Thiotepa, busulfan, and cyclophosphamide as a preparative regimen for allogeneic transplantation for advanced myelodysplastic syndrome and acute myelogenous leukemia.

Sixty-two adults underwent marrow or blood stem cell transplantation from an HLA-matched related donor using high-dose thiotepa, busulfan, and cyclophosphamide (TBC) as the preparative regimen for treatment of advanced myelodysplastic syndrome (MDS) (refractory anemia with excess blasts with or without transformation) or acute myelogenous leukemia (AML) past first remission. All evaluable patients engrafted and had complete donor chimerism. A grade 3-4 regimen-related toxicity occurred in eight (13%) patients, and a diagnosis of MDS was the only independent risk factor for grade 3-4 regimen-related toxicity (hazard ratio 9.25, P = 0.01). Day-100 treatment-related mortality (TRM) was 19%. Poor-prognosis cytogenetics increased the risk of day-100 TRM (hazard ratio 11.4, P = 0.003), and use of tacrolimus for graft-versus-host disease prophylaxis reduced the risk of day-100 TRM (hazard ratio 0.13, P = 0.027). For all patients, the three-year relapse rate was 43% (95% CI, 28%-58%). Refractoriness to conventional induction chemotherapy prior to transplantation was an independent risk factor for relapse (hazard ratio 10.8, P = 0.02). Three-year survival was 26% (95% CI, 14%-37%); survival rates were 29% for those transplanted for AML in second remission, 31% transplanted for AML in relapse, and 17% with MDS, and there were no independent risk factors for survival. TBC is an active preparative regimen for advanced AML. Patients with advanced MDS appeared to have a higher risk of toxicity and early mortality, and alternative preparative regimens should be considered for these patients.     

Cytoreductive treatment with clofarabine/ara-C combined with reduced-intensity conditioning and allogeneic stem cell transplantation in patients with high-risk, relapsed, or refractory acute myeloid leukemia and advanced myelodysplastic syndrome

The combination of cytoreductive chemotherapy with reduced-intensity conditioning (RIC) is a highly effective antileukemic therapy. Purpose of this retrospective analysis was to evaluate the antileukemic efficacy and toxicity of clofarabine-based chemotherapy followed by RIC and allogeneic stem cell transplantation (SCT) for high-risk, relapsed, or refractory acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). From May 2007 until October 2009, a total of 27 patients underwent allogeneic SCT after treatment with clofarabine and ara-C for 5d and RIC (4Gy TBI/cyclophosphamide/ATG). Prophylaxis of graft-versus-host disease (GvHD) consisted of cyclosporine and mycophenolate mofetil. Unmanipulated G-CSF mobilized PBSC (n=26) or bone marrow cells (n=1) were transplanted from unrelated (n=21) or matched related (n=6) donors. Non-hematological toxicities of this regimen mainly affected liver and skin and were all reversible. Seven patients relapsed within a median time of 5.7 months. The overall survival (OS) and relapse-free survival rates were 56% and 52% at 2 yr, respectively. In this cohort of patients, cytoreduction with clofarabine/ara-C (ClAraC) followed by RIC allogeneic SCT was well tolerated and showed good antileukemic efficacy even in patients with high-risk AML or MDS, with engraftment and GvHD-incidence comparable to other RIC regimens.     

Treatment of refractory undifferentiated acute myelogenous leukemia with all-trans-retinoic acid

A patient is described with undifferentiated acute myeloblastic leukemia refractory to two courses of daunorubicin and cytosine arabinoside. Because some the myeloblasts developed morphologic features of promyelocytes, the patient was treated with all-trans-retinoic acid (ATRA) in an attempt to promote maturation. Cytogenetic studies and sensitive molecular analysis did not reveal any abnormality classically associated with acute promyelocytic leukemia. Serial bone marrow biopsies demonstrated myeloid maturation, and the patient uneventfully went into a sustained complete remission. A review of the literature confirms this to be an apparently hitherto undescribed response to ATRA that may have therapeutic implications in similar patients. © 1994 Wiley-Liss, Inc.     

Clinical effect of increasing doses of lenalidomide in high-risk myelodysplastic syndrome and acute myeloid leukemia with chromosome 5 abnormalities

Background

Patients with chromosome 5 abnormalities and high-risk myelodysplastic syndromes or acute myeloid leukemia have a poor outcome. We hypothesized that increasing doses of lenalidomide may benefit this group of patients by inhibiting the tumor clone, as assessed by fluorescence in situ hybridization for del(5q31).

Design and Methods

Twenty-eight patients at diagnosis or with relapsed disease and not eligible for standard therapy (16 with acute myeloid leukemia, 12 with intermediate-risk 2 or high-risk myelodysplastic syndrome) were enrolled in this prospective phase II multicenter trial and treated with lenalidomide up to 30 mg daily for 16 weeks. Three patients had isolated del(5q), six had del(5q) plus one additional aberration, 14 had del(5q) and a complex karyotype, four had monosomy 5, and one had del(5q) identified by fluorescence in situ hybridization only.

Results

Major and minor cytogenetic responses, assessed by fluorescence in situ hybridization, were achieved in 5/26 (19%) and 2/26 (8%) patients, respectively, who received one or more dose of lenalidomide, while two patients achieved only a bone marrow response. Nine of all 26 patients (35%) and nine of the ten who completed the 16 weeks of trial responded to treatment. Using the International Working Group criteria for acute myeloid leukemia and myelodysplastic syndrome the overall response rate in treated patients with acute myeloid leukemia was 20% (3/15), while that for patients with myelodysplastic syndrome was 36% (4/11). Seven patients stopped therapy due to progressive disease and nine because of complications, most of which were disease-related. Response rates were similar in patients with isolated del(5q) and in those with additional aberrations. Interestingly, patients with TP53 mutations responded less well than those without mutations (2/13 versus 5/9, respectively; P=0.047). No responses were observed among 11 cases with deleterious TP53 mutations.

Conclusions

Our data support a role for higher doses of lenalidomide in poor prognosis patients with myelodysplastic syndrome and acute myeloid leukemia with deletion 5q. (Clinicaltrials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT00761449","term_id":"NCT00761449"}}NCT00761449).     

难治性急性髓性白血病治疗进展

难治性急性髓性白血病的治疗,仍是当今临床血液学一个难以突破的棘手问题,国内外多种治疗效果均不满意.本文就新型化疗药的应用、传统药物的新用、靶向治疗、造血干细胞移植等方面内容作一综述.     

MA方案与ID-Ara-C方案治疗难治性及复发性急性髓细胞性白血病疗效观察

目的 探讨难治,复发性白血病的治疗方法。方法 用ＭＡ方案和ＩＤ－Ａｒａ－Ｃ方案治疗３４例成人难治性及复发性急性髓细胞性白血病（ＡＭＬ）。结果 完全缓解（ＣＲ）率为３２．４％,有效率４１．２％;其中难治组ＣＲ率为２１．４％,复发组ＣＲ率为４０％（Ｐ〉０．５０）;ＭＡ方案组ＣＲ率为３７．５％;ＩＤ－Ａｒａ－Ｃ方案组ＣＲ率为２０％（Ｐ〉０．０５）,随访观察,取得ＣＲ的１１例病人,中位ＣＲ期为１２月（３～     

Idarubicin in combination with intermediate-dose cytarabine in the treatment of refractory or relapsed acute leukemias

13 patients with refractory or relapsed acute lymphoblastic leukemia (ALL) and 7 patients with acute myeloid leukemia (AML) were treated with a regimen that included idarubicin 12 mg/m2 intravenously daily for 3 d plus cytarabine 2 g/m2 by infusion over 3 hours daily for 3 d. There were 10 remissions (ALL:7; AML:3) in the 15 relapsed patients and 4 (ALL:3) in the 5 patients with primary refractory disease. Severe myelosuppression was observed in all patients. Toxicity of this regimen caused nausea and vomiting, stomatitis, infections and/or liver enzymes increase. Cardiac toxicity was not observed. 2 patients died in aplasia of Gram-negative septicemia and brain hemorrhage. In conclusion, the combination of idarubicin and intermediate-dose cytarabine (IDARA-C) seems to be highly effective and sufficiently well-tolerated for the treatment of refractory and relapsed acute leukemias.     

Frequent genomic abnormalities in acute myeloid leukemia/myelodysplastic syndrome with normal karyotype

Background

Acute myeloid leukemia is a clonal hematopoietic malignant disease; about 45–50% of cases do not have detectable chromosomal abnormalities. Here, we identified hidden genomic alterations and novel disease-related regions in normal karyotype acute myeloid leukemia/myelodysplastic syndrome samples.

Design and Methods

Thirty-eight normal karyotype acute myeloid leukemia/myelodysplastic syndrome samples were analyzed with high-density single-nucleotide polymorphism microarray using a new algorithm: allele-specific copy-number analysis using anonymous references (AsCNAR). Expression of mRNA in these samples was determined by mRNA microarray analysis.

Results

Eighteen samples (49%) showed either one or more genomic abnormalities including duplication, deletion and copy-number neutral loss of heterozygosity. Importantly, 12 patients (32%) had copy-number neutral loss of heterozygosity, causing duplication of either mutant FLT3 (2 cases), JAK2 (1 case) or AML1/RUNX1 (1 case); and each had loss of the normal allele. Nine patients (24%) had small copy-number changes (< 10 Mb) including deletions of NF1, ETV6/TEL, CDKN2A and CDKN2B. Interestingly, mRNA microarray analysis showed a relationship between chromosomal changes and mRNA expression levels: loss or gain of chromosomes led, respectively, to either a decrease or increase of mRNA expression of genes in the region.

Conclusions

This study suggests that at least one half of cases of normal karyotype acute myeloid leukemia/myelodysplastic syndrome have readily identifiable genomic abnormalities, as found by our analysis; the high frequency of copy-number neutral loss of heterozygosity is especially notable.     

Chronic myelogenous leukemia and Sweet syndrome

We report a 64-year-old woman with chronic myelogenous leukemia of 3 years duration who developed Sweet syndrome. Improvement in her blood counts after hydroxyurea was not associated with a decrease in size of the skin lesions. However, the cutaneous lesions of Sweet syndrome quickly resolved with systemic prednisone. Sweet syndrome has only been documented in the literature for five other chronic myelogenous leukemia patients. The characteristics, treatment, and differential diagnosis of this disorder in chronic myelogenous leukemia patients are reviewed.     

Possible association between Budd-Chiari Syndrome and gemtuzumab ozogamicin treatment in a patient with refractory acute myelogenous leukemia

Gemtuzumab ozogamicin (GO; CMA-676; Mylotarg) is a chemotherapeutic agent approved for the treatment of CD33-positive acute myelogenous leukemia in patients of age 60 years or older after first relapse. Hepatic veno-occlusive disease has been reported to develop as a late complication of gemtuzumab ozogamicin treatment. A patient who developed Budd-Chiari Syndrome with hepatic vein thrombosis following treatment with GO is presented. This complication has not been previously reported, and it deserves to be considered as a possible adverse effect of gemtuzumab ozogamicin.     

Relationship between patients' age, bone marrow karyotype, and outcome of induction therapy in acute myelogenous leukemia

Bone marrow karyotypes were performed in 88 cases of adult acute myelogenous leukemia (AML) at diagnosis and classified NN (normal), AA (abnormal), and AN (mixture of normal and abnormal metaphases). A clear relationship was found between karyotype and complete remission (CR) rate: 58% CR in (NN + AN) cases; 14% CR in AA cases (P less than .009). This relationship was even stronger when only patients under 60 years of age were studied. Considering failures of induction treatment, no relationship was found between the NN/AN/AA classification and a drug resistance. In patients over 60, the worse prognosis could be explained by an inferior ability to tolerate intensive treatment.     

Hypocholesterolemia in acute myelogenous leukemia

Plasma-cholesterol concentrations were determined in 85 acute myelogenous leukemia patients. Measurements were repeated in 28 cases during remission. Mean plasma-cholesterol concentration (+/- SD) at diagnosis was 3.95 mmol/l (+/- 1.29). 47 patients (55.3%) had hypocholesterolemia (less than 3.87 mmol/l). Among the main clinical, hematologic and biochemical parameters, only high leukocyte counts were correlated with hypocholesterolemia. As far the FAB subtypes are concerned, the lowest cholesterol levels were observed in leukemias with monocytic component. However, although the same FAB subtypes showed significantly higher leucocytes counts than the other subtypes, both parameters were independently related to low cholesterol levels. Remission was associated with a significant increase in cholesterol levels in those patients with low cholesterol concentrations or high leukocyte counts at diagnosis. These results support the idea that initial hypocholesterolemia in acute myelogenous leukemia is related to the tumoral mass present at diagnosis.     

Conservative treatment for patients over 80 years with acute myelogenous leukemia

In order to evaluate the best treatment of very elderly patients with AML, we have retrospectively analyzed 60 cases of patients aged more than 80 years, with a diagnosis of AML and observed from January 1988 to December 1998. Six of these patients were subsequently referred to other centers; of the remaining 54 patients, 20 (37%) received only supportive care, whereas 34 (63%) required palliative chemotherapy to control leukocytosis, after a median time from diagnosis of 9 days (range 0-253). Median overall survival was 13 weeks (range 1-105): 21 (39%) and 6 (11%) patients survived more than 6 and 12 months, respectively. Twenty-eight patients (51.8%) died from progressive disease, 19 (35.1%) died from AML-related or unrelated causes in the phase of stable disease, while in 7 patients the cause of death was unknown. In univariate analysis, PS > 2 and WBC > 50 x 10(9)/L had an adverse prognostic significance on survival. Our results, as compared with those reported in the literature for patients over 80 years treated with intensive chemotherapy, support the idea that intensive chemotherapy is usually not indicated in very elderly patients with AML, and that conservative treatment and the primary strategy of "watch-and-wait" presently seems to be the best choice.     

Low-dose arabinosyl cytosine in acute leukemia after a myelodysplastic syndrome and in elderly leukemia

Low-dose arabinosyl cytosine (ARA-C) was tested in 15 patients with acute leukemia after a myelodysplastic syndrome (MDS) and in six elderly patients with acute nonlymphoid leukemia (ANLL). The drug was given subcutaneously at 10 mg/m2, every 12 hr for 2 weeks, every 28 days. The overall response rate was 19% (one complete remission, three partial responses), and the median duration of response was 4 months. No particular features at diagnosis were predictive of response. Pancytopenia and marrow hypoplasia occurred after 44 (78%) of 56 courses of therapy and were more severe in nonresponders. Four patients died during the aplasia following ARA-C therapy. Subcutaneous low-dose ARA-C was of limited benefit and bore a noticeable hematologic toxicity.     

Transformation of chronic myelomonocytic leukemia to acute lymphoblastic leukemia: Case report and review of the literature of lymphoblastic transformation of myelodysplastic syndrome

If chronic myelomonocytic leukemia (CMML) transforms into an acute leukemic phase, the blast crisis is invariably myeloid. Occasionally, the other subtypes of myelodysplastic syndrome (MDS) (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation) have been noted to transform into acute lymphoblastic leukemia (ALL). We now report a case of CMML that transformed into ALL and we review the literature of 13 other cases of MDS with ALL transformation. Such cases provide suggestive clinical evidence that MDS can involve a pluripotent stem cell. © 1955 Wiley-Liss, Inc.     

A high BMI is a risk factor in younger patients with de novo acute myelogenous leukemia

Overweight and obese patients have an increased risk to develop several malignancies and, additionally, body mass index (BMI) impacts on outcome in several solid tumors. However, little is known for AML. We analyzed a cohort of 3526 patients with AML treated in three prospective multicenter trials within the German Study Alliance Leukemia. In multivariate analyses, we identified BMI as an independent risk factor for both DFS (HR 1.014, P = 0.0217) and OS (HR 1.015, P < 0.0036). Interestingly, overweight and obesity seemed to be a risk factor predominantly in patients with de novo AML younger than 65 yr with intermediate risk and adverse cytogenetics. Overweight with a BMI ≥25 kg/m² best discriminated the worse outcome and led to an absolute reduction in long‐term survival of 5–7% in the group of all younger patients (3‐yr OS 39.9% vs. 47.3%; 10‐yr OS 28.7% vs. 33.8%, P = 0.0002). Additionally, response to induction therapy was significantly reduced in these patients (76.9% vs. 82.8%, P < 0.0001). Thus, in younger patients with de novo AML, overweight and obesity are risk factors for impaired response to induction therapy, DFS and OS. This effect is, in part but not fully, explained by dose reduction such as dose‐capping at a body surface area of 2 m².     

Intensive chemotherapy with idarubicin, cytarabine, etoposide, and G-CSF priming in patients with advanced myelodysplastic syndrome and high-risk acute myeloid leukemia

In an attempt to improve the complete remission (CR) rates and to prolong the remission duration especially in elderly patients >50 years of age, we have used a combination chemotherapy of idarubicin (10 mg/m² IV×3 days), cytarabine (AraC, 100 mg/m² CIVI×7d), and etoposide (100 mg/m²×5 days) in combination with granulocyte colony-stimulating factor (G-CSF) priming [5 mg/kg SQ day 1 until absolute neutrophil count (ANC) recovery] for remission induction. Responding patients received two consolidation courses of idarubicin, AraC, and etoposide, followed by a late consolidation course of intermediate-dose AraC (600 mg/m² IV every 12 h×5 days) and amsacrine (60 mg/m² IV×5 days). A total of 112 patients (57 male/55 female) with a median age of 58 years (range: 22–75) have been entered and are evaluable for response: 19 refractory anemia with excess of blast cells in transformation (RAEB-T), 84 acute myeloid leukemia (AML) evolving from myelodysplastic syndrome (MDS), and 9 secondary AML after chemotherapy/radiotherapy. The overall CR rate was 62%, partial remission (PR) rate 10%, treatment failure 16%, and early death rate 12%. The CR rate was higher in patients 60 years (68 vs 55%), mainly due to a lower early death rate (5 vs 21%, p<0.001). After a median follow-up of 58 months, the median overall survival is 14.5% and median duration of relapse-free survival 8 months. After 60 months, the probability of CR patients to still be in CR and alive is 16% (20% in patients 60 years and 13% in patients >60 years), while the probability of overall survival is 12% (15% in patients 60 years and 9% in patients >60 years). Compared to our previous trial (AML-MDS Study 01-92) which was done with identical chemotherapy but no G-CSF priming in 110 patients with RAEB-T, AML after MDS, or secondary AML (identical median age, age range, and distribution of subtypes), the CR rate in all patients, as well as CR rate, overall survival, and relapse-free survival in patients >60 years have significantly been improved. Thus, intensive chemotherapy with G-CSF priming is both well tolerated and highly effective for remission induction in these high-risk patients.     

A phase I study of lenalidomide plus chemotherapy with idarubicin and cytarabine in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome

Patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) have poor outcomes and hematopoietic cell transplantation (HCT) is the only curative treatment. New targeted therapies improved survival in select patients with specific mutations, however management of patients without these molecular alterations is an unmet need. We conducted a phase one study of lenalidomide in combination with cytarabine/idarubicin salvage chemotherapy in patients with R/R AML and high-risk myelodysplastic syndromes. A total of 33 patients were enrolled in the study (30 AML, 3 MDS), and treated at three dose levels with 3 + 3 design. Dose-limiting toxicity (DLT) was seen in eight patients, including four hematologic DLTs. The most commonly observed non-hematologic serious adverse events were febrile neutropenia, rash, sepsis and renal injury. Dose level −1, consisting of 25 mg/d lenalidomide D1-21, 1 g/m² cytarabine D5-8, and 8 mg/m² idarubicin D5-7 was determined to be the maximum tolerated dose. Note, 15/33 (45%) of patients were able to receive pre-planned 21 days of lenalidomide. Overall, 18 patients achieved complete remission (CR) (n = 14) or CR with incomplete count recovery (CRi) (n = 4) with total CR/CRi rate of 56%. The 1-year and 2-year overall survival (OS) were 24% and 10%, respectively. Among responders, 10/18 underwent allogeneic HCT and had a 1-year OS of 40%. There was no molecular pattern associated with response. These data demonstrate that the combination had clinical activity in R/R AML. This regimen should be further investigated for patients who relapsed after HCT, and as a bridge therapy to HCT. ( ClinicalTrials.gov identifier: NCT01132586).     

Terminal acute myelogenous leukemia in a patient with congenital agranulocytosis

Congenital agranulocytosis terminating in acute myelogenous leukemia has been previously reported in only two cases of adolescent males. We describe the clinical and laboratory features of a 13-year-old male with congenital agranulocytosis, treated with G-CSF with initial good neutrophil response, who subsequently developed acute myeloid leukemia. This rare complication may define a preleukemic subset of patients for whom G-CSF therapy is ineffective. The diagnostic challenges of this case are presented.     

Acute myelogenous leukemia in an adult with thrombocytopenia with absent radii syndrome

Acute myelogenous leukemia with t(8;21)(q22;q22) developed in a 42-yr-old woman having thrombocytopenia with absent radii syndrome (TARS). Standard induction and postremission therapies were safely administered. With each successive chemotherapy, the onset of platelet recovery was not delayed, but peak platelet counts were persistently suppressed. Nine months after achieving complete hematologic and cytogenetic remission, she remains severely thrombocytopenic (platelet count 6-12 x 109/L). She is, however, asymptomatic and transfusion independent. Of interest is the transient normalization of platelet count (rebound relative thrombocytosis). Our report and review of the literature suggests that TARS, contrary to previous belief, may be associated with increased risk of acute leukemia.