The hyper-CVAD regimen in adult acute lymphocytic leukemia

The regimen of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) has demonstrated significant activity in adult lymphocytic leukemia (ALL) and in other hematologic malignancies, including Burkitt's disease, lymphoblastic lymphoma, mantle cell lymphoma, and multiple myeloma. This article presents the rationale for the development of this regimen, describes the program, summarizes the results of the large clinical trials developed at the University of Texas M. D. Anderson Cancer Center, and discusses strategies to improve the results.     

Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia.

PURPOSE: To evaluate the efficacy and toxicity of Hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone), a dose-intensive regimen, in adult acute lymphocytic leukemia (ALL). PATIENTS AND METHODS: Adults with newly diagnosed ALL referred since 1992 were entered onto the study; treatment was initiated in 204 patients between 1992 and January 1998. No exclusions were made because of older age, poor performance status, organ dysfunction, or active infection. Median age was 39.5 years; 37% were at least 50 years old. Mature B-cell disease (Burkitt type) was present in 9%, T-cell disease in 17%. Leukocytosis of more than 30 x 10(9)/L was found in 26%, Philadelphia chromosome-positive disease in 16% (20% of patients with assessable metaphases), CNS leukemia at the time of diagnosis in 7%, and a mediastinal mass in 7%. Treatment consisted of four cycles of Hyper-CVAD alternating with four cycles of high-dose methotrexate (MTX) and cytarabine therapy, together with intrathecal CNS prophylaxis and supportive care with antibiotic prophylaxis and granulocyte colony-stimulating factor therapy. Maintenance in patients with nonmature B-cell ALL included 2 years of treatment with mercaptopurine, MTX, vincristine, and prednisone (POMP). RESULTS: Overall, 185 patients (91%) achieved complete remission (CR) and 12 (6%) died during induction therapy. Estimated 5-year survival and 5-year CR rates were 39% and 38%, respectively. The incidence of CNS relapse was low (4%). Compared with 222 patients treated with vincristine, doxorubicin, and dexamethasone (VAD) regimens, our patients had a better CR rate (91% v 75%, P <.01) and CR rate after one course (74% v 55%, P <.01) and better survival (P <.01), and a smaller percentage had more than 5% day 14 blasts (34% v 48%, P =.01). Previous prognostic models remained predictive for outcome with Hyper-CVAD therapy. CONCLUSION: Hyper-CVAD therapy is superior to our previous regimens and should be compared with established regimens in adult ALL.     

Outcome of adults with acute lymphocytic leukemia after second salvage therapy

BACKGROUND.

The outcome of adults with acute lymphocytic leukemia (ALL) who undergo second salvage therapy has been characterized poorly. This is important with regard to investigational approaches aimed at helping this subset of patients. The objectives of the current study were to predict outcomes and determine the prognostic factors associated with second salvage therapy in patients with ALL.

METHODS.

In this study, 288 patients were analyzed who received second salvage therapy for ALL at the authors' institution.

RESULTS.

Overall, 53 patients (18%) achieved a complete response (CR). The median remission duration was 7 months and the median survival was 3 months. In multivariate analysis, prognostic factors that were associated independently with achieving CR were duration of first CR and platelet count. Patients with a first CR <36 months and platelet counts <50 × 10⁹/L had an expected CR rate of 7%. In multivariate analysis, prognostic factors that were associated independently with survival were duration of first CR, percentage bone marrow blasts, platelet count, and albumin level. The expected 12‐month survival rates for patients with 0 or 1, 2, 3, or 4 adverse factors were 33%, 14%, 8%, and 0%, respectively. A repeat multivariate analysis using landmark assessment at 6 weeks selected achievement of CR as adding significantly to the survival benefit (P = .0001; hazard ratio, 0.51). Only 22 patients (8%) were able to undergo allogeneic stem cell transplantation as second salvage therapy, and their 1‐year survival rate was 18%.

CONCLUSIONS.

The outcome of adults with ALL undergoing second salvage therapy is poor. Novel effective therapies against ALL are needed in this subset of patients. Cancer 2008. © 2008 American Cancer Society.     

Long-term follow-up results of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult acute lymphocytic leukemia

BACKGROUND: Modern intensive chemotherapy regimens have improved the prognosis for patients with adult acute lymphocytic leukemia (ALL). With these regimens, the complete response rates are now reported to be > 80%, and the long-term survival rates range from 30% to 45%. The current analysis updated the long-term results with the original hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD) program, with a median follow-up time of 63 months. METHODS: Between 1992 and 2000, 288 patients were treated with Hyper-CVAD. The median age of the patients was 40 years, and 59 patients (20%) were > or = age 60 years. The incidence of Philadelphia chromosome (Ph)-positive ALL was 17%, and the incidence of of T-cell ALL was 13%. RESULTS: A complete response (CR) was achieved in 92% of patients. The induction mortality rate was 5% (2% if the patient's age was < 60 years, and 15% if the patient's age was > or = 60 years). With a median follow-up time of 63 months, the 5-year survival rate was 38% and the 5-year CR duration rate was 38%. Multivariate analysis of prognostic factors for CR duration identified the following adverse factors: age > or = 45 years, leukocytosis > or = 50 x 10(9)/L, poor performance status (an Eastern Cooperative Oncology Group score of 3-4), Ph-positive disease, French-American-British L2 morphology, > 1 course to achieve CR, and Day 14 bone marrow blasts > 5%. Patients were divided into low-risk (risk score 0-1; 37%), intermediate risk (risk score 2-3; 36%), and poor-risk groups (risk score > or = 4; 27%) with 5-year CR duration rates of 52%, 37%, and 10%, respectively. CONCLUSIONS: Compared with the previous VAD regimens, Hyper-CVAD was associated with significantly better CR rates, CR duration, and survival. The long-term follow-up results of Hyper-CVAD were favorable. Comparison of Hyper-CVAD with other established adult ALL regimens is warranted.     

GM-CSF treatment in patients with B-chronic lymphocytic leukemia

The effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) on the number of granulocytes in peripheral blood and myeloid cells in the bone marrow were studied in seven patients with chronic lymphocytic leukemia (CLL). The neutrophil count in the peripheral blood rose by a median of 193% (range 142-980%), p = 0.02, and the increase persisted for more than 2 weeks after discontinuation of the treatment. The percentage of myeloid cells in bone marrow increased by 166% (range--57-1800%). In neutropenic CLL patients with recurrent infections GM-CSF treatment may constitute a new treatment modality.     

改良Hyper-CVAD方案治疗27例淋巴母细胞性淋巴瘤疗效分析

淋巴母细胞性淋巴瘤(lymphoblastic lymphoma,LBL)是较为少见的高度侵袭性淋巴瘤,约占非霍奇金淋巴瘤的4%以及儿童和青少年非霍奇金淋巴瘤发病率的35%,是危害青少年生命的主要恶性肿瘤之一。LBL具有恶性程度高、进展速度快、死亡率高、易侵犯骨髓和神经系统等特点。LBL来源于前体的T淋巴细胞或B淋巴细胞,LBL与急性淋巴细胞白血病是同一疾病的不同表现形式,2者在细胞生物学特征(如形态学、免疫表型、细胞和分子遗传学等)以及治疗策略和转归上具有高度的一致性。     

Treatment of adult patients with acute lymphocytic leukemia in relapse

Thirty-eight patients with a diagnosis of relapsed acute lymphocytic leukemia were accrued to a treatment program of reinduction therapy by the Eastern Cooperative Oncology Group (ECOG). A combination of mitoxantrone, etoposide (VP-16), and high-dose cytarabine (ARA-C) were administered over a five day period. Thirty-four patients were eligible for follow-up subsequent to treatment. Twenty-seven patients were in first relapse and seven were in second relapse. Fifteen of the thirty-four patients treated were given two cycles of induction chemotherapy. The complete remission (CR) rate for the entire group treated was 17%. The median duration of the CR was 2.4 months and the estimated median survival for first relapse patients was 4.5 months and 5.0 months for second relapse patient group. There were five deaths attributable to toxicity associated with the chemotherapy. The study emphasizes the difficulty in achieving durable remissions in adult patients with relapsed ALL.     

Malignant histiocytosis occurring in patients with acute lymphocytic leukemia.

Five cases of malignant histiocytosis (MH) in patients being treated for acute lymphocytic leukemia (ALL) have been previously reported. Two additional cases are described here, all known cases are reviewed, and the phenomenon is discussed. The most tenable explanation for this phenomenon appears to be that ALL and MH may have been interrelated in these patients with both diseases originating from a common stem cell.     

CAG方案治疗低增生性急性髓系白血病29例

 目的　观察CAG方案治疗低增生性急性髓系白血病（AML）的临床疗效。方法　对29例低增生性AML患者采用CAG方案,阿柔比星（Acla）14 mg／m2,第1天至第4天,静脉注射;阿糖胞苷（Ara-C）10 mg／m2,第1天至第14天,每12 h皮下注射;粒细胞集落刺激因子（G-CSF）200 μg／m2,第1天至第14天,皮下注射,并于第1次注射Ara-C之前12 h开始使用,最后一次注射Ara-C前12 h停用;当中性粒细胞>10×109／L时,暂时减少或停用G-CSF。结果　29例患者中完全缓解（CR）14例（48.3 %）,部分缓解（PR）7例（24.1 %）,总有效率72.4 %,治疗失败（NR）7例,早期死亡1例。结论　CAG方案治疗低增生性AML安全有效,可有效缩短外周血粒细胞减少的时间,降低化疗相关死亡率。     

Hyper—CVAD／MA方案治疗28例中国人非霍奇金淋巴瘤的有效性及安全性

目的评估Hyper-CVAD／MA强化方案治疗28例中国人T细胞性和侵袭性／高度侵袭性B细胞性非霍奇金淋巴瘤患者的有效性和安全性。方法回顾性分析28例2005年1月至2008年9月用Hyper—CVAD／MA方案治疗的初治或复治的B细胞或T细胞非霍奇金淋巴瘤患者的有效性和安全性。结果在27例可评价疗效的包括T细胞和B细胞淋巴瘤的病例中,有效率是70．4％;在13例可评价疗效的B细胞淋巴瘤中,有效率是84．6％。27例患者均发生Ⅲ度或Ⅳ度的骨髓抑制,有2例治疗相关死亡。结论Hyper—CVAD／MA方案治疗中国人T细胞性和侵袭性／高度侵袭性B细胞性非霍奇金淋巴瘤,有效率高,但毒副作用也显著,剂量需要进一步摸索。     

Aberrant DNA methylation in pediatric patients with acute lymphocytic leukemia

BACKGROUND: Aberrant methylation of promoter-associated cystosine-guanine (CpG) islands is an epigenetic modification of DNA frequently observed in adult patients with acute lymphocytic leukemia (ALL). This epigenetic modification has been associated with gene silencing, malignant transformation, and aging. It is not known whether there are epigenetic differences between pediatric patients and adult patients with ALL. METHODS: To investigate the methylation characteristics of pediatric patients with ALL and to determine whether DNA methylation can explain prognostic or biologic differences between pediatric and adult patients, the authors analyzed the methylation status of 7 promoter-associated CpG islands in 16 pediatric patients with ALL and compared them with the methylation characteristics of a cohort of adult patients with ALL. The genes analyzed included the estrogen receptor gene (ER), multidrug resistance gene 1 (MDR1), p15, C-ABL, CD10, p16, and p73. RESULTS: The mean methylation densities of ER, MDR1, CD10, p15, and C-ABL were 25.4%, 16.4%, 5.23%, 4.24%, and 4%, respectively. P16 was methylated in 11.7% of patients, and p73 was methylated in 17.6% of patients. One patient (6.2%) had methylation of 0 genes, 15 patients (93.7%) had methylation of >/= 1 gene, and 4 patients (25%) had methylation of 3-4 genes. Methylation of all these genes was < 2% (or methylation specific polymerase chain reaction negative) in nonneoplastic tissues. A significant inverse correlation was observed between methylation of CD10 and CD10 expression. No differences were observed between the methylation characteristics of pediatric patients and adult patients. CONCLUSIONS: The results indicate that DNA methylation is common in pediatric patients with ALL and that methylation of the genes studied does not account for prognostic differences between pediatric patients and adult patients with ALL.     

Outcome of acute myeloid leukemia patients with hyperleukocytosis in Brazil

Acute myeloid leukemia (AML) with a high white blood cell (WBC) count at presentation has been associated with an increased early mortality rate, usually secondary to leukostasis. However, the value of the WBC count at which there is a high risk of early death (ED) and the efficiency of supportive treatments remain unclear. In this report, a series of 187 consecutive adult patients with AML in our institution was reviewed. The outcome of 40 patients with WBC above 50 × 10⁹ L⁻¹ (hyperleukocytosis) was compared to 147 patients with a leukocyte count lower than 50 × 10⁹ L⁻¹. The group with hyperleukocytosis showed a significantly shorter OS (P < 0.0001) and a higher rate of ED (P = 0.0008). Even when the data from ED patients were removed from analysis, we still detected a shorter OS in patients with hyperleukocytosis (P = 0.0049), which suggests that high WBC number influences long-term survival, and not only ED. We also observed higher lactic dehydrogenase (LDH) and serum creatinine levels in the group of patients with hyperleukocytosis (P = 0.0003 and 0.0406, respectively). Besides considering all the patients with ED, we could observe higher levels of lactic dehydrogenase, a serum creatinine and nitrogen urea (P = 0.0056, P = 0.0008 and P < 0.0001, respectively). Pulmonary involvement was more frequent in patients with ED (P = 0.0277). In conclusion, hyperleukocytosis confers a poorer prognosis in patients with AML.     

Results of the hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone regimen in elderly patients with acute lymphocytic leukemia

BACKGROUND.

Understanding the causes of failure in older patients with acute lymphocytic leukemia (ALL) may help improve treatment strategies for patients in this particular age group.

METHODS.

The objectives of the current study were to define the causes of death in older patients (aged ≥60 years) with ALL during induction and consolidation‐maintenance with a dose‐intensive regimen of alternating 8 courses of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper‐CVAD) with high doses of methotrexate and cytarabine followed by maintenance with 6‐mercaptopurine, vincristine, methotrexate, and prednisone and to compare their outcomes with the outcomes of older patients who received earlier, less intensive regimens and younger patients who received hyper‐CVAD. One hundred twenty‐two older patients who received hyper‐CVAD were compared with 34 older patients who received less intensive regimens and with 409 younger patients who received hyper‐CVAD.

RESULTS.

The complete response (CR) rates in older patients receiving hyper‐CVAD, older patients receiving other regimens, and younger patients receiving hyper‐CVAD were 84%, 59%, and 92%, respectively (P < .001); and the respective induction mortality rates were 10%, 12%, and 2% (P not significant in older patients). The incidence of disease resistance during induction was 5%, 27%, and 2%, respectively (P < .001). The majority of deaths were related to infections. Among patients who achieved a CR, death in CR was noted in 34%, 15%, and 7% of older patients receiving hyper‐CVAD, older patients receiving other regimens, and younger patients, respectively (P < .001); and the respective rates of recurrence were 40%, 80%, and 48% (P = .004). The estimated 5‐year survival rates were 20%, 9%, and 48%, respectively (P < .001).

CONCLUSIONS.

The results of the current study suggested that intensifying the chemotherapy in older patients with ALL reduced the incidence of leukemia resistance but increased the incidence of death in CR from myelosuppression‐associated infections. The overall benefit:risk ratio was favorable. Identifying novel, low‐intensity agents/regimens for older patients with ALL may improve the results further. Cancer 2008. © 2008 American Cancer Society.     

Differential expression of survivin in bone marrow cells from patients with acute lymphocytic leukemia and chronic lymphocytic leukemia

Survivin, a member of the inhibitor of apoptosis protein (IAP) gene family, has been detected widely in fetal tissue and in a variety of human malignancies. In the current study, we investigated the expression of IAP family proteins in bone marrow samples from acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL) and control cases by quantitative real-time RT-PCR method and an immunohistochemical approach. Overexpression of survivin and cIAP2 mRNA was significant in CLL bone marrow cells (P < 0.05, respectively) compared with control samples. By immunohistochemistry, survivin was detected in a few scattered myeloid cells in all cases of control bone marrow. Concerning the ALL bone marrow, more than half the cases demonstrated positive expression of survivin (8 out of 13), while the majority of CLL cases (20 out of 21) exhibited intense expression of survivin. The differential subcellular localization of survivin was distinct between ALL and CLL cases. ALL cells essentially revealed nuclear localization of survivin as well as cytoplasmic signals in some cases, while CLL cells from the majority of cases predominantly showed cytoplasmic expression. Next, RT-PCR was performed for the expression of survivin and its splicing variant, survivin-2B and survivin-deltaEx3 in ALL and CLL cells, as the distribution of these variants would be regulated by nuclear/cytoplasmic transport system. In both ALL and CLL bone marrow samples, the expression of wild-type survivin was more predominant than that of survivin-2B or survivin-deltaEx3, although the expression of survivin-deltaEx3 was prominent in samples from survivin-expressing ALL cases. Thus, the splicing of survivin mRNA may be differently regulated in ALL and CLL cells, causing distinct manners of nuclear/cytoplasmic transport of survivin protein. In conclusion, our observations indicate a differential regulatory mechanism for the expression of IAP family proteins in ALL and CLL cells, although the functions of IAP families and the mechanisms of nuclear/cytoplasmic transport of survivin should be clarified in future studies.     

Pentostatin, cyclophosphamide, and rituximab regimen in older patients with chronic lymphocytic leukemia

BACKGROUND: The prevalence of chronic lymphocytic leukemia (CLL) increases with age. Although chemoimmunotherapy (CIT) has dramatically improved response rates in patients with CLL, some CIT regimens are not well tolerated by many patients >or=70 years of age. METHODS: Sixty-four previously untreated patients with CLL and serum creatinine <1.5 times the upper limit of normal who met National Cancer Institute (NCI) 96-WG criteria for treatment received pentostatin (2 mg/m(2)), cyclophosphamide (600 mg/m(2)), and rituximab (375 mg/m(2)). The authors measured performance status at study entry and used age, weight, and baseline creatinine to calculate creatinine clearance (CrCl). RESULTS: Eighteen of 64 (28%) patients were ages >or=70 years. Although individuals ages >or=70 years were more likely to have delayed treatment cycles (28% vs 7%; P=.03), there were no significant differences in the number of cycles administered, need for dose reductions, or grade 3-4 hematologic, infectious, or other toxicities. No significant differences in overall response rate, complete response rate, or progression-free survival were observed by age. Twenty-five (39%) patients had a CrCl < 70 mL/min (range, 34-67). Although individuals with CrCl < 70 were more likely to require dose reduction (24% vs 5%; P=.05), there were no significant differences in the number of cycles administered or grade 3-4 hematologic, infectious, or other toxicities. No significant difference in overall response rate, complete response rate, or progression-free survival were observed between patients with CrCl >or= 70 mL/min and those with CrCl < 70 mL/min. CONCLUSIONS: In this clinical trial, the PCR regimen was well tolerated by older patients and individuals with CrCl 相似文献   

HAG方案治疗老年急性髓系白血病临床观察

目的:探讨HAG方案治疗老年急性骨髓系白血病(AML)的疗效及不良反应.方法:选择老年急性骨髓系白血病26例,治疗组14例采用HAG方案诱导治疗.对照组12例采用传统HA治疗.结果:治疗组CR64.2%,有效率75.8%,治疗相关死亡率7.1%;对照组CR58.3%,有效率75%,治疗相关死亡率16.6%.两组间完全缓解率、有效率差异无统计学意义(P＞0.05). 治疗相关死亡率两组间差异有统计学意义(P＜0.05).两组间骨髓恢复时间,所需浓缩红细胞及单采血小板数差异有统计学意义(P＜0.05).结论:HAG方案治疗老年急性骨髓系白血病与传统HA方案对比,不仅完全缓解率及有效率高,而且可降低并发症及治疗相关死亡率,骨髓抑制时间短,输血量少,易为患者接受.     

FLAG方案治疗复发/难治的急性髓系白血病患者的临床研究

目的研究FLAG方案治疗复发和难治的急性髓系白血病患者的疗效。病例与方法采用FLAG治疗的为复发和难治性的18～60岁的AML患者,急性早幼粒细胞白血病除外。同时选择既往采用非FLAG治疗的患者作为历史对照组。FLAG方案,即:氟达拉滨30mg/m~2,d1～d5,Ara-C 2g,d1～d5,粒细胞集落刺激因子(G-CSF)5μg/ kg d0直到白细胞恢复超过>1.5×10~9/L。结果FLAG治疗组患者21例完全缓解(CR),CR率为53.85%;对照组患者8例完全缓解,CR率为24.24%;FLAG治疗组患者CR率显著高于对照组(P<0.05)。治疗组患者中位随访时间为7个月(0～17个月),中位OS为6个月(0～17个月)。21例CR的患者随访PFS,中位PFS为10个月(4～17个月)。结论FLAG方案是复发、难治的急性髓系白血病患者治疗的较好选择。