating factor (G-CSF) is given after bone marrow transplantation (BMT) to shorten the neutropenic phase. Its effects have not been evaluated in a large patient population. PATIENTS AND METHODS: We studied 1,789 patients with acute leukemia receiving BMT and 434 patients receiving peripheral-blood stem cells (PBSCs) from HLA-identical siblings from 1992 to 2002 and reported the findings to the European Group for Blood and Marrow Transplantation. Among the BMT and PBSC patients, 501 (28%) and 175 (40%), respectively, were treated with G-CSF during the first 14 days after the transplantation. The outcome variables were entered into a Cox proportional hazards model. RESULTS: BMT and PBSC patients treated with G-CSF had a faster engraftment of absolute neutrophils greater than 0.5 x 10(9)/L (P <.01), but platelet engraftment ( > 50 x 10(9)/L) was slower (P <.001). In the BMT patients, acute graft-versus-host disease (GVHD) grades II to IV was 50% +/- 5% (+/- 95% CI) in the G-CSF group versus 39% +/- 3% in the controls (relative risk [RR], 1.33; P =.007, in the multivariate analysis). The incidence of chronic GVHD was also increased (RR, 1.29; P =.03). G-CSF was associated with an increase in transplantation-related mortality (TRM; RR, 1.73; P =.00016) and had no effect on relapse but reduced survival (RR, 0.59; P <.0001) and leukemia-free survival rates (LFS; RR, 0.64; P =.0003). No such effects of G-CSF were seen in patients receiving PBSC. CONCLUSION: After BMT, platelet engraftment was delayed, and GVHD and TRM were increased. Survival and LFS were reduced. This suggests that G-CSF should not be given shortly after BMT.

AML with 11q23/MLL abnormalities as defined by the WHO classification: incidence, partner chromosomes, FAB subtype, age distribution, and prognostic impact in an unselected series of 1897 cytogenetically analyzed AML cases.

Acute myeloid leukemia (AML) cases with 11q23 abnormalities involving the MLL gene comprise one category of recurring genetic abnormalities in the WHO classification. In an unselected series of 1897 AML cases, 54 patients with an 11q23/MLL rearrangement were identified, resulting in an incidence of 2.8%. The incidence of AML with MLL rearrangement was significantly higher in therapy-related AML (t-AML) than in de novo AML (9.4% vs 2.6%, P <.0001). The frequency of MLL rearrangements was significantly higher in patients younger than 60 years (5.3% vs 0.8%, P <.0001). While the incidence of MLL rearrangements in AML M4, M5a, and M5b was 4.7%, 33.3%, and 15.9%, respectively, it was found in only 0.9% of all other French-American-British (FAB) subtypes (P <.0001). Compared with AML with intermediate karyotype, AML with 11q23/MLL rearrangement had a worse outcome, which was rather comparable with AML with unfavorable karyotype. Compared with t-AML, the median overall survival (OS) of de novo AML with MLL rearrangement was significantly better (2.5 vs 10 months, P =.0143). No significant differences in median OS were observed between cases with t(9;11) compared with all other MLL rearrangements (10.0 vs 8.9 months, P =.36). In conclusion, the category AML with 11q23/MLL abnormalities accounts for 2.8% of unselected AML, is closely associated with monocytic differentiation, and has a dismal prognosis. (

HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative conditioning for patients with hematologic malignancies.

A hematopoietic cell transplantation (HCT) approach was developed for elderly or ill patients with hematologic malignancies that employed nonmyeloablative conditioning to avoid common regimen-related toxicities and relied on graft-versus-tumor effects for control of malignancy. Eighty-nine patients, median age 53 years, were given fludarabine (90 mg/m2) and 2 Gy total body irradiation. Marrow (n = 18) or granulocyte colony-stimulating factor (G-CSF)-stimulated peripheral blood mononuclear cells (G-PBMCs; n = 71) were transplanted from unrelated donors matched for human leukocyte antigen A (HLA-A), -B, -C antigens and -DRB1 and -DQB1 alleles. Postgrafting immunosuppression included mycophenolate mofetil and cyclosporine. Donor T-cell chimerism was higher for G-PBMCs compared with marrow recipients. Durable engraftment was observed in 85% of G-PBMCs and 56% of marrow recipients. Cumulative probabilities of grade II, III, and IV acute graft-versus-host disease (GVHD) were 42%, 8%, and 2%, respectively. Nonrelapse mortality at day 100 and at 1 year was 11% and 16%, respectively. One-year overall survivals and progression-free survivals were 52% and 38%, respectively. G-PBMC recipients had improved survival (57% vs 33%) and progression-free survival (44% vs 17%) compared with marrow recipients. HLA-matched unrelated donor HCT after nonmyeloablative conditioning is feasible in patients ineligible for conventional HCT. G-PBMCs conferred higher donor T-cell chimerism, greater durable engraftment, and better progression-free and overall survivals compared with marrow.

Prognosis of inv(16)/t(16;16) acute myeloid leukemia (AML): a survey of 110 cases from the French AML Intergroup.

Acute myeloid leukemias (AMLs) carrying inv(16)/t(16;16) chromosomal abnormalities are associated with a good prognosis. However, studies of this AML subtype have been hampered by the few number of patients reported, frequently collectively considered with those with AML carrying the t(8;21) translocation. We performed a retrospective study in 110 patients with inv(16)/t(16;16) AML (median age, 34 years) prospectively enrolled in 6 trials conducted in France between 1987 and 1998, with the aim to investigate prognostic factors for complete remission (CR) achievement and outcome of CR patients in this AML subtype. CR rate was 93%. Bad-prognosis factors for CR achievement were higher white blood cell count (WBC) and lower platelet count (optimal cutpoints at 120 and 30 x 109/L, respectively). At 3 years, estimated overall survival, disease-free survival (DFS), and cumulative incidence of relapse were 58%, 48%, and 42%, respectively. In multivariate analysis, (1) advanced age (optimal cutpoint, 35 years) was the only factor for shorter DFS and (2) advanced age and low platelet count were the 2 factors for shorter survival of CR patients. Outcome of CR patients (1) was not influenced by WBC and cytogenetic findings and (2) was similar among patients allocated to receive allogeneic transplantation, high-dose, or intermediate-dose cytarabine. Interestingly, advanced age was associated with a trend for more frequent additional chromosome abnormalities and predictive of higher cumulative incidence of relapse rather than death in first CR. These results markedly contrast with those reported in patients with t(8;21) AML in whom WBC, and not age, was the main high-risk factor for relapse, DFS, and survival.

[Epidemiological analysis of leukemia survival in Cracow for cases registered in 1980-1990]. / Ewolucja przezycia chorych na bialaczki w Krakowie--przypadków zarejestrowanych w latach 1980-1990.

The aim of the study was epidemiological analysis of survival from all types of leukemia occurring in Cracow in the years 1980-1990. The study was focused on survival times in patients according to a) cytologico-clinical type of leukemia, b) timeframe in which treatment was initiated (between 1980-1985 and 1986-1090). All patients diagnosed of leukemia between the years 1980-1990, living in Cracow and whose cytologico-clinical picture was determined had their survival times and censored survival times established. Survival until 1997 was taken into account. For each cytologico-clinical type of leukemia survival function according to Kaplan-Meier was calculated. The Cox model was implemented to analyze the risk of death depending on the period in which the disease appeared--two time frames were established 1980-1985 and 1986-1990. Other parameters considered were; age, sex and area in which the patient lived (suburb). Practically in all types of leukemia a higher probability of survival was found in patients in whom leukemia was diagnosed (and consequently treated) in the second period i.e., 1986-1990. The highest achievement was observed in acute lymphoblastic leukemia in children, in which the relative 5-year survival probability rose from 35% in the years 1980-1985 to 78% in the years 1986-1990, thus achieving the level of well developed countries. A similar picture was seen in chronic lymphocytic leukemia where the relative 5 year survival probability rose from 57% to 77%, and in chronic granulocytic leukemia where the 5 year survival probabilities were accordingly 23% and 39%. All cited values for the second period of analysis are at the levels noted in the United States and in Europe. The positive changes in the survival times observed in patients with leukemia seen in the second half of the 80-ies (in comparison to the period 1980-1985) has been interpreted as the result of advancements in therapy of the disease in Cracow.