Acute pancreatitis associated with interferon alpha therapy for chronic myelogenous leukemia

Acute pancreatitis related to interferon alpha therapy is very rare. We report two patients with chronic myelogenous leukemia (CML) who developed acute pancreatitis following treatment with interferon alpha. A review of the literature on the association of pancreatitis and interferon alpha is provided. Possible pathophysiologic mechanisms are also discussed.     

Dasatinib and interferon alpha synergistically induce pyroptosis-like cell death in philadelphia chromosome positive acute lymphoblastic leukemia

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) is a high-risk disease subtype with a dismal prognosis. Inhibiting BCR-ABL kinase alone is insufficient to eradicate Ph+ALL clones, and alternative BCR-ABL-dependent and -independent pathways need to be targeted as an effective strategy. Our study revealed that the combination of dasatinib and interferon-α showed synergistic activity against Ph+ALL, inducing mitochondrial dysfunction and causing necrosis-like cell lysis. Mechanistic studies showed that the induced cell death was caspase-3-independent. Canonical necroptosis signals, such as RIP1 and MLKL, were not activated; instead, the pyroptosis executor Gasdermin D was upregulated expression and activated. The expression levels of extracellular ATP and IL-1β were also upregulated, both of which are markers of pyroptotic cell death. In a murine Ph+ALL model, the dual drug treatment prolonged the survival of tumor-bearing mice. More importantly, we incorporated the dual drugs to maintenance therapy in 39 patients who were unfit for allogeneic stem cell transplantation (allo-HSCT). The median follow-up was 28.5 months, the 4-year disease-free survival and overall survival rates were 52.2% and 65.2%, respectively. Our data suggest that the combination of dasatinib and interferon-α has potential synergistic activity against Ph+ALL and shows promise as a maintenance therapy for Ph+ALL patients who are unfit for allo-HSCT.     

Cytarabine added to interferon improves the cost-effectiveness of initial therapy for patients with early chronic phase chronic myelogenous leukemia

The French Chronic Myeloid Leukemia Study Group prospective randomized study results indicate that the addition of cytarabine to alpha interferon (IFN-alpha) increases the rate of major cytogenetic response and prolongs survival in patients with early chronic phase chronic myelogenous leukemia (CML). The French group study design permitted a single crossover to include or discontinue cytarabine or interferon. Endpoints were overall survival, complete hematologic remission (CHR) at six months, and major cytogenetic response at 12 months. We modified a published Markov model that compared IFN-alpha alone to IFN-alpha plus cytarabine and included the possibility of crossover as in the French study. The model permits allogeneic and autologous stem cell transplantation (SCT), and follows cytogenetic response and acceleration of CML through death. Treatment response, toxicity, and survival are drawn from the French Chronic Myeloid Leukemia Study Group population of 810 patients on an intention-to-treat model. Survivals are extended to 62 months based on currently available follow-up. Costs from a United States oncology specialty institution, and state utilities from previous research and a quality-adjusted Time Without Symptoms or Toxicity analysis of the subject study were discounted at 3% per annum. At the median cohort age of 50, cytarabine offers 21 months of added median survival to IFN-alpha, which itself is superior to conventional chemotherapy by 21 months. Cost-effectiveness estimates for cytarabine added to IFN-alpha range from $7,000 per quality-adjusted life year (QALY) to $35,000 per QALY, under all plausible assumptions superior to IFN-alpha alone. The model is sensitive to the quality of life on therapy, as well as to remission rate with additive cytarabine, although the cost-effectiveness calculations are robust over the entire range of clinical assumptions. Based on data from the French study, cytarabine added to IFN-alpha substantially improves the cost-effectiveness of initial therapy for early chronic phase CML.     

Marked reduction of BCR-ABL fusion chromosome positive cells with interferon therapy combined with short-term imatinib in chronic myelogenous leukemia

A 71-year-old man with chronic myelogenous leukemia received interferon therapy for 21 months, but did not have complete cytogenetic response. Imatinib was then added to the former therapy. Imatinib was prescribed for only 12 days and discontinued because of severe erythema. Since then, however, marked reduction of bcr-abl fusion chromosome positive cells was observed, and this state has been maintained to the present day even though treatment has consisted only of interferon. we discuss efficacy of the combined therapy, composed of interferon and imatinib, for chronic myelogenous leukemia and other bcr-abl fusion chromosome positive diseases.     

Treatment of Philadelphia chromosome-positive early chronic phase chronic myelogenous leukemia with daily doses of interferon alpha and low-dose cytarabine.

PURPOSE: To evaluate the efficacy of the combination of interferon alpha (IFN-alpha) and daily low-dose cytarabine (ara-C) in the treatment of patients with early chronic-phase chronic myelogenous leukemia (CML) (within 1 year of diagnosis). Improving the degree of hematologic and cytogenetic response in patients with Philadelphia chromosome (Ph)-positive CML may improve prognosis. Both IFN-alpha and ara-C induce cytogenetic responses as single-agent therapy in CML. PATIENTS AND METHODS: One hundred forty patients with Ph-positive early chronic-phase CML received subcutaneous injections of IFN-alpha 5 megaunits/m2 daily and ara-C 10 mg daily. Their median age was 46 years; 53% had good-risk disease, 33% had intermediate-risk disease, and 14% had poor-risk disease. Their results were compared with those of patients receiving IFN-alpha with or without intermittent ara-C (7 days/mo). RESULTS: A complete hematologic response (CHR) was achieved in 92% of patients. A cytogenetic response was seen in 74%: it was major in 50% (Ph-positive < 35%) and complete in 31% (Ph-positive 0%). With a median follow-up of 42 months, the 4-year estimated survival rote was 70% (95% confidence interval, 61% to 79%). Significant side effects included fatigue (43%; grade 3/4, 11%), weight loss (19%; grade 3/4, 11%), muscle and bone aches (20%; grade 3/4, 7%), oral ulcers (4%), diarrhea (6%), and neurologic changes (27%, grade 3/4, 6%). The median dose of IFN-alpha was 3.7 megaunits/m2 daily, mainly because of reductions for myelosuppression (70% of cases); the median ara-C dose was 7.5 mg daily. Prognostic risk groups were predictive for response to the IFN-alpha plus ara-C combination. The incidence of CHR was higher with IFN-alpha plus daily ara-C compared with IFN-alpha plus intermittent ara-C and IFN-alpha alone (no ara-C) (92% v 84% v 80%, P = .01), as were the incidences of cytogenetic response (74% v 73% v 58%; P = .003) and major cytogenetic response (50% v 38% v 38%; P = .06). The median time to achievement of major cytogenetic response was significantly shorter than that for previous IFN-alpha regimens (7 v 10 v 12 months; P < .01). However, with the present follow-up, the survival and time to blastic transformation were similar. CONCLUSION: The combination of IFN-alpha plus daily low-dose ara-C seems to be promising for the treatment of CML. High rates of CHR and cytogenetic response were observed with acceptable toxicity and a lower daily dose of IFN-alpha compared with our previous studies.     

Down-regulation of peripheral blood cell interferon receptors in chronic myelogenous leukemia patients undergoing human interferon (HuIFN alpha) therapy

Our interest in studying interferon (IFN) receptor activity in peripheral blood cells (PBCs) from patients with chronic myelogenous leukemia (CML) receiving therapeutic doses of partially purified leukocyte IFN (IFN alpha) stems from a need for more adequate monitoring of IFN therapy. The binding of 35S-labelled recombinant DNA-derived leukocyte clone A IFN (35S-rIFN alpha A) to PBCs from 8 patients with CML was determined before and during IFN alpha treatment. The patients' mean pretherapy binding level (0.049 femtomoles of bound 35S-rIFN alpha A) was in the range of values obtained from 4 normal donors (mean of 0.054 femtomoles bound). Within 24 hr of the first IFN alpha dose, the mean femtomoles bound decreased 10-fold and remained low during the course of IFN alpha treatment. In I/I patient, we demonstrated that this decreased binding was due to a loss in number of IFN receptors. The apparent number of receptors after 5 doses of IFN alpha decreased from approximately 600 receptors per cell at pretherapy to approximately 75 receptors per cell, with no difference in the dissociation constants (1.13 X 10(-10)M, 0.968 X 10(-10)M, before and during treatment, respectively). In 4/4 patients, we demonstrated indirectly that the decreased binding was not due to receptor saturation as a result of residual circulating IFN alpha. In 3/3 patients, we demonstrated a gradual recovery of binding capacity after incubating the patients' PBCs at 37 degrees C. Within 2-7 days in vivo recovery of binding, comparable to pretherapy levels, was observed in 3/3 patients whose IFN alpha therapy was discontinued. Combining all these data, we conclude that in both responding and nonresponding patients with CML, IFN alpha exposure induces decreased binding of labelled IFN when a single recombinant DNA-derived IFN species is used. We feel the supporting data indicate that the decreased binding capacity may be due to receptor down-regulation. In the limited number of patients studied thus far, there was no correlation between clinical hematologic response and occurrence of down-regulation, however, down-regulation of cell surface receptors may be required to sustain a biological effect. Further studies of both the kinetics of down-regulation and activation of key enzyme systems are required to fully evaluate the relevance of these findings.     

Synergistic antiproliferative effect of interferon alpha and azidothymidine in chronic myelogenous leukemia

The possible synergistic interaction between azidothymidine (AZT) and interferon alpha (rIFN-alpha 2a) in the treatment of chronic myelogenous leukemia (CML) was studied in vitro using marrow or peripheral blood hematopoietic progenitors from 10 patients with CML in the mixed (CFU-GEMM) colony culture assay. Used singly, either agent inhibited erythroid (BFU-E) and granulocyte-macrophage (CFU-GM) CML hematopoietic progenitor proliferation in a dose-dependent fashion, with the inhibitory effect being more pronounced on BFU-E than on CFU-GM colony-forming cells. The combination of both drugs in therapeutic concentrations exerted a significant synergistic inhibition on CML stem cells as assessed by the median-effect principle and isobologram equation analysis. A suboptimal dose of AZT (0.5 mumol/l) synergistically augmented the effect of rIFN-alpha 2a whereas an inactive dose of 10 U/ml rIFN-alpha 2a similarly enhanced the CML stem cell growth inhibition exerted by AZT. Our data indicate that AZT may augment the already established therapeutic benefits of IFN-alpha in CML.     

Recombinant alpha 2B interferon in combination with oral chemotherapy in late chronic phase chronic myeloid leukaemia.

The place of alpha interferon (IFN) therapy in the treatment of chronic myeloid leukaemia (CML) is under intensive investigation at present. It is now established that as a single agent it can provide good disease control in the chronic phase and that cytogenetic responses will occur in a minority of patients. However its impact on long term survival has been less certain. Optimal haematological and cytogenetic results have to date been seen when IFN is used in the early phase of the disease, i.e. within one year of diagnosis. We have performed a prospective single arm study on the effect on survival of the addition of low dose IFN (9 mU/week) to conventional oral chemotherapy in patients who were at a median of 19 months from the initial diagnosis at the time of study entry. Comparison of this cohort with a control group of CML patients treated with oral chemotherapy only at the same participating institutions gave an estimated 72% reduction in the risk of death as a result of IFN therapy. Median survival for the IFN group has not been reached at 43 months compared with a median survival of 33 months for the chemotherapy alone group. These results suggest that the introduction of low dose IFN at any stage in the chronic phase may produce a worthwhile improvement in survival.     

A phase 2 study of MK-0457 in patients with BCR-ABL T315I mutant chronic myelogenous leukemia and philadelphia chromosome-positive acute lymphoblastic leukemia

Aurora kinase overexpression has been observed in patients with hematologic malignancies. MK-0457, a pan-aurora kinase inhibitor that also inhibits the ABL T315I mutant, was evaluated to treat patients with chronic myelogenous leukemia (CML) or Philadelphia chromosome (Ph+) acute lymphoblastic leukemia (ALL) with the T315I mutation. Adults with Ph+ chronic phase (CP)-, accelerated phase (AP)- or blast phase (BP)-CML, or ALL and documented BCR-ABL T315I mutation were treated with a 5-day continuous infusion of MK-0457 administered every 14 days at 40 mg/m²/h, 32 mg/m²/h or 24 mg/m²/h. Fifty-two patients (CP, n=15; AP, n=14; BP, n=11; Ph+ ALL, n=12) were treated. Overall, 8% of patients achieved major cytogenetic response; 6% achieved unconfirmed complete or partial response; 39% had no response. Two patients (CP CML) achieved complete hematologic response. No patients with advanced CML or Ph+ ALL achieved major hematologic response. The most common adverse event (AE) was neutropenia (50%). The most common grade 3/4 AEs were neutropenia (46%) and febrile neutropenia (35%). MK-0457 demonstrated minimal efficacy and only at higher, intolerable doses; lower doses were tolerated and no unexpected toxicities were observed. These data will assist in the development of future aurora kinase inhibitors and in the selection of appropriate target patient populations.     

Leukocyte interferon in the treatment of chronic myelogenous leukemia in second chronic phase

Four patients with Philadelphia chromosome positive CML were treated with 18-42 x 10(6) IU of purified natural leukocyte IFN-alpha per week, after high-dose chemotherapy for blast phase and attainment of 2nd chronic phase. The second blast phase occurred within 3 months in 3 patients, but one patient is still in second chronic phase after 22 months of treatment. Treatment consisted of interferon only during the first year, and interferon in combination with hydroxyurea during the second year. During the second year suppression of the Philadelphia chromosome was seen in one patient, with 20% Philadelphia negative bone marrow metaphases. The toxicity of purified natural leukocyte IFN-alpha was similar to the toxicity of recombinant IFN-alpha. Antibodies to IFN-alpha were not detected in any patient.     

Imatinib therapy for patients with chronic myelogenous leukemia

Chronic myelogenous leukemia (CML) is a clonal hematopoietic disorder caused by the reciprocal translocation between chromosome 9 and 22. As a result of this translocation, a novel fusion gene, BCR-ABL, is created on Philadelphia (Ph) chromosome, and the constitutive activity of the BCR-ABL protein tyrosine kinase plays a critical role in the disease pathogenesis. Imatinib mesylate, a selective BCR-ABL tyrosine kinase inhibitor, was first given to a patient with CML in June 1998. Since then, it has continued to demonstrate remarkable efficacy in treating patients with CML. Based upon the results of early phase I and II studies, a phase III study (IRIS Study) that was randomized to first-line imatinib (400 mg/day) or to standard treatment with interferon+low-dose Ara-C, was conducted on 1,106 patients newly diagnosed (within 6 months) with chronic-phase CML. After median follow-up of 30 months, imatinib showed significantly superior tolerability, hematologic and cytogenetic responses (major cytogenetic response, 90%; complete cytogenetic response, 82%), and overall survival (95% without censoring allo-HSCT). Although imatinib is the first-line therapy and has changed the paradigm of CML treatment strategy, questions remain as to the meaning of cytogenetic and molecular response, curability, optimal dose, and relation with allo-HSCT.     

Philadelphia chromosome positive chronic myelogenous leukemia developing in a patient with acute lymphoblastic leukemia.

A patient with acute lymphoblastic leukemia (ALL) in remission for over five years and with no systemic chemotherapy for over two years developed a peripheral blood and bone marrow granulocytosis. While in remission from the ALL, cytogenetic studies revealed a normal karyotype. With the development of peripheral and marrow granulocytosis, repeat cytogenetic preparations demonstrated the presence of the Philadelphia chromosome. The long interval between the onset of ALL and GML, as well as the normal karyotype during remission from the ALL, causes us to favor the hypothesis that two separate diseases are present.     

Approval summary: imatinib mesylate capsules for treatment of adult patients with newly diagnosed philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase.

PURPOSE: The purpose is to describe the Food and Drug Administration (FDA) review and approval of imatinib (Gleevec; Novartis Pharmaceuticals, East Hanover, NJ) for treatment of adult patients with newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia (CML) in chronic phase. EXPERIMENTAL DESIGN: The FDA reviewed data in electronic format from a randomized controlled clinical trial of 1106 adult patients with newly diagnosed Philadelphia chromosome-positive CML in chronic phase, comparing imatinib with the combination of IFN-alpha and cytarabine. RESULTS: Imatinib showed clinically and statistically significantly better results for time-to-progression to accelerated phase or blast crisis, progression-free survival, complete hematological response rate, and cytogenetic response rate. With a median follow-up of 14 months, a maximum follow-up of 19.5 months, and an expected median survival of 5-6 years on the IFN-alpha/cytarabine control arm, few of the expected progressions to accelerated or blast phase or deaths have occurred. Imatinib was also better tolerated. Edema, nausea, rigors, neutropenia, and headache were more frequent in women. Only 57% of the IFN-alpha target dose was administered, and only 68% of patients received any cytarabine. However, this does not appear to adequately explain the superiority of imatinib observed in this trial. Results of a population pharmacokinetic study in a subgroup of 371 patients and a separate rifampin-imatinib drug-drug interaction study in healthy volunteers are presented. CONCLUSIONS: On December 20, 2002, imatinib was granted accelerated approval under subpart H, rather than regular approval. Follow-up is short compared with the natural history of chronic phase CML or more mature results with established therapies such as IFN-alpha or transplantation. If imatinib should stop working after 1.5-2 years, the results could be importantly different from the present analysis. As a Phase IV postmarketing commitment, the applicant has agreed to provide follow-up reports on this imatinib study annually for the next 6 years.     

Oral idarubicin in patients with late chronic phase chronic myelogenous leukemia or chronic myelomonocytic leukemia

Patients with chronic myelogenous leukemia (CML) who have failed or cannot receive interferon alpha (IFN-alpha) based regimens or patients with advanced chronic myelomonocytic leukemia (CMML) have very limited current therapeutic options. Hence, there is a need to develop new strategies for these patients. This study was undertaken to determine the efficacy and toxicity of a chronic low-dose oral idarubicin regimen in these patients as positive data has been generated on this agent in shorter schedules given to patients with other hematological malignancies. Eighteen patients were treated on study. The starting dose of oral idarubicin was 2 to 5 mg/m2 daily depending in initial WBC count. This dose was escalated in the absence of Grade 4 myelosuppression or Grade 3 or 4 extramedullary toxicity. Oral idarubicin was given daily for 28 days followed by a 21 day break off treatment in repeated cycles until there was evidence of disease progression or intolerable toxicity. The dose of idarubicin was adjusted, at 2-week intervals, by 25% to maintain a white blood cell (WBC) count between 2 and 4x10(9)/L and a platelet count of >75x10(9)/L. The dose was reduced by 25% for grade 2 extramedullary toxicity and held until toxicity resolved to grade 2 or better for grade 3 toxicity. Oral idarubicin was then restarted at 75% of the initial dose. Five out of 14 CML patients achieved a complete hematologic remission. No CMML patient responded (median survival 3 months). The overall median survival was 24 months. CML patients had a median survival of 28 months. Major toxicities (myelosuppression, gastrointestinal, cardiac) were infrequent with a median cumulative dose of 1110 mg/m2 (range 54-9750). Five patients have received oral idarubicin for > 1 year with no overt cardiotoxicity, reaching median cumulative dose of 2756 mg/m2 (range 2550-9750) which is higher than those documented in prior studies. We conclude that oral idarubicin is sufficiently safe and active to warrant phase II studies investigating it as part of interferon-based regimens in patients with advanced CML.     

The significance of myelosuppression during therapy with imatinib mesylate in patients with chronic myelogenous leukemia in chronic phase

BACKGROUND: Imatinib mesylate induces high rates of hematologic and cytogenetic response in patients with chronic myelogenous leukemia (CML). During therapy with imatinib, up to 45% of patients with CML reportedly experience myelosuppression > or = Grade 3, requiring interruption of therapy and/or dose reductions. The significance of myelosuppression for response to imatinib is unknown. METHODS: The authors analyzed 143 patients with late chronic-phase CML who were treated with imatinib after failing interferon. Univariate and multivariate analyses were performed to determine patient characteristics that were correlated with myelosuppression response and the association between myelosuppression and cytogenetic response. RESULTS: Neutropenia > or = Grade 3 (according to National Cancer Institute Common Toxicity Criteria) occurred in 64 patients (45%), and thrombocytopenia > or = Grade 3 occurred in 31 patients (22%). Any myelosuppression > or = Grade 3 was associated with a lower rate of major (P = 0.04) or complete (P = 0.01) cytogenetic responses. This was more pronounced with myelosuppression that lasted > 2 weeks. The major cytogenetic response rate was 58% with Grade > or = 3 myelosuppression compared with a rate of 75% without Grade > or =3 myelosuppression (P = 0.03); the complete cytogenetic response rates were 36% and 63%, respectively (P = 0.001). In a multivariate analysis, pretreatment platelet count, imatinib dose reductions, and duration of myelosuppression were associated significantly with response. CONCLUSIONS: Myelosuppression is an independent adverse factor for achieving cytogenetic response with imatinib in patients with CML. Intervention with hematopoietic growth factors in patients with CML who are treated with imatinib should be investigated.     

The value of intensive combination chemotherapy for juvenile chronic myelogenous leukemia

Nine children with juvenile chronic myelogenous leukemia (JCML) were diagnosed in an 8-year period from 1977 to 1984. The clinical courses and outcomes of five patients who received minimal or no chemotherapy were compared with that of four patients who were treated with intensive acute nonlymphoblastic leukemia (ANLL) combination chemotherapy. None of the five patients in the former group achieved clinical remission and their survivals were 1, 4, 4, 7, and 29 months, respectively. All four patients in the latter group achieved clinical remissions that lasted 11, 21, 21, and 27 + months, respectively. The durations of their survival (21, 26, 30, and 32 + months) were significantly better than the five patients who received minimal or no chemotherapy (P less than .05). Despite hospitalizations for chemotherapy and for treatment of chemotherapy-associated complications, the clinical status and quality of life of the children who achieved clinical remission were superior to those who remained in relapse. Although intensive chemotherapy induced lengthy remissions, three of the four patients have relapsed. Cytogenetic and cell culture data indicated that the monocytic-macrophage cells characteristic of JCML appeared to be suppressed during remission rather than totally eliminated. We recommend that ANLL-type combination chemotherapy be used as the initial treatment of JCML because of its promptness in effecting clinical remissions. Improved maintenance and consolidation protocols have to be developed to produce durable remissions and cures. Alternatively, bone marrow transplantation may be a useful option soon after remission is achieved with chemotherapy.     

Treatment of philadelphia chromosome-positive, accelerated-phase chronic myelogenous leukemia with imatinib mesylate.

PURPOSE: Imatinib mesylate, a specific Bcr-Abl tyrosine kinase inhibitor, has shown encouraging activity in chronic myelogenous leukemia (CML). EXPERIMENTAL DESIGN: We treated 237 patients (median age, 50 years; age range, 18-82 years) with Philadelphia chromosome (Ph)-positive accelerated-phase CML with oral imatinib mesylate at daily doses of 400 mg (26 patients) or 600 mg (211 patients) and evaluated response and survival characteristics in univariate and multivariate analyses. RESULTS: Among the 200 patients with accelerated-phase CML for whom follow-up was 3 months or more, rates of complete and partial hematological response were 80% and 10%. Cytogenetic responses were evident in 90 patients [45%; complete response in 47 patients (24%) and partial response (Ph 1-34%) in 21 patients (11%)]. The estimated 18-month survival rate was 73%. The estimated complete hematological response rate at 18 months was 68%; that for cytogenetic response was 82%. In multivariate analyses, a diagnosis-to-treatment interval of 3 years or more, splenomegaly, and peripheral blasts predicted poor major cytogenetic response; age >60 years, marrow basophilia, and clonal evolution predicted poor survival. The 600-mg drug dose was associated with better cytogenetic response and survival in univariate analysis (P < 0.01) but not in multivariate analysis. Landmark analysis showed that achieving a cytogenetic response at 3 months or a major cytogenetic response (Ph < 35%) at 6 months was associated with better long-term survival. Seven of 15 patients who were in a second chronic phase achieved major cytogenetic response. The incidence of severe nonhematological toxic effects was 23%; drug discontinuation for severe toxicity was needed in 3% of patients. CONCLUSIONS: Imatinib mesylate was active against Ph-positive, accelerated-phase CML, and the prognostic factors identified in this study could aid in tailoring treatment strategies to specific risk groups.     

Results of a phase II trial of a combination of oral cytarabine ocfosfate (YNK01) and interferon alpha-2b for the treatment of chronic myelogenous leukemia patients in chronic phase.

Cytarabine ocfosfate (YNK01) is a prodrug analogue of cytarabine which is resistant to systemic deamination after oral administration. Following initial studies indicating significant anti-tumour activity of YNK01 a phase II trial was initiated in order to assess the tolerability and efficacy of a combination of this agent with interferon alpha-2b (IFN-alpha2b) in recently diagnosed chronic phase CML patients (n = 98). The treatment was subdivided into cycles consisting of 4 weeks of continuous administration of IFN-alpha-2b (3 MU/m(2)/day 1st week and then 5 MU/m(2)/day) and 14 days of oral YNK01 (600 mg/day 1st cycle). At the end of each cycle the dose of YNK01 was adjusted according to the blood count observed during the previous 4 weeks. The median time from diagnosis to inclusion in the trial was 2 months (range 6 days to 7.5 months). At 12 weeks, 62 patients (63%; 95% CI, 54-73) achieved a complete hematological response. At 24 weeks, of 98 patients, two achieved a complete cytogenetic response, 14 a partial response (16% major cytogenetic response rate; 95% CI, 9-24) and 34 a minor response; 19 patients were not evaluable for cytogenetic response. During the trial, 20 patients progressed to accelerated (6) or blastic phases (14). The median time to progression was 15 months (range 2-38 months). At 3 years the overall survival was 79% (95% CI, 70-88). Although the complete hematological response rate compared favorably with the 40% response rate previously obtained with the subcutaneous formulation of Ara-c, the cytogenetic response rate was less than expected. Most of the patients experienced side-effects and all permanently stopped YNK01. Although the combination seems attractive the initial dose of 600 mg per day is probably too high and should be reconsidered in further trials.     

亚砷酸钠治疗加速期慢性粒细胞性白血病的疗效观察

目的:观察亚砷酸钠治疗加速期性粒细胞性白血病(CML)的临床疗效.方法:依据外周血白细胞数,每日静脉滴注亚砷酸钠10～15mg.结果:经过平均40. 5天治疗,7例诊断为加速期慢性粒细胞白血病患者中,3例CR,4例PR,患者对亚砷酸钠均耐受良好,并见到临床与血液学及CFU-GM的明显改善,但无Ph染色体及融合基因改变.结论:亚砷酸钠可通过诱导细胞凋亡而用于CML加速期患者的临床治疗.