A phase I-II trial of escalating doses of mitoxantrone with fixed doses of cytarabine plus fludarabine as salvage therapy for patients with acute leukemia and the blastic phase of chronic myelogenous leukemia

BACKGROUND: Cytarabine is an essential drug for inducing remission of acute myelogenous leukemia, and it is also one the most effective drugs used as salvage therapy for patients with all types of relapsed acute leukemia. Nevertheless, there is considerable room for improvement in the treatment of patients with relapsed leukemia in terms of both the reinduction rate and the duration of response. Fludarabine has been shown to augment responses to cytarabine, possibly by increasing the intracellular concentrations of the active metabolite cytarabine triphosphate. Higher-than-standard doses of mitoxantrone have been shown to augment responses to cytarabine, possibly by increasing the DNA strand breaks induced by topoisomerase II; these strand breaks cannot be effectively repaired in the presence of cytarabine triphosphate. This preliminary study was designed to determine whether moderately high doses of mitoxantrone could be added to the combination of fludarabine and cytarabine in an attempt to improve the combination's antileukemic efficacy. METHODS: Fifty-five adults with relapsed or refractory acute leukemia or the blastic phase of chronic myelogenous leukemia (CML) received salvage therapy with the FLAM regimen, which consisted of fludarabine, cytarabine, and increasing doses of mitoxantrone. RESULTS: Even with doses of mitoxantrone escalated to as much as 60 mg/m(2) over 4 days, dose-limiting toxicity was not observed. Overall, the complete response rate was 27.3% (15 of 55 patients, including 4 of 17 with acute myelogenous leukemia [AML], 4 of 12 with acute lymphocytic leukemia [ALL], and 7 of 26 with the blastic phase of CML). The median time to complete response was 42 days. Toxicity other than myelosuppression was manifested primarily as hyperbilirubinemia, which was reversible in all cases. Poor performance status and undifferentiated blastic phase of CML were poor prognostic factors for response to FLAM. CONCLUSIONS: The FLAM regimen is an active salvage regimen and should be formally evaluated in Phase II studies of patients with AML, ALL, and the myeloid and lymphoid blastic phases of CML.     

Short course high dose mitoxantrone with high dose cytarabine is effective therapy for adult lymphoblastic leukemia

Mitoxantrone is effective in the treatment of acute myelogenous leukemia and, in combination with either vincristine-prednisone or cytarabine (HiDAc), it is also effective in acute lymphoblastic leukemia (ALL). As mitoxantrone exhibits a steep dose-response curve against ovarian cancer cells and acute myeloid leukemia cells in vitro, we evaluated the safety and efficacy of high dose mitoxantrone with HiDAc in the treatment of ALL. Patients received mitoxantrone 20-37.5 mg/m2 daily for 2 days or 1 dose of 40-80 mg/m2 and HiDAc 3 g/m2 over 3 h once daily for five doses. All eight of the patients with previously untreated disease and eight of ten patients with ALL in relapse achieved complete remission (CR). The untreated patients included two with Philadelphia positive ALL who also achieved CR (one after one course of mitoxantrone-HiDAc, and one after one course of mitoxantrone-HiDAc followed by one additional dose of vincristine and daily prednisone). Seven of the eight previously untreated patients who achieved CR are still in remission. The one T-cell ALL has relapsed at 2 months after CR. The toxicity was acceptable. The regimen thus induces a remission rate equivalent to that of traditional vincristine-prednisone. The 'quality of remission' may be superior, and this therapy should be explored as a primary induction therapy in patients with ALL.     

Phase II study of troxacitabine, a novel dioxolane nucleoside analog, in patients with refractory leukemia.

PURPOSE: To investigate the activity of a novel dioxolane L-nucleoside analog, troxacitabine (L-(-)-OddC, BCH-4556), in patients with refractory leukemia. PATIENTS AND METHODS: Study participants were patients with refractory or relapsed acute myeloid (AML) or lymphocytic (ALL) leukemia, myelodysplastic syndromes (MDS), or chronic myelogenous leukemia in blastic phase (CML-BP). Troxacitabine was provided as an intravenous infusion for more than 30 minutes daily for 5 days at a dose of 8.0 mg/m(2)/d (40 mg/m(2) per course). Courses were given every 3 to 4 weeks according to antileukemic efficacy. RESULTS: Forty-two patients (AML, 18 patients; MDS, one patient; ALL, six patients; CML-BP, 17 patients) were treated. Median age was 51 years (range, 23 to 80 years); 22 patients were male. Stomatitis was the most significant adverse event, with three patients (7%) and two patients (5%), respectively, experiencing grade 3 or 4 toxicity. Ten patients (24%) had grade 3 hand-foot syndrome, and two patients (5%) had grade 3 skin rash. One patient (2%) had grade 3 fatigue and anorexia. Marrow hypoplasia occurred between days 14 and 28 in 12 (75%) of 16 assessable patients with AML. Two complete remissions and one partial remission (18%) were observed in 16 assessable patients with AML. None of six patients with ALL responded. Six (37%) of 16 assessable patients with CML-BP experienced a return to chronic-phase disease. CONCLUSION: Troxacitabine has significant antileukemic activity in patients with AML and CML-BP.     

Breakpoints in Philadelphia chromosome (Ph1)-positive leukemias

We studied chromosome 22 breakpoints in 24 Philadelphia (Ph1)-positive leukemias. Nineteen of 21 patients with chronic myelogenous leukemia (CML) possessed a chromosomal break within the 5.8 kilobase (kb) breakpoint cluster region (bcr). Furthermore, in one of three cases of acute lymphocytic leukemia (ALL), we found a chromosomal rearrangement in the bcr locus. No chromosomal rearrangements were found in two cases of CML and two cases of ALL using several restriction enzymes. The bcr rearrangement is highly specific for CML. Further analyses will be necessary to determine whether some cases without bcr rearrangement have another specific locus of rearrangement. Two of three cases of CML with blastic crisis had rearrangement of the immunoglobulin gene and T-cell receptor gene. One CML patient with blastic crisis, who achieved complete remission but relapsed thereafter, was found to have the same immunoglobulin gene rearrangement in the blastic crisis and relapse phases, suggesting that the same clone was involved in both crisis and relapse.     

慢性粒细胞白血病急变期与急性白血病细胞形态学特征差异分析

目的：探讨慢性粒细胞白血病急变期与急性白血病细胞形态学特征差异.方法：对11例急变期的慢性粒细胞白血病及52例初发急性白血病的骨髓及外周血细胞形态学差异进行分析.结果：11例慢性粒细胞白血病急变期患者,2例为急淋变,9例为急粒变.52例初发白血病,急性淋巴细胞白血病15例,急性非淋巴细胞白血病37例.慢性粒细胞白血病急粒变患者外周血嗜酸和或嗜碱细胞高于正常值,血小板多大于50×109/L,骨髓增生极度活跃,各期细胞均可见,原始及早幼粒细胞明显增高,伴有嗜酸和或嗜碱粒细胞增多,NAP积分可正常,这与急性粒细胞白血病有所差异.慢性粒细胞白血病急淋变患者外周血涂片可见早幼粒细胞及嗜酸、嗜碱粒细胞增多,这与急性淋巴细胞白血病不同.此外,尚需结合临床病史及细胞遗传学检查予以鉴别.结论：慢性粒细胞白血病患者急变期外周血及骨髓多有嗜酸及嗜碱粒细胞增多,早幼粒细胞增多,同时结合NAP,临床病史及细胞遗传学检查可与急性白血病相鉴别.     

Etoposide, 6-thioguanine and idarubicin, an oral combination regimen (ETI) for the induction treatment of acute leukemia

Twenty patients with advanced acute leukemia (16 acute myeloid leukemia (AML), three myeloid blast crisis (BC) of chronic myeloid leukemia (CML), one acute lymphatic leukemia) were treated with a peroral regimen consisting of etoposide 80 mg/m2 and 6-thioguanine 100 mg/m2 twice daily for 5 days, and idarubicin 15 mg/m2 once daily for 3 days (ETI). Two AML patients were in first relapse. All the other patients with acute leukemia had a later relapse or were refractory to primary or salvage treatment. One to six ETI cycles were given. Four AML patients achieved remission and one patient with BC of CML entered the second chronic phase. Clearing of the blood of leukemic cells was seen in seven additional patients. Infection was the most common complication, gastrointestinal toxicity was not a major problem. In conclusion, peroral ETI treatment has a marked antileukemic effect even in an advanced disease, and the toxicity is moderate and well acceptable.     

Phase II trial of amsacrine plus intermediate-dose Ara-C (IDAC) with or without etoposide as salvage therapy for refractory or relapsed acute leukemia

OBJECTIVE: The current trial attempted to evaluate the efficacy and toxicity of a salvage therapy consisting of amsacrine plus intermediate-dose Ara-C (IDAC) with or without etoposide for acute leukemia patients in refractory or relapsed states. METHODS: A total of 51 patients with refractory or relapsed acute leukemia were included in the current trial. Twenty-nine patients with acute myeloid leukemia (AML) received a salvage therapy of amsacrine plus IDAC and etoposide, while 22 patients with acute lymphoblastic leukemia (ALL) received amsacrine plus IDAC. RESULTS: The overall complete remission rate was 55% (45% for AML, 68% for ALL) and the median duration of overall survival was 144 days (95% confidence interval = 101-186 days). Grade 3, 4 infectious toxicities were observed in 43 patients (87%), while treatment-related toxicity, excluding infectious causes, included heart failure from myocarditis (n = 1) and central nervous system toxicity (n = 1). CONCLUSION: A salvage therapy consisting of amsacrine plus IDAC with or without etoposide appears to be safe and an effective bridge therapy into a stem cell transplantation programme for patients with refractory or relapsed acute leukemia.     

Troxacitabine, a novel dioxolane nucleoside analog, has activity in patients with advanced leukemia.

PURPOSE: To investigate the toxicity profile, activity, and pharmacokinetics of a novel L-nucleoside analog, troxacitabine (BCH-4556), in patients with advanced leukemia. PATIENTS AND METHODS: Patients with refractory or relapsed acute myeloid (AML) or lymphocytic (ALL) leukemia, myelodysplastic syndromes (MDS), or chronic myelogenous leukemia in blastic phase (CML-BP). Troxacitabine was given as an intravenous infusion over 30 minutes daily for 5 days. The starting dose was 0.72 mg/m(2)/d (3.6 mg/m(2)/course). Courses were given every 3 to 4 weeks according to toxicity and antileukemic efficacy. The dose was escalated by 50% until grade 2 toxicity was observed, and then by 30% to 35% until the dose-limiting toxicity (DLT) was defined. RESULTS: Forty-two patients (AML: 31 patients; MDS: six patients [five MDS + one CMML]; ALL: four patients; CML-BP: one patient) were treated. Median age was 61 years (range, 23 to 79 years), and 29 patients were males. Stomatitis and hand-foot syndrome were the DLTs. The MTD was defined as 8 mg/m(2)/d. The pharmacokinetic behavior of troxacitabine is linear over the dose range of 0.72 to 10.0 m/m(2). Approximately 69% of troxacitabine was excreted as unchanged drug in the urine. Marrow hypoplasia occurred between days 14 and 28 in 73% of AML patients. Three complete remissions and one partial remission were observed in 30 assessable AML patients. One MDS patient achieved a hematologic improvement. A patient with CML-BP achieved a return to chronic phase disease. CONCLUSION: Troxacitabine has a unique metabolic and pharmacokinetic profile and significant antileukemic activity. DLTs were stomatitis and hand-foot syndrome. Troxacitabine merits further study in hematologic malignancies.     

Abnormal regulation of the myc gene in myeloid leukemia

To study the regulation of expression of the myc protooncogene, cells from normal individuals and patients with acute myelogenous leukemia (AML), and chronic phase and blastic crisis of chronic myeloid leukemia (CML) cells were put in overnight culture in the presence or absence of fetal calf serum. Myc expression in normal marrow cells and chronic phase CML cells fell after culturein vitro. In contrast, myc expression was maintained or increased in a majority of the AML and blastic crisis CML specimens. These data demonstrate that the regulation of myc expression is disordered in many AML and blastic crisis specimens but not in chronic phase CML cells.     

Mitoxantrone for refractory and relapsed acute leukemia

Seventy-seven patients with relapsed or refractory acute leukemia and three with acute blastic chronic myeloid leukemia (CML) were treated in an open Phase II study using mitoxantrone 12 mg/m2 intravenously daily X 5 days. Complete remission (CR) was achieved in 32 of 80 (40%), including 23/45 (52%) with relapsed acute nonlymmphocytic leukemia (ANLL), four of 12 (33%) with relapsed acute lymphocytic leukemia ALL, four of 17 (24%) with ANLL refractory to daunorubicin + cytosine arabinoside, and one of three (33%) with refractory ALL. None of the patients with acute blastic CML achieved CR. Median survival time for all patients was 121 days. Median duration of complete response was 303 days with ten of 32 patients in continuing CR for periods varying from 44+ to 1210+ days. Apart from moderately prolonged hematologic suppression toxicity was mild and subjective side effects were tolerable. Mitoxantrone is an active agent in the treatment of acute leukemia and demonstrates incomplete cross resistance with duanorubicin. Mitoxantrone should be considered for first-line therapy in ANLL.     

Carboplatin plus cytarabine in the treatment of high-risk acute myeloblastic leukemia.

Thirty-one patients (20 male and 11 female; median age 51 years (16-79)) with high-risk acute myeloblastic leukemia (AML) (20 refractory AML and 11 secondary AML (s-AML) (four to myelodysplastic syndrome, five to chemo/radiotherapy, one to aplastic anemia and one blastic chronic myelogenous leukemia (B-CML)) were treated with CBDCA (300 mg/m2/day x 5 days in continuous i.v. infusion) plus intermediate-dose Ara-C (500 mg/m2/day x 3 days in rapid i.v. infusion). Nine patients (29%) achieved CR (five s-AML (three myelodysplastic syndromes, one CML and one ALL) and four refractory AML) and 11 patients had resistant disease. There were 11 early deaths (35%). Median disease-free survival of the nine responders was 4 months. The main toxicity was hematological, febrile episodes took place in nearly all the patients (96%). The CBDCA plus Ara-C regimen showed an evident antileukemic activity in high-risk leukemia. However, the lack of long-term disease-free survivors shows the need for innovative postremission strategies. The high initial response rate seen in AML secondary to myelodysplastic syndromes (MDS) warrants further investigation of CBDCA in combination regimens for MDS patients.     

High levels of 5′-nucleotidase activity in blastic chronic myelogenous leukemia with common all-antigen

The activity of 5′-nucleotidase (5′-N) on the surface of leukemia cells was determined in 44 patients with blast crisis of chronic myelogenous leukemia (CML) and in 52 patients with acute myeloblastic (AML) or acute lymphoblastic (ALL) leukemia. The phenotype of blast cells was classified according to immunological surface markers, including the common ALL-antigen (cALLA). High 5′-N activities were found in the presence of cALLA, whereas low to undetectable levels were characteristic for cALLA-negative leukemias, the difference being highly significant (p 0.0001). While there was a certain overlap of 5′-N levels between cALLA-positive ALL and cALLA-negative AML, no overlap of 5′-N was observed between cALLA-positive lymphoid and cALLA-negative myeloid blast crisis of CML. Thus, 5′-N affords an additional easily-testable biochemical marker that may have its diagnostic and prognostic value especially in the case of blastic chronic myelogenous leukemia.     

Fludarabine and cytarabine as a sequential infusion regimen for treatment of adults with recurrent, refractory or poor prognosis acute leukemia

We did a retrospective analysis on the safety and efficacy of sequential infusion fludarabine and cytosine arabinoside (ara-C) in treating refractory, recurrent or poor prognosis acute leukemia in adult patients. Forty-five adult patients with acute myelogenous leukemia (AML) or acute lymphoblastic leukemia (ALL) received a total of 68 courses of sequential continuous infusion of fludarabine for 2 days (total dose 71.5 mg/m(2) ) followed by 3 days of ara-C (total dose 7590 mg/m(2) ). Thirty-nine patients had refractory or recurrent disease, and six had other adverse prognostic features. Thirty-six patients had AML, seven had ALL, and two had CML in blastic phase. Complete remission was seen in 20 patients (44%), and partial remission in 5 patients (11%), giving a total response rate of 56%, similar for both AML and ALL. Duration of response to prior therapy did not affect the response rate. All 3 patients with Philadelphia chromosome positive ALL obtained complete remission. Median remission duration was 4.7 months (range 0.6-36.6), and median overall survival was 5.0 months (0.7-40+). Median overall survival was 10.1 months in responders. Pulmonary toxicity was seen in 8 patients, of whom 2 died from adult respiratory distress syndrome. No cardiac toxicity was observed, but 3 patients had transient cerebellar toxicity. Profound myelosuppression was seen in all patients. We conclude that the sequential infusion of fludarabine and ara-C is an effective non-cardiotoxic regimen for adults with refractory, recurrent or poor prognosis acute leukemia, may be particularly useful for resistant Philadelphia chromosome positive ALL, and may warrant further investigation in this subset. Pulmonary rather than neurological toxicity may be a unique side effect of the regimen.     

Modern Management of Chronic Myelogenous Leukemia (CML)

INTRODUCTION In the untreated state, patients with chronic myelogenous leukemia (CML) generally are asymptomatic and do not require urgent or intensive therapy. Resolution of the signs and symptoms of the disease using standard therapies is achievable without significant toxicity or risk to the patient. However, unlike acute myelogenous leukemia (AML), where true remissions can be obtained, in CML, despite attaining “hematologic” remission, persistence of the abnormal malignant clone as evidenced by the presence of the Philadelphia chromosome-positive (Ph+) cells is characteristic. Eventually all patients with CML, despite control of their disease in the chronic state, will enter a blastic or terminal phase resembling acute leukemia which, for the most part, is resistant to therapy. Patients with CML can expect a median survival of approximately 36-40 months (1) which has not changed appreciably in the last five decades. The recognition of this has led to the pursuit of more aggressive therapy using chemotherapy, immunotherapy, and chemoradiotherapy with marrow transplantation. This review focuses on the treatment of CML in the chronic phase, the use of aggressive therapy to obtain true remission and possible cure, and the therapeutic options available to patients who have entered the blastic phase.     

Etoposide in combination with intermediate dose cytosine arabinoside (ID ARA C) given with the intention of further myeloablative therapy for the treatment of refractory or recurrent hematological malignancy.

Thirty-four patients with refractory or recurrent high grade non-Hodgkin's lymphoma (NHL) or acute leukemia were treated with a combination of etoposide, 100 mg/m2 daily, and ara C, 1 g/m2 twice daily, for 5 days (VPARAC). This therapy was given in the anticipation that remissions thus achieved would be 'consolidated' with myeloablative therapy supported by bone marrow transplantation (BMT). The complete remission rate (CR) in patients with NHL was 3/18 (17 per cent) with partial responses (PR) seen in a further four patients, giving an overall response rate of 39 per cent. Four patients (three in CR, one in PR) proceeded to the planned consolidation treatment. Complete remission was achieved in 2/8 (25 per cent) patients with acute myelogenous leukemia (AML) and in 2/8 patients with acute lymphoblastic leukemia (ALL). Three of these patients subsequently had myeloablative consolidation therapy with BMT. There were four treatment-related deaths (NHL, two; AML, one; ALL, one). In poor risk patients with high grade NHL and acute leukemia, VPARAC is an effective remission induction programme in 21 per cent of patients. Seven of the original 34 patients received the intended 'curative' therapy, of whom only four are alive and well 1 year later.     

Amsacrine is safe and effective therapy for patients with myocardial dysfunction and acute leukemia

The role of amsacrine in inducing remission in patients with cardiac disease and acute leukemia was evaluated. There were 17 patients with acute myelogenous leukemia (AML), six with acute lymphocytic leukemia (ALL), and one with biphenotypic leukemia. In this series of 24 patients whose disease had relapsed and who had reduced left ventricular ejection fraction, nine had a complete remission, seven with AML and two with ALL. In addition, four of six with newly diagnosed acute leukemia and reduced left ventricular ejection fraction also responded. Among nine patients who underwent endomyocardial biopsy, none had morphologic changes of sufficient degree to account for drug-induced heart failure. Patients with preexisting arrhythmias received amsacrine without incident if their serum potassium level was higher than 4.0 mEq/l at the time of drug administration. Amsacrine is safe and effective therapy for patients with acute leukemia and cardiac disease.     

Mitoxantrone, vincristine, and prednisone in adults with relapsed or primarily refractory acute lymphocytic leukemia and terminal deoxynucleotidyl transferase positive blastic phase chronic myelocytic leukemia

A combination of mitoxantrone, vincristine, and prednisone was used to treat 19 patients with acute lymphocytic leukemia. Of these, 12 were patients with acute lymphoblastic leukemia (ALL) (9 in first relapse and 5 primarily refractory to standard induction therapy with daunorubicin, vincristine, and prednisone), 2 had a phenotypic ALL relapse after an initial diagnosis of acute myelocytic leukemia and 5 had terminal deoxynucleotidyl transferase positive blastic phase chronic myelogenous leukemia (BCML). Eight patients with ALL (and of these, four with primarily anthracycline resistant disease), and two with BCML achieved complete remission. Five patients died in induction (three ALL from sepsis and two BCML from bleeding), and five had progressive disease. Median duration of response was 5 months, with two primarily refractory ALL patients remaining in continuing complete remission at 28 and 31 months. Treatment was well tolerated, with minimal nausea and vomiting, and oral mucositis. Posttreatment transient hepatic dysfunction was seen in 80% of patients. Mitoxantrone, vincristine, and prednisone are an active combination for the treatment of relapsed or refractory ALL and of terminal deoxynucleotidyl transferase positive BCML. The finding that four of five primarily refractory ALL patients were induced in complete remission supports the contention that mitoxantrone and anthracyclines are not cross-resistant.     

Homoharringtonine is safe and effective for patients with acute myelogenous leukemia.

Homoharringtonine (HHT) is a cephalotaxine alkaloid with reported efficacy in acute myelogenous leukemia (AML). In a phase II trial, we evaluated HHT 5 mg/m2 by continuous infusion daily for 9 days in patients with relapsed or refractory acute leukemia and blastic phase of chronic myelogenous leukemia (BLCML). Sixty-six patients were entered. There were 40 males and 26 females with a median age of 41 years (range 15-81). Of 43 patients with relapsed AML, seven achieved a complete remission (16%, 95% confidence interval 5%-27%). Although 11 patients with AML primarily resistant to an anthracycline/cytarabine combination did not respond, two of three patients primarily resistant to low-dose cytarabine achieved complete remission. No patients with acute lymphoblastic leukemia, biphenotypic leukemia, or BLCML responded. Hypotension during the administration of HHT was the most difficult toxicity encountered, requiring multiple interruptions of therapy in several patients and the administration of intravenous saline. Fluid retention and weight gain occurred in 29% of patients. Transient asymptomatic hyperglycemia was observed in 63% of patients. Other toxicity was mild and included nausea and vomiting, diarrhea, mucositis, hepatic dysfunction, and cardiac arrhythmias. As expected, severe myelosuppression occurred in all patients. HHT is well tolerated, but with unique problems associated with administration. It has demonstrable efficacy in pre-treated patients with AML, but its role in the treatment of this disease remains to be defined.     

Expression of nucleolar antigen p145 in bone marrow cells of patients with myeloid leukemias

The expression of a cell cycle-related nucleolar protein (p145) antigen was examined in the bone marrow aspirates of 45 individuals, three of whom had no malignant disease; 30 had a diagnosis of acute myeloid leukemia (AML), and 12 suffered from chronic myeloid leukemia (CML). While no evidence of p145 expression was found in the three normal bone marrow samples, it was noted to be the highest in patients with active leukemia, be they AML or blastic crisis of CML. There was a direct correlation between the percentage of blasts and the percentage of p145-positive cells in all patients. Double labeling with tritiated thymidine and p145 in AML patients with active leukemia showed that the majority of S-phase cells contained p145. Myeloblasts in both chronic phase and blastic crisis of CML expressed p145. Nine of 12 AML patients studied during remission had less than 5% p145-positive cells, but three showed 11%, 16%, and 33% positive cells. Since functionally/morphologically, these marrows were normal, the appearance of p145 may indicate a proliferative abnormality preceding maturation arrest and development of relapse. Thus we conclude that p145 is more commonly associated with immature cells and may serve as an early indicator of relapse in AML, but requires further study with larger numbers of patients.