Repeated high-dose cyclophosphamide,BCNU and VP-16-213 and autologous bone marrow transplantation in adult acute lymphocytic leukemia in first remission

In adult acute lymphocytic leukemia (ALL) cure is rare. The purpose of this study was to try to improve remission duration and survival by administration of two courses of high-dose chemotherapy, each followed by autologous bone marrow rescue, in first remission. Chemotherapy consisted of cyclophosphamide, BCNU and VP-16-213. Rescue bone marrow was fractionated over a discontinuous albumin gradient to minimize contamination with leukemic cells. Fourteen patients entered the study. Median total remission duration was 14 months. Three patients relapsed after one course of treatment. Five patients relapsed after the second course. Four patients died after the second course and two patients remain alive and well in unmaintained remission, with a total remission duration of 42+ and 47+ months. It is concluded that this regimen is toxic but, with careful selection of patients, may lead to long-term unmaintained remissions.     

High dose melphalan, BCNU and etoposide with autologous bone marrow transplantation for Hodgkin's disease

Thirty-eight patients with previously treated Hodgkin's disease were given high dose combination chemotherapy using melphalan and BCNU and autologous bone marrow transplantation. In 25 patients etoposide was added in conventional dosage. During the course of the study the dose of melphalan was increased from 80 to 140 mg m-2 and the dose of BCNU from 300 to 600 mg m-2. The response rate was 76% with 53% complete remission. Forty-five per cent of the patients are free of disease at 4-20 months follow-up. There were eight (26%) treatment-related deaths due to lung damage (seven cases) and irreversible cardiac failure (one case). Fatal lung damage occurred only in patients receiving 600 mg m-2 of BCNU with high dose melphalan. The dose of BCNU given with high dose melphalan should not exceed 500 mg m-2. This treatment is effective against relapsed Hodgkin's disease but must be used cautiously. The best time for its use remains to be determined.     

Total body irradiation, thiotepa, and cyclophosphamide as a conditioning regimen for children with acute lymphoblastic leukemia in first or second remission undergoing bone marrow transplantation with HLA-identical siblings.

PURPOSE: Allogeneic hematopoietic stem-cell transplantation (HSCT) from HLA-identical siblings can be used to treat children with acute lymphoblastic leukemia (ALL). However, a significant proportion of patients with ALL who undergo HSCT relapse. For this reason, we prospectively evaluated a preparative regimen that included total body irradiation (TBI), thiotepa (TT), and cyclophosphamide (CY) in patients with high-risk ALL in first complete remission (CR) and in children with ALL in second CR. PATIENTS AND METHODS: Forty children (median age, 9 years; range, 1 to 18 years) with ALL in first or second CR who underwent allogeneic HSCT from HLA-identical siblings were conditioned with a combination of fractionated TBI, TT (10 mg/kg), and CY (120 mg/kg over 2 days). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine administered intravenously at a dose of 1 to 3 mg/kg/d for the first 21 days and subsequently orally at a dose of 6 mg/kg/d. RESULTS: All assessable patients were engrafted, with a median time of 11 and 24 days for neutrophil and platelet recovery, respectively. The preparative regimen was well tolerated. Only one patient died as a result of regimen-related causes. Eight patients relapsed at a median time of 8 months after transplantation (range, 3 to 9 months), and this determined a cumulative probability of relapse of 23%. Twenty-six of 40 patients (65%) are alive and in complete hematologic remission, with a median observation time of 36 months (range, 14 to 57 months), which results in a disease-free survival (DFS) at 3 years of 65%. The 13 patients who underwent transplantation in first CR had a DFS of 85%, whereas the 27 patients who underwent HSCT in second CR had a DFS of 56%. CONCLUSION: These data suggest that TT is an effective cytotoxic drug that can be safely added to the classical TBI-CY regimen. Because of its cell cycle-independent action, good CNS diffusion, and limited extramedullary toxicity, TT may contribute to increasing the percentage of children with ALL who are successfully cured with allogeneic BMT.     

Autologous bone marrow transplantation following high-dose chemotherapy with cyclophosphamide,BCNU and VP-16 in small cell carcinoma of the lung and a review of current literature

Four patients with limited disease small cell carcinoma of the lung were treated with high-dose cyclophosphamide (120 mg/kg over days 1 and 2), BCNU (400 mg/m² over days 1 and 2) and VP-16 (200 mg days 1–5) used as intensification treatment after conventional chemotherapy. To ameliorate hematopoietic toxicity, autologous bone marrow cells collected and cryopreserved prior to treatment were reinfused on day 8. In three patients clinical response was evaluable. Two achieved a complete remission: one died without evidence of tumor after 3 months; the other had a regional relapse after 6 months. One patient who had progression of disease on conventional chemotherapy was refractory to high-dose treatment. Three patients developed diffuse interstitial pneumonitis 3 weeks after treatment and two died of respiratory failure. High-dose intensification chemotherapy with autologous marrow reinfusion may complement the effects of standard combination chemotherapy in small cell carcinoma of the lung. The current status of this approach is reviewed.     

氟达拉滨代替环磷酰胺的移植前预处理方案对髓系白血病疗效的Meta分析

目的:评价氟达拉滨代替环磷酰胺的移植前预处理方案对髓系白血病的疗效及安全性。方法:计算机检索筛选获取所有移植前预处理方案为白消安+环磷酰胺（BU+CY）或白消安+氟达拉滨（BU+FLU）的临床对照研究,评价纳入研究的质量并进行资料提取后,采用Stata 12.0软件进行Meta分析。结果:共纳入9篇文献,其中2篇随机对照试验,7篇病例对照研究,Meta分析结果显示:BU+FLU预处理方案恶心呕吐反应比BU+CY方案较小（P=0.031）;肝脏毒性、心脏毒性均小于BU+CY组（P=0.009,P=0.004）,且5年OS优于BU+CY组（P=0.000）。结论:BU+FLU的预处理方案或许可以取代传统的BU+CY方案。     

High dose BCNU chemotherapy with autologous bone marrow transplantation and full dose radiotherapy for grade IV astrocytoma

In a series of 22 patients, high dose BCNU (800-1,000mg m-2) with autologous bone marrow transplantation was given as the first post-surgical treatment for grade IV astrocytoma and followed by full dose radiotherapy. When compared to historical experience and matched to control patients in national studies, there appeared to be a small prolongation of survival but no increase in the proportion of long survivors. Acute myelosuppression was mild but toxicity to lung and liver was substantial and limited further dose escalation. Late bone marrow failure was seen in 4 patients. Pharmacokinetic studies were performed and suggested that the late marrow failure was due to persistence of BCNU at the time of marrow return. Despite the suggestion of a prolongation of survival this approach is not routinely recommended and a randomised trial is probably not justified.     

High-dose cytarabine and total body irradiation with or without cyclophosphamide as a preparative regimen for marrow transplantation for acute leukemia

Twenty-nine patients were conditioned for allogeneic marrow transplant with cytarabine (ara-C) (3 g/m2 every 12 hours for 12 doses) and total body irradiation (TBI) (200 cGy daily for six days) with or without cyclophosphamide (CY) (60 mg/kg) to determine toxicity and efficacy. Four patients had chronic myelogenous leukemia (CML) in accelerated phase or blast crisis, and 25 patients had acute leukemia, 24 at stages later than first remission. Three patients (10%) had fatal regimen-related toxicity and another 10% experienced severe toxicity in at least one organ system. The addition of CY to the ara-C and TBI regimen was not associated with an increase in the frequency of severe toxicity. Twenty-five of 29 patients engrafted eight to 33 days posttransplant: three died early before engraftment, and one patient failed to engraft. Ten of 29 patients are alive without disease, and the actuarial probability of disease-free survival for the entire group at 3 years is 33%. Three of ten patients with acute nonlymphocytic leukemia (ANL), six of 15 with acute lymphocytic leukemia (ALL), and one of four with CML are alive and disease free 25 to 42 months (median, 30 months) after transplant. High-dose ara-C (HDara-C) and TBI with or without CY can be administered with approximately the same toxicity as CY plus TBI. Phase III studies appear warranted to determine if these newer regimens provide improved results compared with currently used regimens.     

High-dose cyclophosphamide, BCNU, and etoposide followed by autologous bone marrow rescue as treatment for adult acute leukemia in relapse

High-dose cyclophosphamide, 1,3-bis-(2 chloroethyl)-1-nitrosourea (BCNU), and VP-16-213 followed by autologous bone marrow rescue was administered to 29 adult patients with acute leukemia in relapse who had failed to respond to prior salvage treatment, with the following results: 14 patients (48%) achieved complete remission (CR), two patients died early of infection and hemorrhage during hypoplasia, and 13 patients had relapsed with leukemia after an initial hypo-plastic phase. Median remission duration was 3 1/2 months (range, 1-8 months). Maintenance treatment with cyclophosphamide and VP-16, which was given to six patients, did not prolong remission duration. Subsequent salvage treatment was well tolerated by both responders and patients who failed to reach CR. This regimen, which is active in both acute lymphocytic leukemia and acute myelogenous leukemia, had a mild toxicity.     

Standard conditioning regimen and t-depleted donor bone marrow for transplantation in chronic myeloid leukemia

Between January 1984 to June 1985, 18 Ph¹ positive chronic myeloid leukemia (CML) patients in chronic phase (CP) underwent allogeneic bone marrow transplantation (BMT) from HLA identical and MLC negative siblings. The median age was 32.5 yr and median disease duration of CML at time of BMT was 19.3 months. The pretransplant conditioning regimen consisted of cyclophosphamide (CTX) (120 mg/kg) and 10.20 Gy total body irradiation (TBI) at 6 doses of 1.7 Gy each, administered in 3 daily fractions over 2 days at a dose rate of 15–20 cGy/min. To prevent graft-vs-host disease (GvHD) we used methotrexate (MTX) in one patient and cyclosporin-A (CYA) in the other 17 patients. In addition to CYA, given until day +365, 10 patients received donor marrow depleted of T cells with CAMPATH-1. The residual marrow lymphocytes were always <1%. The rate of engraftment was significantly correlated with the number of nucleated cells infused. Neither GvHD nor graft failure were observed among CAMPATH-1 patients. In this group one cytogenetic and one hematologic relapse occurred. The overall actuarial survival at 24 months is 78%. Of the 10 patients treated with donor marrow depleted of T cells, 9 are alive after a median follow-up of 9 months (range 5–18), with an actuarial survival of 90%.

Of the other 8 patients transplanted with untreated marrow, 5 are alive after a median followup of 19.3 months (range 3.7–24) and the actuarial survival is 63.8%. This pilot study seems to demonstrate that T-cell depletion of donor bone marrow with CAMPATH-1 is effective to prevent GvHD, while the risk of graft failure can be avoided using a “standard” conditioning regimen including a fractionated TBI with a fast dose rate and a prolonged administration of CYA at the maximum tolerable dosage. While the high frequency of relapses suggests the employ of more aggressive anti-leukemic conditioning regimens in CAMPATH-1 treated marrow recipients.     

氟达拉滨替代环磷酰胺的清髓性预处理化疗联合异基因造血干细胞移植治疗急性白血病的对照研究

目的 探讨氟达拉滨替代改良BuCy方案中环磷酰胺的预处理方案在异基因造血干细胞移植中的安全性及有效性.方法 对45例急性白血病患者进行异基因造血干细胞移植,其中23例采用改良BuCy预处理化疗,22例采用BuFlu方案（氟达拉滨每天40 mg/m2,用5d,来替代改良BuCy方案中的环磷酰胺）进行预处理化疗.移植均采用外周血造血干细胞移植.移植后观察比较两组预处理方案相关不良反应、植入、移植物抗宿主病（GVHD）、感染发生和长期随访下的无病生存情况.结果 除改良BuCy组1例患者死于预处理后脑出血,其余患者均获得成功植入.两组患者预处理不良反应发生率差异无统计学意义（P＞0.05）;BuFlu组患者病毒感染较改良BuCy组高（P=0.009）,而Ⅲ～Ⅳ度急性GVHD发生率较低[26.1％（6/23）比4.5％（1/22）,P=0.046].中位随访41个月,改良BuCy组非复发死亡4例（17.4％）,BuFlu组非复发死亡2例（9.1％）（P=0.665）.两组复发率分别为30.3％（7/23）和40.9％（9/22）（P=0.474）;5年总生存率分别为（55.1±l 1.9）％和（61.4±10.8）％（P=0.659）,无事件生存率分别为（44.5±12.1）％和（22.1±12.3）％（P=0.747）.结论 氟达拉滨替代改良BuCy方案中环磷酰胺的预处理化疗耐受性较好,严重GVHD发生率低,总生存率无明显差异.应用时应注意移植中感染及复发的风险.     

自体骨髓混合HLA半相合异基因骨髓移植治疗急性白血病

 目的 观察自体骨髓混合HLA半相合异基因骨髓移植治疗急性白血病的疗效及移植相关并发症。方法 对7例急性白血病患者先实施经液体培养（与IL-2共孵育,1 000 U／ml骨髓血）和微波照射法体外净化的自体骨髓移植,2 ~ 5 d后输注一定量HLA半相合同胞兄妹的异基因骨髓。结果 中性粒细胞和血小板恢复的平均时间为+27 d和+29 d,3例发生Ⅲ~ Ⅳ度急性移植物抗宿主病（aGVHD）并死亡,其中1例并发肝静脉闭塞症。另外4例发生Ⅱ度aGVHD,HLA基因检测和（或）性染色体分析均呈混合嵌合现象并持续半年左右,这4例长期无病存活时间分别117,106,101,85个月,5年无病生存4例。结论 混合骨髓移植具有疗效好、复发率低、患者可获长期生存及相对安全可行等特点,但仍有必要进一步优化同／异基因骨髓细胞的比例及植入时机,并采取一定程度的移植物抗宿主病（GVHD）预防措施。     

The pharmacokinetics and toxicity of two application schedules with high-dose VP-16 in patients receiving an allogeneic bone marrow transplantation

BACKGROUND: Etoposide is one of the few drugs being used in conditioningregimens because of the ease with which its dosage can be escalatedby a factor of 6 compared to the normal dose. The best schedulein high-dose chemotherapy is not known. PATIENTS AND METHODS: We evaluated the pharmacokinetics (PK) of high-dose VP-16 duringtwo different schedules (6- hour and 3x1-hour infusions) andthe toxicity of the two application modes in patients with leukemiawho underwent allogeneic bone marrow transplantation. RESULTS: A significant difference (p=0.008) in the volume of distributionat steady state was observed. The mean V⁵⁵ was 0.21 L/kg inthe 6-hour group and 0.36 in the 3x1-hour group. The total drugexposure time with plasma levels >100 ng/ml is significantlylonger in the ‘split’ group (74 vs. 143 h). OtherPK parameters such as plasma clearance and area under the curvewere not significantly different. Leukocyte recovery to WBClevels >0.2 and >0.5/nl as well as platelet recovery tostable counts >50/nl was significantly (p 0.002, 0.009 and0.04) prolonged in the ‘split’ group (3.7 vs. 12.3,8.3 vs. 14.3 and 25 vs. 35 d). The liver toxicity as indicatedby bilirubin peak levels was significantly (p=0.02) more severein the ‘split’ group (1.7 vs. 5.4 mg/dl). CONCLUSION: The area under the curve as a measure of total drug exposurecannot be correlated to the observed higher toxicity in thepatient group with the ‘split’ application mode.The drug exposure time as well as the three high peak plasmalevels may be more important. high-dose VP-16, pharmacokinetics, toxicity, application sched, allogeneic bone marrow transplantation     

Early myelodysplastic syndrome after allogeneic bone marrow transplantation for acute myeloid leukemia

A 19-year-old male with de novo acute myeloid leukemia (AML) in complete remission received a bone marrow transplant from a HLA-matched donor. Because of major incompatibility for ABO blood type, bone marrow mononuclear cells of the donor were infused after conditioning including total body irradiation (TBI). Engraftment was confirmed on day +23. On day +91, recipient ABO blood genotype was detected in burst forming-unit erythroid (BFU-E) using polymerase chain reaction. Thereafter, myelodysplastic syndrome (MDS) of recipient origin rapidly developed and progressed into a chronic myelomonocytic leukemia-like disorder. An association between MDS and TBI is suggested.     

Host metaphases after chemoradiotherapy and allogeneic bone marrow transplantation for acute nonlymphoblastic leukemia

The post-transplant cytogenetic data were reviewed for 191 recipients of sex-mismatched marrow after conditioning with chemoradiotherapy as treatment for acute nonlymphoblastic leukemia. Host metaphases were detected transiently in unstimulated marrow from 12/184 patients and in PHA-stimulated peripheral blood from 18/140 patients during the first 100 days after transplantation. Of the 14 patients with HM who survived more than 150 days, five have relapsed, and nine are alive and in remission 509-1783 days after detection of HM. There was no significant correlation between transient detection of HM and pretransplant remission status, HLA matching, radiation regimen or graft-vs-host disease. We conclude that transient detection of HM by conventional cytogenetics is not related to any single peritransplant parameter and does not predict relapse.     

Radiation-free preparation for allogeneic bone marrow transplantation in adults with acute lymphoblastic leukemia.

PURPOSE: The study was undertaken to investigate the effectiveness of allogeneic bone marrow transplantation from HLA-identical siblings after preparation with busulfan and cyclophosphamide in adults with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Thirty-nine patients aged 15 to 42 years underwent transplantation at three different centers from November 1984 through November 1990. All patients received 16 mg/kg busulfan and 120 mg/kg cyclophosphamide as preparative therapy. Cyclosporine plus methotrexate or cyclosporine plus corticosteroids with or without methotrexate were given for prevention of graft-versus-host disease (GVHD). RESULTS: Twelve patients died of treatment-related complications, 12 patients relapsed, and 15 patients are leukemia-free survivors. For 27 patients in group 1 (first remission, second remission, first relapse), the estimated leukemia-free survival (LFS) rate is 42.3% (95% confidence interval [CI], 22.9% to 71.7%) at 3 years. For 12 patients with more advanced disease (group 2), the 1-year LFS rate is 13.5% (95% CI, 0% to 37.1%). Chronic GVHD occurred at an estimated incidence of 63.3% and developed significantly more frequently among patients who received corticosteroids for prevention of acute GVHD. Chronic GVHD was associated with a significantly lower incidence of relapse and with improved LFS rates. CONCLUSION: LFS rate in this study is comparable to that obtained with radiation-containing regimens; however, the effectiveness of this preparative regimen in ALL requires further study.     

Reduced intensity conditioning prior to allogeneic stem cell transplantation for patients with acute myeloblastic leukemia as a first-line treatment

BACKGROUND: Thirty-three patients (median age 52; range 26-60) with acute myeloblastic leukemia (AML) were included in a pilot study of allogeneic stem cell transplantation (Allo-SCT) following a reduced-intensity conditioning (RIC). METHODS: Patients achieving first complete remission (CR1) were selected for their high-risk clinical and/or leukemic features. All patients received two courses of consolidation chemotherapy including one high-dose cytarabine course. Among them, 13 patients in addition received a high-dose melphalan course followed by autologous SCT. Then, all patients received an RIC Allo-SCT combining fludarabine, busulfan, and antithymocyte globulin. RESULTS: All patients engrafted had cumulative incidences of Gluksberg System Grade 2 acute and chronic graft-versus-host-disease (GVHD) of 24 (9-39%) and 64 (48-80%), respectively. Three patients died from nonrelapse causes (NRD) (cumulative incidence: 9%, 95% confidence interval (CI): 0-19) and 6 relapsed (cumulative incidence: 18%, 95% CI: 5-31). With a median follow-up of 18 months (range 7-52) after Allo-SCT, 26 patients are alive, of whom 24 remained in CR1 for a 2-year overall survival and leukemia-free survival (LFS) probabilities of 79 (range 61-90%) and 76 (range 59-87%), respectively. In a 'landmark' analysis starting on Day 100, the occurrence of chronic GVHD was associated with a lower relapse rate (0% vs. 44%: P = 0.007) and improved outcome (LFS; 95% vs. 53%, P = 0.007; overall survival, 95% vs. 61%, P = 0.05). CONCLUSIONS: We conclude that the sequential combination of intensive chemotherapy and allogeneic immunotherapy might offer relatively low NRD and leukemia relapse rates even in high-risk patients.     

Allogeneic bone marrow transplantation for patients with high-risk acute lymphoblastic leukemia

Seventy-four consecutive patients with high-risk acute lymphoblastic leukemia (ALL) were given cyclophosphamide (CY; 50 mg/kg on each of 4 days) plus total body irradiation (TBI; 300 rad on each of 4 days) followed by a human leukocyte antigen (HLA)-identical allogeneic bone marrow transplant (BMT). Eighteen patients in first complete remission (CR1), 36 in CR2, 16 in CR3, and four in CR4 were transplanted. Patients in CR1 were transplanted 1 to 8 months (median, 3 months) after attaining CR. All 18 patients in CR1 had one or more poor risk factors: age more than 18 (N = 17), initial leukocyte count greater than or equal to 20,000 (N = 11), Ph 1 chromosome (N = 2), delay in attaining CR more than 6 weeks (N = 8), or extramedullary disease (N = 1). Of those transplanted in CR2, 72% had relapsed on therapy. The 5-year event-free survival (EFS) rates for patients transplanted in CR1, CR2, and CR3 are 42%, 43%, and 25%, respectively, at median follow-up times of 57, 54, and 72 months, respectively. Children aged less than 18 years transplanted in CR2 have a 5-year EFS rate of 54%. All CR4 patients died early after transplant. The actuarial probability of relapse is 20%, 26%, and 48% for those transplanted in CR1, CR2, and CR3, respectively. Although there was substantial transplant-associated mortality, it decreased over the decade of the study (P = .01). This study indicates that BMT offers an attractive alternative to postremission chemotherapy in patients in CR1 with poor prognostic factors and in patients in second remission.     

Evaluation for the development of 11q23 rearrangements in lymphoma patients treated with a high dose VP-16 and cyclophosphamide salvage regimen

Patients with relapsed or refractory lymphoma often require treatment with aggressive chemotherapy. At McGill University, a combination of high dose VP-16 and cyclophosphamide (VP-CY) is commonly used as a salvage regimen. In recent years, cytogenetic abnormalities of the long arm of chromosome 11 at band 23 (11q23) have been linked to the use of VP-16, and may be associated with secondary myelodysplastic syndrome or acute leukemia. Therapy related 11q23 anomalies have not been widely studied in lymphoma patients. We have identified and reviewed the course of 107 patients who have been treated with VP-CY. Thirty-five patients remain alive and 21 consented to participate in our study. Patient bone marrows were studied morphologically, cytogenetically and molecularly, to identify any new changes that may have developed over the course of their treatment, with a special emphasis on the search for 11q23 rearrangements. Mean time between VP-CY treatment and marrow evaluation was 3.6 years. Of the 21 patients, 5 had Hodgkin's disease (HD) and 16 had non Hodgkin's lymphoma (NHL). They received a total of 30 cycles of VP-CY. Response rate was 100%, with 16 complete and 5 partial responses. Eighteen patients later underwent autologous stem cell transplantation. At the time of study, 19 of the patients were disease free and 2 were in relapse. On morphological analysis, 12 marrows appeared normal and 6 showed mild dyserythropoiesis. Standard cytogenetics was done to examine for any new chromosomal translocations or deletions. All cytogenetic studies yielded normal results. Molecular analysis by Southern blot was done on 15 patients in a search for 11q23 rearrangements, including the partial tandem duplication of ALL-1. All molecular studies were normal. We conclude that the use of VP-CY, given in our treatment schedule, does not appear to be associated with an increased risk of developing 11q23 rearrangements.