Combined therapy for treatment of acute leukemia and myelodisplastic syndrome

FIELD: medicine; oncology.

SUBSTANCE: invention can be used for treatment of an acute myelogenetic leukemia or myelodysplastic syndrome. For this purpose use a combination of preparations hemetuzumab ozohamicin, daunorubicin and cytarabinum in certain doses and regimens.

EFFECT: invention promotes effective treatment of the specified diseases due to synergistic effect at influence of these preparations on an organism.

2 cl, 2 ex

The technical field to which the invention relates.

Available methods of treatment and pharmaceutical combinations for the treatment of acute leukemia, particularly acute myelogenous leukemia and myelodysplastic syndrome. In the methods of treatment and pharmaceutical combinations used cytotoxic conjugate against CD33 in combination with at least one compound selected from the group consisting of anthracycline and similar pyrimidine or purine nucleoside, in particular gemtuzumab ozogamicin, daunorubicin and tsitarabina.

The prior art to which the invention relates.

Acute leukemia is usually a rapidly progressive leukemia, characterized by replacement of normal bone marrow blast cell clone resulting from malignant transformation of hematopoietic stem cells. There are two types of acute leukemia, acute lymphoblastic leukemia (ALL) and acute myeloblastic leukemia (AML). ALL is the most frequent malignant neoplasm in children, but also occurs in adolescents and has a second lower peak emergence of adults. AML, also known as acute myeloid leukemia and acute military leukemia, is a more frequent acute leukemia in adults, and its share is increasing with age, AML but also occurs in children For both types of acute leukemia, the main goal of treatment is to achieve complete remission with disappearance of abnormal clinical characteristics, returning to normal amounts of blood cells and normal hematopoesis in bone marrow blast cells <5%, the number of neutrophils >1000-1500, platelet counts >100000 and the disappearance of the leukaemic clone; however, the regimen of medicines for the treatment of ALL and AML varies. The Merck Manual, Sec. 11, Ch. 138 (17^thed. 1997); Museum, E., Cancer (2001) 92(5):1059-1073. The goal of initial therapy is the induction of remission. Treatment of AML differs from ALL mainly in the fact that patients with AML answer fewer drugs and have more frequent relapses.

Patients with AML who have achieved complete remission, live longer than patients who did not achieve this, and only patients who achieved complete remission, are potentially curable if complete remission is maintained for at least three years. Museum, E., Cancer(2001) 92(5): 1059, 1060. The degree of induction of remission in patients with AML ranges from 50 to 85%, and in patients older than 50 years and especially in those over 65 years are less likely to achieve remission. Long-term relapse-free period of life occurs in a smaller percentage of patients, 20-40%, and increases to 40-50% in the younger patients after treatment with bone marrow. Patients with secondary AML have a poor prognosis. The Merck Manual, Sec. 11, Ch. 138 (17^thed. 1997).

Treatment of AML is the problem of the ranks, because the normal precursor stem cells are sensitive to applied agents, and therapy aimed at myeloid leukemic clones, causing the destruction of part of a pool of normal stem cells. Induction of remission is usually possible with intensive chemotherapy. Complete remission, as installed, is achieved in younger patients up to 80% of cases and in approximately 50% of older patients (the majority among patients with AML), but patients after induction of severe neutropenia and the degree of remission in some degree depends on supportive care. The degree of remission is lower in patients with unfavorable prognostic factors, such as poor performance, AML secondary to myelodysplasia or antitumor agents, a high number of white blood cells, features of resistance to many drugs and adverse cytogenetics. Löwenberg, B., et al., N. Engl. J. Med. (1999) 341:1051-62; Correction. ibid.; 1484. The most unsatisfactory medical possibilities in the treatment of patients with AML over the age of 70 years. In these elderly patients with AML is difficult to achieve complete remission, but the improvement in their quality of life is the goal of treatment, which should achieve.

The established modes based on citarabinom, the analogue of pyrimidine nucleoside, with anthracyclines by daunorubicin. Löwenberg b, et al., N. Engl. J. Med. (1999) 341:1051-62; Correction. ibid.; 1484; Burnett, A.K. & Eden, O.B., Lancet (1997) 349:270-275; Hiddemann, W., et al., J. Clin. Oncol. (1999) 17:3569-76. The first successful modes included tioguanin, which is still used in some medical centers, although, according to most, it does not provide any additional benefits, and tioguanin was excluded from most of the protocols of induction. Alternatives to daunorubicin include idarubitsin and mitoxantrone. Löwenberg, B., et al., N. Engl. J. Med. (1999) 341:1051-62; Correction. ibid.; 1484. Etoposide was added to the protocols of induction citarabinom and daunorubicin with better results in younger patients.

The primary mode of induction for the treatment of AML includes the introduction of citarabinom by continuous intravenous (IV) infusion for 7 days with anthracyclines, such as daunorubicin or idarubitsin entered in the/within 3 days within a given period, usually within the first three days. The Merck Manual, Sec. 11, Ch. 138 (17^thed. 1997). This widely used mode of treatment of AML is known as mode 3+7 and gives a complete remission in 60-80% of cases. De Nully Brown, P., et al., Leukemia (1997) 11:37-41. Treatment usually leads to a significant mielosupression often for long periods before recovery of the bone marrow. Other side effects of these two drugs include chemical arachnoiditis, toxicity to the myocardium and neurotoxicity. the La remission mode of induction can be repeated usually a total of three times. Before repeating the mode of induction of doing analysis of bone marrow fourteen days after completion of the last mode of induction. If bone marrow is removed completely, i.e. there is a complete answer, the doctor will wait until then, until the number of peripheral blood cells will be restored, before the introduction of another mode of induction. If the analysis of the bone marrow still demonstrates the existence of a disease, i.e. there is a partial or minimal response, the mode of induction should be repeated without waiting for recovery of the amount of peripheral blood cells of the patient. The waiting period between modes of induction is, therefore, from twenty-eight to thirty-five days for patients with complete response and from fourteen to twenty one days for meets partially or minimally. For patients with recurrent AML standard induction therapy citarabinom and daunorubicin does not give a good degree of response, typically <40%, and the prognosis for such patients is unfavorable.

After remission to overcome the disease can be held the second mode of treatment using the same or other medicines known as firming therapy. However, the high percentage of patients suffering from recurrence even in groups with intensive postremission firming chemotherapy. De Nully Brown, P., et al., Leukemia (1997) 11:37-41.

APAR is installed trends are towards the use of more intensive modes of induction. The use of high doses of citarabinom in doses up to 3 g/m²every twelve hours for up to six days a week (with daunorubicin and etoposide)reportedly improves the duration of first remission and relapse-free period of life compared with standard doses of citarabinom. Bishop, J.F., et al., Blood (1996) 87:1710-1717. Equally important may be the timing cycles of induction: intensive distribution in time (when the second cycle was given 10 days after the first) improves disease-free period of life, despite the higher number of deaths associated with toxicity, in comparison with a standard interval of 14 days or more. Woods, W.G., et al., Blood (1996) 87:4979-4989.

Once induced remission, it is important additional treatment (postremission therapy to prevent relapse. Löwenberg, B., et al., N. Engl. J. Med. (1999) 341:1051-62; Correction. ibid.; 1484; Burnett, A.K. & Eden, O.B., Lancet (1997) 349:270-275; Hiddemann, W., et al., J. Clin. Oncol. (1999) 17:3569-76. Features include additional chemotherapy or allogeneic, or autologous bone marrow transplantation. Long-term relapse-free period of approximately 50% of patients is possible with the use of these options in patients with first remission. However, discussion is the choice of the used features. When the most successful chemotherapy regimens used high doses of citarabinom in t is an increase up to 4 courses and this, obviously, is comparable with bone marrow transplantation for survival. Mayer, R.J. et al., N. Engl. J. Med. (1994) 331:896-903; Cassileth, P.A., et al., N. Engl. J. Med. (1998) 339:1649-1656. Therefore, some supporters of the policy of intensive postremission therapy leave transplantation for relapse, especially in patients with favorable cytogenetics. Edenfield, W.J. & Gore, S.D., Semin. Oncol. (1999) 26:21-34.

Other medication used in the treatment of AML is gemtuzumab ozogamicin (Mylotarg®). Gemtuzumab ozogamicin was approved in may 2000 GV United States for the treatment of AML in patients with first relapse aged 60 years or older and were not considered candidates for other cytotoxic therapy. Gemtuzumab ozogamicin impose a two-hour I.V. infusion at a dose of 9 mg/m². The second dose can be entered through fourteen days. While many patients treated with gemtuzumab ozogamicin achieved complete remission, a significant number of patients had a delay in the recovery of platelets or incomplete recovery of platelets. Physician''s Desk Reference (56^thed. 2002). In patients who have undergone stem cell transplantation after treatment with gemtuzumab ozogamicin, there occlusal disease of the veins of the liver (VOD), which is potentially fatal. Tack, D.K. et al., Bone Marrow Transplantation (2001) 28(9):895-897. In July 2001, it was reported that u b is selected, receiving gemtuzumab ozogamicin, which did not stem-cell transplantation, developed increased by as much as 10% risk of developing significant hepatotoxicity and the possible morbidity and mortality, although most of these patients received gemtuzumab ozogamicin in not previously tested or combinations not specified in the instructions for admission to the scheme. Giles, F.J., et al., Cancer (2001) 92(2):406-413. As with the standard induction treatment citarabinom-daunorubicin, the degree of response of patients with AML relapse on treatment with gemtuzumab ozogamicin can be <40%.

Attempts were made to use combination therapy with the use of gemtuzumab ozogamicin with limited success. In one study, elderly patients not previously treated about AML, was introduced gemtuzumab ozogamicin by 2-hour I.V. infusion at a dose of 9 mg/m²on the 1st and 15th day MICE (mitoxantrone, citarabinom and etoposide), and they were introduced in the form of one or two courses for seven days after the evaluation of response to gemtuzumab ozogamicin (between 28 and 35 days after the last infusion). Significant not hematological side effects have included, among other things, VOD (6%), arrhythmia (6%) and infection (24%). At the end of a full programme of induction thirteen patients were in complete remission (38,2%) and 3 achieved complete remission with incomplete vosstanovlenie the platelets (8,8%) when the total degree of response 47%, without improvements compared to existing therapy in relation to AML. Amadori, S., et al., "Sequential Administration of Gemtuzumab Ozogamicin (GO) and Intensive Chemotherapy for Remission Induction in Previously Untreated Patients with AML over the Age of 60: Interim Results of the EORTC Leukemia Group AML-15A Phase II Trial", Blood (2001) 98:587a.

In another study of patients with poor prognosis AML (age >70 years, myelodysplasia, leukemia, developed after exposure to toxic agents) were treated with either Protocol, referred to as "AML 9503", in which the patient received two "pulse" of chemotherapy, each consisted of 2 g/m²tsitarabina (high dose tsitarabina), injected at time = 0 and time = 12 hours, and mitoxantrone in the amount of 35 mg/m²immediately after the second dose tsitarabina, and the second "pulse" was given after 96 hours, or they were treated according to Protocol, referred to as "AML 9798", according to which the patient received two "pulse" of chemotherapy, each consisted of 2 g/m²tsitarabina entered at time = 0 and time = 12 hours, and mitoxantrone in the amount of 35 mg/m²immediately after the second dose tsitarabina, and the second "pulse" was given after 96 hours, followed by the introduction of amifostine. The degree of complete remission for AML 9503 was 30%, and for AML 9798 40%. When chemotherapy was changed by adding a single dose of gemtuzumab ozogamicin in the amount of 9 mg/m²three days before the first pulse of chemotherapy, two of whom, amireh treated thus patients with resistant AML was achieved complete remission. Preisler, H.,D., et al., "Synergistic Antileukemia Effects of Mylotarg and Chemotheraphy in AML", Blood (2001) 98:193b.

In the performed study, patients aged<60 years received H-DAT mode 3+10 (daunorubicin 45 mg/m²1, 3, 5 day; cytarabine 400 mg/m²bd 1-10 days; tioguanin 100 mg/m²bd 1-10 days) with gemtuzumab ozogamicin (3 or 6 mg/m²obtained in the form of a 2-hour infusion on day 1). The second course was H-DAT 3+8 with the same dose of gemtuzumab ozogamicin as in course 1. Despite the fact that both doses of 3 mg/m²and 6 mg/m²gemtuzumab ozogamicin were valid in these two modes, there was an increased hepatotoxicity when gemtuzumab ozogamicin was given at a dose of 6 mg/m²in the first year, and after that it was decided to use 3 mg/m²gemtuzumab ozogamicin 1 and 2 courses. Kell, J.W, et al., "Effects of Mylotarg™ (Gemtuzumab Ozogamicin, GO) in Combination with Standard Induction Chemotherapy in the Treatment of Acute Myeloid Leukaemia (AML): A Feasibility Study", Blood (2001) 98:123a-124a.

In an additional study, patients aged<60 years received H-DAT mode 3+10 (daunorubicin 50 mg/m²daily by slow intravenous introduction on 1, 3, 5 days; cytarabine 200 mg/m²/introduction bd 1-10 days; tioguanin 100 mg/m²bd oral, 1-10 days) or S-DAT mode 3+10 (daunorubicin 50 mg/m²daily by slow intravenous introduction on 1, 3, 5 days; cytarabine 100 mg/m²/introduction bd 1-10 days; tioguanin 100 mg/m²bd oral, 110 days) with 3 or 6 mg/m ²gemtuzumab ozogamicin as induction therapy. The second course H-DAT mode 3+8 (daunorubicin 50 mg/m²daily by slow intravenous introduction on 1, 3, 5 days; cytarabine 200 mg/m²/introduction bd 1-8 days; tioguanin 100 mg/m²bd oral, 1-10 days) or S-DAT mode 3+8 (daunorubicin 50 mg/m²daily by slow intravenous introduction on 1, 3, 5 days; cytarabine 100 mg/m²/introduction bd 1-8 days; tioguanin 100 mg/m²bd oral, 1-10 days) was performed with gemtuzumab ozogamicin in the amount of 3 mg/m²or without it. Firming therapy consisted of chemotherapy MACE (MACE: amsacrine 100 mg/m²daily by a one-hour perfusion (5% dextrose in 1-5 days); cytarabine 200 mg/m²by daily continuous I.V. infusion for 1-5 days; etoposide 100 mg/m²daily by a one-hour I.V. infusion on 1-5 days) with gemtuzumab ozogamicin in the amount of 3 mg/m²or without it. Patients who received gemtuzumab ozogamicin in courses 1 and 2 were characterized by delayed recovery of hematological parameters and VOD, one of them died. The dose of 6 mg/m²gemtuzumab ozogamicin also been associated with increased hepatotoxicity. It was concluded that may be given 3 mg/m²gemtuzumab ozogamicin H-DAT in course 1 and course 3 with MACE, but that the appointment of two courses gemtuzumab ozogamicin in the induction and the and increasing doses of gemtuzumab ozogamicin to 6 mg/m ²associated with increased toxicity and is not recommended. Burnett, A.K. and Kell, J., "The Feasibility of Combining Immunoconjugate and Chemotherapy in AML", Hematology J. (June 2002) Vol.3, supp.1, p.156.

In another preliminary study to evaluate the safety and efficacy of gemtuzumab ozogamicin gave AML patients>60 years de novo and c patients with relapse/refractory treatment in combination therapy with citarabinom. Six patients were treated citarabinom by continuous infusion of 100 mg/m²/day 1 to 7 days and gemtuzumab ozogamicin in the amount of 6 mg/m²1 and 15 days. Despite the fact that the combination was well tolerated, four patients died. To reduce the duration of myelosuppression after induction therapy gemtuzumab ozogamicin was administered at 1 and 8 days in the amount of 6 mg/m²1 day and 4 mg/m²on the 8th day. Of the seven patients who were treated, three achieved complete remission. Durrant, S., et al., Proc. Amer. Soc. Clin. Oncol. (2002) 21:271a.

To assess the safety and efficacy of gemtuzumab ozogamicin as part of combination therapy for AML in the United States of America designed a phase I/II study of the combination of gemtuzumab ozogamicin with citarabinom and daunorubicin. Part of a phase I study began in October 2000, and a preliminary report was published on the 43rd Congress of the American society of Hematology in electronic form 6 November 2001, and p is a printed form 7 November 2001 DeAngelo, D., et al., "Preliminary Report of the Safety and Efficacy of Gemtuzumab Ozogamicin (Mylotarg®) Given in Combination with Cytarabine and Daunorubicin in Patients with Acute Myeloid Leukemia", Blood (2001) 98:199(b). This message explains the treatment of three patients - one with de novo AML and two AML with recurrent/resistant to treatment, citarabinom in the amount of 100 mg/m²/day by continuous infusion of 1 to 7 days, daunorubicin in the amount of 45 mg/m²1 to 3 days and gemtuzumab ozogamicin in the amount of 6 mg/m²on the 4th day (dosage group 1). The combination was well tolerated, was not observed DLT (dose limiting toxicity (DLT), and two patients achieved remission. Three patients with AML with recurrent/resistant to treatment were then included in the group with the next dose, in which the dose of gemtuzumab ozogamicin was increased to 9 mg/m²(dosage group 2), the combination was well tolerated, but all three patients did not respond to treatment. Six additional patients, three with de novo AML and three with AML with recurrent/resistant to treatment, were included in the group with dose level of 9 mg/m². Treatment again was well tolerated, and no DLT was observed. However, there were 2 episode 3 the degree of increase in ALT/AST, not related to the medication, and 2 episode 4 the extent not related to the medication shortness of breath. All 3 patients with de novo AML achieved remission, and they recovered as ANC > 1500/μl and platelets > 100000/µl at 26, 28 and 36 days, respectively the military. Patients were then included in the group with the next dose, in which the dose tsitarabina was increased to 200 mg/m²/day dosage group 3). Infusion of combination therapy was well tolerated, but the DLT was observed in four out of six of the patients included in this group, and one patient with untreatable AML developed hepatic VOD soon after completion of induction therapy, and death on the 28th day. Another patient with de novo AML died from cardiac arrest on day 24 and also had a reversible increase in ALT of 3 degrees. In light of the above results concluded that six additional patients should be included in group 1 for expansion of safety data and, if it is determined that the combination of citarabinom 100 mg/m²/day of daunorubicin 45 mg/m²and gemtuzumab ozogamicin 6 mg/m²good portable in the extended group, you should begin the part of the phase II study, and it should be included approximately 45 patients with de novo AML. DeAngelo, D., et al., above. The effectiveness of combination citarabinom 100 mg/m²/day of daunorubicin 45 mg/m²and gemtuzumab ozogamicin 6 mg/m²or the effectiveness of this combination in comparison with the effectiveness of standard chemotherapy AML it was impossible to determine because of the limited number of patients included in part of a phase I study.

MIA is toplantisi syndrome (MDS) is a group of syndromes (prelacy, refractory anemia, Ph-negative chronic miliitary leukemia, chronic myelomonocytic leukemia, idiopathic myeloid metaplasia), usually detected in patients with >50 years of age. His percentage is not known, but it is increased, probably partly because of the increasing proportion of older people in the population and growth of leukemia associated with treatment. Its development may be associated with exposure to benzene and radiation. In placozoa phase of some of the secondary leukemias (for example, after exposure to toxic agents) may be modified and defective products of the cells with the diagnostic characteristics of myelodysplasia. The Merck Manual, Sec. 11, Ch. 138 (17^thed. 1999).

MDS is characterized by a clonal proliferation of hematopoietic cells, including erythroid, myeloid and megakaryocyte form. Bone marrow is normal or excess cells, and inefficient hematopoi causes various cytopenia, with the most frequent anemia. Impaired production of cells is also associated with abnormal cell morphology in the bone marrow and blood. Hematomas may occur outside the bone marrow, leading to hepatomegaly and splenomegaly. Sometimes the diagnosis is myelofibrosis or it may develop in the process of developing MDS. The MDS clone is unstable and has a tendency to progress to AML. Forecast DL the patient with MDS is highly dependent on the FAB classification and any related disease. Patients with untreatable anemia or untreatable anemia with sideroblasts disease will be less likely to progress to more aggressive forms, and they can die from not associated with disease of reasons. The Merck Manual, Sec. 11, Ch. 138 (17^thed. 1999).

There is no established treatments for MDS. Therapy is supportive with RBC transfusions, platelet transfusions from bleeding and antibiotic therapy against infections. In some patients, therapy with cytokines (EPO to maintain the required centres of erythropoiesis, granulocyte-colony stimulating factor for the management of severe symptomatic muscle problems and, when available, thrombopoetin for severe thrombocytopenia) can serve as an important support hematopoiesis. Allogeneic bone marrow transplantation is not recommended in patients >50 years. Colony-stimulating factors (e.g., colony stimulating factor granulocyte, colony-stimulating factor granulocyte-macrophage) increase the number of neutrophils, and erythropoietin increases the production of RBC in 20-25% of cases, but the advantages in survival has not been demonstrated. The MDS response to chemotherapy AML is similar to that for AML with regard to age and karyotype. The Merck Manual, Sec. 11, Ch. 138 (17^thed. 1997).

Thus, there is a need for an improved treatment of patients with acute leukemia or myelodysplastic syndrome which will give a higher degree of complete remission, thereby increasing the prospects for survival of such patients. Unexpectedly, it was found that combination therapy using cytotoxic conjugate against CD33 in combination with anthracyclines and similar pyrimidine or purine nucleoside, in particular gemtuzumab ozogamicin, daunorubicin and cytarabine, respectively, significantly improves the efficiency compared to combined therapy with daunorubicin and citarabinom one or gemtuzumab ozogamicin.

A brief statement of the substance of the invention

In the present invention proposes a method of treatment of acute leukemia or MDS, which includes an introduction to the needy in the specified treatment to the patient a cytotoxic conjugate against CD33 in combination with at least one compound selected from the group consisting of anthracycline and similar pyrimidine or purine nucleoside, in an amount effective to alleviate symptoms of the acute myelogenous leukemia or myelodysplastic syndrome. Being treated with acute leukemia preferably represents AML.

In the preferred implementation of the cytotoxin in the cytotoxic conjugate against CD33 selected from the group consisting of calicheamicin and espiramicina.

In another preference is sustained fashion the implementation of anthracycline selected from the group consisting of doxorubicin, daunorubicin, idarubitsina, aclarubicin, zorubicin, mitoxantrone, epirubicin, karubitina, nogalamycin, menogaril, picarubicin and valrubicin.

In another preferred implementation, the analogue of pyrimidine or purine nucleoside selected from the group consisting of citarabinom, gemcitabine, trifluridine, ancitabine, enocitabine, azacitidine, doxifluridine, pentostatin, broxuridine, involving capecitabine, cladribine, decitabine floxuridine, fludarabine, gogarten, puromycin, tegafur, tesofensine and tubercidin.

The present invention further provides a method of treating a patient suffering from acute leukemia or MDS, which includes the introduction of the patient: (a) gemtuzumab ozogamicin in the amount of about 3 mg/m²approximately 9 mg/m²per day; (b) daunorubicin, preferably of daunorubicin hydrochloride in the amount of about 45 mg/m²approximately 60 mg/m²per day; and (C) tsitarabina in the amount of approximately 100 mg/m²approximately 200 mg/m²a day.

In the preferred implementation of gemtuzumab ozogamicin is in the amount of about 6 mg/m²a day.

In another preferred implementation of daunorubicin, preferably daunorubicin hydrochloride, is at stake is the amount of 45 mg/m ²a day.

In another preferred implementation of cytarabine is in the amount of 100 mg/m²a day.

The present invention further provides a method of treatment of acute leukemia or syndrome MDS, which includes an introduction to the needy in this treatment the patient (a) gemtuzumab ozogamicin in the amount of about 3 mg/m²up to 9 mg/m²within one day; (b) daunorubicin in the amount of about 45 mg/m²up to 60 mg/m²a day for three days; and (C) tsitarabina in the amount of approximately 100 mg/m²up to 200 mg/m²a day for at least seven days.

In the preferred implementation of daunorubicin is administered in the first three days of the introduction of citarabinom, preferably in the amount of 45 mg/m²a day.

In another preferred implementation of cytarabine is administered for ten days, more preferably within seven days and preferably in quantities of 100 mg/m²a day.

In another preferred implementation of gemtuzumab ozogamicin administered to the patient on the fourth day the patient tsitarabina, preferably in amounts of 6 mg/m².

In another preferred implementation of cytarabine is administered via continuous infusion, daunorubicin, preferably daunorubicin hydrochloride is administered via an intravenous b is LESNOGO introduction and gemtuzumab ozogamicin administered by 2-hour infusion.

The present invention further provides a pharmaceutical combination to enhance the induction of remission in a patient suffering from acute leukemia or MDS, which includes: (a) the cytotoxic conjugate against CD33, where the cytotoxin in the cytotoxic conjugate against CD33 selected from the group consisting of calicheamicin and espiramicina; (b) anthracycline selected from the group consisting of doxorubicin, daunorubicin, idarubitsina, aclarubicin, zorubicin, mitoxantrone, epirubicin, karubitina, nogalamycin, menogaril, picarubicin and valrubicin; and (c) the analogue of the pyrimidine or purine nucleoside selected from the group consisting of tsitarabina, gemcitabine, trifluridine, ancitabine, enocitabine, azacitidine, doxifluridine, pentostatin, broxuridine, involving capecitabine, cladribine, decitabine floxuridine, fludarabine, gogarten, puromycin, tegafur, tesofensine and tubercidin.

The present invention further provides a pharmaceutical combination to enhance the induction of remission in a patient suffering from acute leukemia or MDS containing gemtuzumab ozogamicin in the amount of about 3 mg/m²approximately 9 mg/m²per day, preferably 6 mg/m²on the day, daunorubicin, preferably of daunorubicin hydrochloride in the amount of about 45 mg/m approximately 60 mg/m²per day, preferably 45 mg/m²on the day, and cytarabine in the amount of approximately 100 mg/m²approximately 200 mg/m²per day, preferably 100 mg/m²a day.

The present invention further provides a method of treatment of acute leukemia or MDS, including

(a) conduct the first course of treatment a patient in need of treatment comprising (i) introduction cytotoxic conjugate against CD33 in one day, where the cytotoxin in the cytotoxic conjugate against CD33 selected from the group consisting of calicheamicin and espiramicina; (ii) introduction of anthracycline selected from the group consisting of doxorubicin, daunorubicin, idarubitsina, aclarubicin, zorubicin, mitoxantrone, epirubicin, karubitina, nogalamycin, menogaril, picarubicin and valrubicin up to three days; and (iii) the introduction of analog pyrimidine or purine nucleoside selected from the group consisting of citarabinom, gemcitabine, trifluridine, ancitabine, enocitabine, azacitidine, doxifluridine, pentostatin, broxuridine, involving capecitabine, cladribine, decitabine floxuridine, fludarabine, gogarten, puromycin, tegafur, tesofensine and tubercidin lasting up to ten days;

(b) the second course of treatment to a patient in need Leche is NII, includes (i) the introduction of a cytotoxic conjugate against CD33 in one day, where the cytotoxin in the cytotoxic conjugate against CD33 selected from the group consisting of calicheamicin and espiramicina; (ii) introduction of anthracycline selected from the group consisting of doxorubicin, daunorubicin, idarubitsina, aclarubicin, zorubicin, mitoxantrone, epirubicin, karubitina, nogalamycin, menogaril, picarubicin and valrubicin up to three days; and (iii) the introduction of analog pyrimidine or purine nucleoside selected from the group consisting of citarabinom, gemcitabine, trifluridine, ancitabine, enocitabine, azacitidine, doxifluridine, pentostatin, broxuridine, involving capecitabine, cladribine, decitabine floxuridine, fludarabine, gogarten, puromycin, tegafur, tesofensine and tubercidin lasting up to ten days; and

(c) the third course of treatment to a patient in need of treatment comprising (i) introduction of anthracycline selected from the group consisting of doxorubicin, daunorubicin, idarubitsina, aclarubicin, zorubicin, mitoxantrone, epirubicin, karubitina, nogalamycin, menogaril, picarubicin and valrubicin up to three days; and (ii) the introduction of the analogue of the pyrimidine or purine nucleoside selected from the group consisting of citarabina gametab is on, trifluridine, ancitabine, enocitabine, azacitidine, doxifluridine, pentostatin, broxuridine, involving capecitabine, cladribine, decitabine floxuridine, fludarabine, gogarten, puromycin, tegafur, tesofensine and tubercidin lasting up to ten days.

The present invention further provides a method of treatment of acute leukemia or MDS, including

(a) conduct the first course of treatment a patient in need of treatment comprising (i) gemtuzumab ozogamicin in the amount of about 3 mg/m²up to 9 mg/m²preferably 6 mg/m²a day for one day; (ii) daunorubicin in the amount of about 45 mg/m²up to 60 mg/m²preferably 45 mg/m²duration per day up to three days; and (iii) cytarabine in the amount of approximately 100 mg/m²up to 200 mg/m²preferably 100 mg/m²duration per day up to ten days;

(b) the second course of treatment to a patient in need of treatment comprising (i) gemtuzumab ozogamicin in the amount of about 3 mg/m²approximately 9 mg/m²preferably 6 mg/m²a day for one day; (ii) daunorubicin in the amount of about 45 mg/m²approximately 60 mg/m²preferably 45 mg/m²duration per day up to three days; and (ii) cytarabine in the amount of approximately 100 mg/m ²approximately 200 mg/m²preferably 100 mg/m²duration per day up to ten days; and

(c) the third course of treatment to a patient in need of treatment comprising (i) daunorubicin in the amount of about 45 mg/m²approximately 60 mg/m²preferably 45 mg/m²duration per day up to three days; and (ii) cytarabine in the amount of approximately 100 mg/m²approximately 200 mg/m²preferably 100 mg/m²duration per day up to ten days.

Detailed description of the invention

The present invention offers a favorable pharmaceutical combinations and methods of treatment of acute leukemia such as AML and myelodysplastic syndrome (MDS), which is used cytotoxic conjugate against CD33, anthracyclin and similar pyrimidine or purine nucleoside. Described herein is a method of treatment and pharmaceutical combinations provide greater complete remission and improved quality of life in these patients compared to the standard scheme 3+7 daunorubicin and tsitarabina. It was unexpectedly found that the preferred implementation using gemtuzumab ozogamicin, daunorubicin and tsitarabina provides a greater degree of complete remission compared to the standard scheme 3+7 daunorubicin and tsitarabina.

One song used in the present invention, is a cytotoxic conjugate against CD33, in which the antibody against CD33 conjugated with a cytotoxic antitumor agent or an antibiotic, such as calicheamicin, selected from among the fermentation of the bacterium Micromonospora echinospora ssp.calichensis, or spiramycin. Calicheamicin described in U.S. patent No. 4970198; 5037651 and 5079233. Espiramicina described in U.S. patent No. 4675187; 4539203; 4554162 and 4837206. Or antibody-based test part of the conjugate specifically binds to the CD33 antigen, dependent on sialic acid protein adhesion detected on the surface of leukemic blasts and immature normal cells of myelomonocytic series, but not on normal hematopoietic stem cells, and acts as a guide unit for delivering a cytotoxic agent to the target cells. The antibody is associated with calicheamicin or espiramicina. When using N-acetyl-gamma-cal is helicin, it is preferable to attach the antibody via a bifunctional linker. Such conjugates and methods for their preparation are described in U.S. patent No. 5733001; 5739116; 5767285; 5877296; 5606040; 5712374 and 5714586, which is incorporated into this description by reference in its entirety.

The preferred form of the cytotoxic conjugate against CD33 for use in the present invention is gemtuzumab ozogamicin, chemotherapeutic agent, composed of recombinant closer to human IgG4, Kappa antibody conjugated with calicheamicin. Gemtuzumab ozogamicin commercially as Mylotarg® (Wyeth Pharmaceuticals, Philadelphia, PA). Or antibody-based test part gemtuzumab ozogamicin specific binds to the CD33 antigen. Gemtuzumab ozogamicin contains amino acid sequences, of which approximately 98.3% of originate from man. Constant region and area frames contain sequences, whereas the region, defining complementarity come from mouse antibodies (p67.6), which binds to CD33. This antibody is connected with N-acetyl-gamma-calicheamicin via a bifunctional linker. Gemtuzumab ozogamicin contains approximately 50% of antibody loaded 4-6 mol calicheamicin per mole of antibody. The remaining 50% of the antibodies are not connected with the derived calicheamicin. Gemtuzumab about gamitin has a molecular weight of from 151 to 153 kDa. Gemtuzumab ozogamicin and the methods of its production are described in U.S. patent No. 5733001; 5739116; 5767285; 5877296; 5606040; 5712374 and 5714586, which is incorporated herein by reference in its entirety. When used as the sole therapeutic agent for the treatment of AML recommended dose gemtuzumab ozogamicin is 9 mg/m²with the introduction in the form of a two-hour intravenous infusion. The recommended course of treatment for one gemtuzumab ozogamicin amounted to a total of two doses with an interval of fourteen days between doses. In combination therapy according to the invention gemtuzumab ozogamicin injected in amounts ranging from about 3 mg/m²up to 9 mg/m²a day.

In U.S. patent No. 5773001 in No. 62, lines 37-46, and example 112 described doses of conjugates calicheamicin, including gemtuzumab ozogamicin, based on equivalents calicheamicin, ie 10 µg calicheamicin/m²protein compared with the clinical description of the dose based on mg/m²the surface of the body. When applying calicheamicin on antibody receive about 27 μg calicheamicin/mg protein. The dose of 9 mg/m²gemtuzumab ozogamicin equivalent to 243 µg calicheamicin/m²the protein. The dose of 6 mg/m²gemtuzumab ozogamicin equivalent to 162 μg calicheamicin/m²the protein. Dose 3 mg/m²gemtuzumab ozogamicin equivalent to 81 mg calicheamicin the on/m ²protein.

Another composition used in the present invention, is anthracyclin, anticancer agent, consisting of 3 parts: painted aglycone, amino sugar and a side chain. The anthracyclines include doxorubicin, daunorubicin, idarubitsin, aclarubicin, zorubicin, mitoxantrone, epirubicin, karubitsin, nogalamycin, menogaril, picarubicin and valrubicin. Cm. directory Merck (13^thed. 2001).

The preferred anthracycline for use in the present invention is daunorubicin. Daunorubicin, also known as daunomycin, is an anthracycline cytotoxic antibiotic rhodomycinone group, obtained from Streptomyces peucetius, which is used for the treatment of acute leukemia. Stedman''s Medical Dictionary (27th^thed. 2002). Daunorubicin contains 4-cycles of anthracycline part, joined by glycosidic bonds to daunosamine, the amino sugar. Daunorubicin may also be isolated from Streptomyces coeruleorubidus and has the following chemical name: (8S-CIS)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-(alpha)-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-naphthacenedione hydrochloride. Daunorubicin is usually administered in the form of the hydrochloride, but doses are expressed in terms of the basis.

The preferred form of daunorubicin used in the present invention, the C is of daunorubicin hydrochloride, cleaners containing hydrochloride salt of daunorubicin. Of daunorubicin hydrochloride is commercially available as Cerubidine® (Bedford Laboratories, Bedford Ohio). It can be described by the chemical name is (1S,3S)-3-acetyl-1,2,3,4,6,11-hexahydro-3,5,12-trihydroxy-10-methoxy-6,11-dioxo-1-naphthacene 3-amino-2,3,6-trideoxy-(alpha)-L-lyxo-hexopyranoside hydrochloride. Its molecular formula is a C₂₇H₂₉NO₁₀·HCl molecular weight 563,99. In the treatment nelimfocitarnaya of acute leukemia in adults, such as AML and ALL, daunorubicin hydrochloride, used as a single agent, caused a complete remission rate of 40 to 50%, and in combination with citarabinom caused complete remission rate from 53 to 65%. Physician''s Desk Reference (56^thed. 2002). Usually daunorubicin is administered daily for three days from 30 to 45 mg/m²by intravenous infusion over two to three days. When modes with high dose daunorubicin is administered daily in a quantity of 50 mg/m²within three days.

Daunorubicin is also available in the form of daunorubicin citrate in liposomes for injection as DaunoXome® (Gilead Sciences, Inc., Foster City, CA). DaunoXome® contains an aqueous solution of citrate salt of daunorubicin encapsulated in lipid vesicles (liposomes)composed of a lipid bilayer of distearoylphosphatidylcholine and Hollister is on (molar ratio 2:1), with an average diameter of approximately 45 nm. The ratio of the mass of the lipid and the drug is 18.7:1 (total lipid: the basis of daunorubicin), the equivalent molar ratio of 10:5:1 distearoylphosphatidylcholine : cholesterol : daunorubicin. Each bottle DaunoXome® contains daunorubicin citrate equivalent to 50 mg base daunorubicin encapsulated in liposomes consisting of 704 mg distearoylphosphatidylcholine and 168 mg of cholesterol. Encapsulates daunorubicin liposomes dispersed in an aqueous medium containing 2125 mg sucrose, 94 mg glycine, 7 mg of the dihydrate of calcium chloride in a total volume of 25 ml/vial. the pH of the dispersion is from 4.9 to 6.0. DaunoXome® administered intravenously over a 60 minute period at a dose of 40 mg/m²in doses, re-entered every two weeks.

The third composition used in the present invention, is the analogue of pyrimidine nucleoside or analogue of purine nucleoside. Typical representatives of such nucleoside analogues are cytarabine, gemcitabine, trifluridine, ancitabine, enocitabine, azacytidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabine, floxuridine, fludarabine, gogarten, puromycin, tegafur, tianfuan and tubercidin. Cm. directory Merck (13^thed. 2001).

The preferred analogue of pyrimidine nucleotide used the m in the present invention, is cytarabine, also known as arabinosylcytosine (aC, araC), arabinocytidine or arabinofuranosylcytosine. Chemically cytarabine is a 4-amino-1-(beta)-D-arabinofuranosyl-2(1H)-pyrimidinone, also known as citizenoriented (C₉H₁₃N₃O₅molecular weight 243,22). Cytarabine is specific in relation to the phase of the cell cycle antineoplastics agent that affects cells only during S-phase of cell division. It is a compound of arabinose and cytosine, which inhibits the biosynthesis of DNA and is used as a chemotherapeutic agent because of its antiviral and inhibiting tumor growth properties. Usually cytarabine is administered in the amount of 100-200 mg/m²daily for five to ten days by continuous intravenous infusion, usually within seven days. Cytarabine can be entered in the quantity of 100 mg/m²the surface of the body twice a day with rapid intravenous injection. However, cytarabine, you can enter up to 3 g/m²in day. When modes with high dose cytarabine is administered in doses up to 3 g/m²by intravenous infusion every 12 hours for up to six days.

Cytarabine has also sold as cytarabine liposomes for injection as DEPOCYT® (Chiron Corporation, Emeryville, CA). DepoCt® is a sterile, suitable for injection suspension of antimetabolite tsitarabina encapsulated in mnogosputnikovye particle-based lipids. Each vial contains 50 mg of citarabinom. Cytarabine, the active ingredient is at a concentration of 10 mg/ml and encapsulated in the particles. Inactive ingredients in the approximate their respective concentrations are cholesterol, 4,1 mg/ml; triolein, 1.2 mg/ml; dioleoylphosphatidylcholine (DOPC), 5,7 mg/ml; and dipalmitoylphosphatidylcholine (DPPG), 1.0 mg/ml. pH is from 5.5 to 8.5. DepoCyt® injected intrathecally.

In the present invention has several ways of treatment of acute leukemia or MDS. In the same way the patient is administered a cytotoxic conjugate against CD33 in combination with at least one compound selected from the group consisting of anthracycline and similar pyrimidine or purine nucleoside, in an amount effective to alleviate the symptoms of acute leukemia such as AML or MDS. Preferably, the cytotoxin in the cytotoxic conjugate against CD33 was calicheamicin or espiramicina. Anthracyclin preferably selected from the group consisting of doxorubicin, daunorubicin, idarubitsina, aclarubicin, zorubicin, mitoxantrone, epirubicin, karubitina, nogalamycin, menogaril, picarubicin and valrubicin is on. The analogue of the pyrimidine or purine nucleoside preferably selected from the group consisting of tsitarabina, gemcitabine, trifluridine, ancitabine, enocitabine, azacitidine, doxifluridine, pentostatin, broxuridine, involving capecitabine, cladribine, decitabine floxuridine, fludarabine, gogarten, puromycin, tegafur, tesofensine and tubercidin. Most preferably, the cytotoxic agent conjugate against CD33 was calicheamicin, anthracyclines was daunorubicin or daunorubicin hydrochloride, and the analogue of pyrimidine or purine nucleoside was cytarabine.

In another method of treating a patient with acute leukemia or MDS enter gemtuzumab ozogamicin in the amount of about 3 mg/m²up to 9 mg/m²per day; daunorubicin, preferably of daunorubicin hydrochloride in the amount of about 45 mg/m²up to 60 mg/m²in a day and cytarabine in the amount of approximately 100 mg/m²up to 200 mg/m²in day. Preferably gemtuzumab ozogamicin enter in the amount of about 6 mg/m²in day. Daunorubicin, preferably of daunorubicin hydrochloride, is preferably introduced in a number of 45 mg/m²in day. Cytarabine is preferably introduced in an amount of 100 mg/m²a day.

In another method of treating a patient with acute leukemia or MDS enter gemtuzumab in the amount of about 3 mg/m ²up to 9 mg/m²within one day; daunorubicin in the amount of about 45 mg/m²up to 60 mg/m²a day for three days and cytarabine in the amount of approximately 100 mg/m²up to 200 mg/m²a day for at least seven days. Preferably daunorubicin is administered in the first three days of the introduction of citarabinom and is preferably introduced in an amount of 45 mg/m²in day. Cytarabine is preferably introduced within ten days, more preferably within seven days and preferably administered in amounts of 100 mg/m²in day. Gemtuzumab ozogamicin preferably administered to the patient on the fourth day the patient tsitarabina and is preferably introduced in an amount of 6 mg/m². In the preferred implementation of cytarabine is administered by continuous infusion, daunorubicin, preferably of daunorubicin hydrochloride administered as an intravenous bolus injection, and gemtuzumab ozogamicin injected through a 2-hour infusion.

The present invention also provides pharmaceutical combinations for enhanced induction of remission in a patient with acute leukemia or MDS. One such pharmaceutical combination for enhanced induction of remission in a patient with acute leukemia or MDS includes cytotoxic conjugate against CD33, anthracyclin and pyrimidine analogue or PUR is the new nuke. The cytotoxin in the cytotoxic conjugate against CD33 may be selected from the group consisting of calicheamicin and espiramicina. Anthracyclin can be selected from the group consisting of doxorubicin, daunorubicin, idarubitsina, aclarubicin, zorubicin, mitoxantrone, epirubicin, karubitina, nogalamycin, menogaril, picarubicin and valrubicin. The analogue of the pyrimidine or purine nucleoside can be selected from the group consisting of citarabinom, gemcitabine, trifluridine, ancitabine, enocitabine, azacitidine, doxifluridine, pentostatin, broxuridine, involving capecitabine, cladribine, decitabine floxuridine, fludarabine, gogarten, puromycin, tegafur, tesofensine and tubercidin.

Other pharmaceutical combination includes gemtuzumab ozogamicin in the amount of about 3 mg/m²up to 9 mg/m²per day, preferably 6 mg/m²on the day, daunorubicin, preferably of daunorubicin hydrochloride in the amount of about 45 mg/m²up to 60 mg/m²per day, preferably 45 mg/m²on the day, and cytarabine in the amount of approximately 100 mg/m²up to 200 mg/m²per day, preferably 100 mg/m²a day.

The nature of acute leukemia and myelodysplastic syndrome requires the introduction of intensive chemotherapy for induction of remission in patients with data ill the deposits. In one implementation of the present invention a single course of combination therapy involves injecting the patient a therapeutically effective amount of a cytotoxic conjugate against CD33 together with one or more chemotherapeutic agents, such as anthracycline and similar pyrimidine or purine nucleoside. The present invention also provides a treatment regime, which used multiple courses of combination therapy, which include cytotoxic conjugate against CD33 and other chemotherapeutic agents. These modes of treatment can be applied at least two courses from up to five courses of treatment, depending on the infusion, the severity of the disease and the patient.

In another method of treatment according to the invention a patient with acute leukemia or MDS subjected to three courses of therapy. In the first course of therapy, the patient is administered a cytotoxic conjugate against CD33 in one day; anthracyclin for a period of three days; and the analogue of the pyrimidine or purine nucleoside over a period of up to ten days. The cytotoxin in the cytotoxic conjugate against CD33 may be selected from the group consisting of calicheamicin and espiramicina. Anthracyclin can be selected from the group consisting of doxorubicin, daunorubicin, ID is rubicin, aclarubicin, zorubicin, mitoxantrone, epirubicin, karubitina, nogalamycin, menogaril, picarubicin and valrubicin. The analogue of the pyrimidine or purine nucleoside can be selected from the group consisting of citarabinom, gemcitabine, trifluridine, ancitabine, enocitabine, azacitidine, doxifluridine, pentostatin, broxuridine, involving capecitabine, cladribine, decitabine floxuridine, fludarabine, gogarten, puromycin, tegafur, tesofensine and tubercidin. The first course of therapy is repeated as the second therapy, wherein the patient is administered a cytotoxic conjugate against CD33 in one day, anthracyclin for a period of three days and the analogue of the pyrimidine or purine nucleoside over a period of up to ten days. The patient may be subjected to a third course of treatment, which involves injecting the patient anthracycline selected from the group consisting of doxorubicin, daunorubicin, idarubitsina, aclarubicin, zorubicin, mitoxantrone, epirubicin, karubitina, nogalamycin, menogaril, picarubicin and valrubicin for a period of three days, and the analogue of the pyrimidine or purine nucleoside selected from the group consisting of citarabinom, gemcitabine, trifluridine, ancitabine, enocitabine, azacitidine, doxifluridine, pentostatin, broxuridine, ka is decitabine, cladribine, decitabine floxuridine, fludarabine, gogarten, puromycin, tegafur, tesofensine and tubercidin over a period of up to ten days.

In another method of treatment of acute leukemia or MDS patients are the first course of therapy, including gemtuzumab ozogamicin in the amount of about 3 mg/m²up to 9 mg/m²preferably 6 mg/m²within one day; daunorubicin in the amount of about 45 mg/m²up to 60 mg/m²preferably 45 mg/m², a day for a period of three days; and cytarabine in the amount of approximately 100 mg/m²up to 200 mg/m²preferably 100 mg/m², a day for a period of up to ten days. The patient is subjected to a second course of therapy, including gemtuzumab ozogamicin in the amount of about 3 mg/m²up to 9 mg/m²preferably 6 mg/m²within one day; daunorubicin in the amount of about 45 mg/m²up to 60 mg/m²preferably 45 mg/m², a day for a period of three days; and cytarabine in the amount of approximately 100 mg/m²up to 200 mg/m²preferably 100 mg/m², a day for a period of up to ten days. The patient may be subjected to a third course of therapy, including daunorubicin in the amount of about 45 mg/m 2up to 60 mg/m²preferably 45 mg/m², a day for a period of three days; and cytarabine in the amount of approximately 100 mg/m²up to 200 mg/m²preferably 100 mg/m², a day for a period of up to ten days.

Amazing and unexpected disclosed here, the result is the ability of the cytotoxic conjugate against CD33, anthracycline and similar pyrimidine or purine nucleoside to act synergistically in the treatment of various symptoms associated with acute leukemia or MDS. Used here, the term "synergistic" refers to the situation where the beneficial effect provided by the introduction of data antineoplastics compositions in combination, is more pronounced than the algebraic sum of the effects that occur when separate introduction of the components of the combination. As shown in the examples below, the combined treatment of cytotoxic conjugate against CD33, anthracyclines and similar pyrimidine or purine nucleoside is synergistic in the treatment of acute leukemia and has increased efficiency, judging by complete remission. This combined treatment has the advantage of achieving the same result at a lower dose of the cytotoxic conjugate against CD33, thus reducing the toxic effect of the conjugate, providing b is more high quality of life and increasing the chances of survival of the patient.

As with other chemotherapeutic drugs for specific patients should be monitored is determined by the decision of the attending physician. Described here agents combination therapy can be entered with immunosuppressive agents, reinforcing and debilitating side effects of agents that are necessary in the opinion of the treating physician.

Therapeutic application of doses of agents used in accordance with the invention, along with other factors affecting the selected dose may vary depending on the agent, the age, weight and clinical condition of the recipient patient, the experience and judgment of the Clinician or practitioner engaged in therapy. Typically, the dose should be sufficient for the induction of complete remission, as defined previously. An effective amount of the pharmaceutical agent is one which provides objectively defined improvement, marked by the Clinician or other qualified observer. Especially, it is preferable to prepare the composition of these antineoplastics connections in unit dosage form for ease of administration and the unification of dosage. Used here, a "unit dosage forms" refers to physically discrete units suitable as single dose for previously treated patients, and each the I unit contains a predetermined quantity antineoplastics compounds, designed to obtain therapeutic action, together with the required pharmaceutical carrier. Used here, the term "pharmaceutically acceptable carrier" includes any and all solvents, medium for dispersion, covering agents, antibacterial and antifungal agents, isotonic and delaying the absorption of agents, etc. that are compatible with the active ingredient and route of administration and other ingredients of the composition, and are not harmful to the recipient.

The pharmaceutical compositions according to the invention, which are, in combination, can also include, depending on the desired composition of a pharmaceutically acceptable non-toxic carriers and diluents, which are defined as solvents commonly used for the preparation of pharmaceutical compositions for administration to animals or humans. The diluent is chosen so that it does not affect the biological activity of the combination. Examples of such diluents are water, saline, ringer's solution, dextrose and Hanks solution. In addition, the pharmaceutical composition or the composition may also include other carriers, adjuvants, or nontoxic, non-therapeutic, non-immunogenic stabilizers, etc. Effective amount of each diluent or carrier to whom must be of such amounts, which is effective for obtaining a pharmaceutically acceptable composition in terms of stability or biological activity and the like.

For parenteral therapeutic injection every antineoplastics connection can be included together with a sterile solution for injection. Sterile solution for injection can be obtained by incorporating antineoplastics compounds in the required amount in an appropriate pharmaceutically acceptable carrier together with various other ingredients, followed by sterilization by filtration. In the case of dispersions, each can be obtained by including additional antineoplastic compounds in sterile solvent, which contains the basic dispersion medium and other necessary ingredients from listed here. In the case of sterile solutions for injection each can be obtained by including additional powder antineoplastics connection and - optional - any additional desired ingredient from its pre-sterilized by filtration of the solution, where the powder is in whatever way is appropriate (for example, vacuum drying and lyophilization). The use of such media and agents well known in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. (1990), Mack PublishingCo., Easton, PA 18042, pages 1435-1712, the disclosure of which is incorporated herein by reference). Incremental active ingredients may also be included in the composition. Specific dose antineoplastic compounds calculated according to the approximate body weight or body surface of the patient. Others considered when determining the appropriate dose factors may include the stage of acute myelogenous leukemia or myelodysplastic syndrome (de novo or recurrent), the severity of the disease, route of administration and the age, sex and medical condition of the patient. Usually a specialist in this area becomes more refinement of the calculations necessary to determine the appropriate dosage for treatment involving each of these compositions. Dose can also be determined using known tests determine the doses used in conjunction with suitable data dose-response. For example, in the scope of the invention is that the dose antineoplastics compounds used in the present invention for the treatment of acute myelogenous leukemia or myelodysplastic syndrome, can be varied to achieve the desired therapeutic effect.

If you choose oral therapeutic introduction, antineoplastics compound may be incorporated with excipients and used in the form of a table is current for swallowing, hominids tablets, pastilles, capsules, elixirs, suspensions, syrups, wafers, etc. or it can be included directly in consumed food. Tablets, lozenges, pills, capsules, etc. can also contain a binder such as tragakant, Arabian gum, corn starch or gelatin; excipients such as dicalcium phosphate; a leavening agent, such as corn starch, alginic acid, etc.; a lubricating agent such as magnesium stearate; sweeteners such as sucrose, lactose or saccharin; or a flavoring, such as peppermint, wintergrove oil or cherry or orange flavoring. When the unit dosage form is a capsule, it may contain in addition to the matter described here type carrier liquid. Can be many other substances as a coating or modification otherwise the physical form of the unit dose. For example, tablets, pills or capsules can be coated with shellac, sugar or both. Of course, any substance used for any unit dosage form should be pharmaceutically pure and substantially non-toxic in the applicable amount. In addition, antineoplastics connection may be included in the preparation and composition with prolonged release. The number antineoplastics connection that is Oh therapeutically useful compositions is such that that is, a suitable dose.

It should be understood that the above detailed description and the following examples are merely illustrative, and should not be taken as limiting the scope of the invention. Can be made various changes and modifications of the disclosed implementations, which should be obvious to experts in the field, without going beyond the concept and scope of the present invention. In addition, all patents, patent applications and publications cited in the present description, is included as a reference.

Examples

Example 1

To assess the safety and efficacy of gemtuzumab ozogamicin as part of a combination therapy of AML was developed phase 1/2 study in the United States of America for the combination of gemtuzumab ozogamicin with citarabinom and daunorubicin. Patients with recurrent, resistant to treatment or arising de novo AML were included in phase 1 from October 2000 to November 2001. The maximum tolerated dose was determined to cytarabine 100 mg/m²/day continuous infusion 1 to day 7, daunorubicin 45 mg/m²when intravenous bolus introduction from 1 to 3 day and 6 mg/m²for gemtuzumab ozogamicin at 2-hour infusion on day 4. The phase 2 study was initiated in November 2001, and it included 42 from planned at this point 5 patients.

A detailed evaluation of safety and efficacy were performed on the first 19 patients treated with this combined mode of induction, and then for at least 28 days. In the middle age group of 46 years (range from 20 to 60) was included sixteen men and three women. In cytogenetic groups with favorable, intermediate and poor prognosis were identified, respectively, one, ten and three patients. Five patients cytogenetic analysis was not conducted. At seventeen patients were identified basal level of leukemic blast cells in the bone marrow with an average percentage of blasts to 60%. Combination therapy was well tolerated, and all nineteen patients received the planned induction therapy.

Three patients (16%) noted NCI stage 3 fever/chills on the day of infusion gemtuzumab ozogamicin. Frequency increase stage 3 AST/ALT was 16%; it was not marked hyperbilirubinemia stage 3 or 4. No cases of occlusion of the hepatic vein/syndrome sinusoidal obstruction. The rate of infection of 3 and grade 4 was 32%. Early mortality when treatment was 0%. For four patients required repeat induction on residual AML citarabinom and daunorubicin approximately 15 days. One of these patients was excluded from the study and was prosecuted in the products of treatment with high dose tsitarabina (HDAC) on the 15th day of the study and therefore was not taken into account when assessing performance.

In fifteen of 18 patients (83%) achieved a complete remission (CR), characterized by the absence of AML blasts in peripheral blood, no extramedullary AML ≤5% of blasts in bone marrow cellularity >20% and detection of peripheral indicator for the absolute value of neutrophils (ANC) ≥1500/µl and platelets ≥100000/µl. Not detected patients with complete remission with incomplete recovery of platelets (CRp). Of the three patients without remission in 2 demonstrated progressive disease, and 1 was achieved remission bone marrow, but it took therapy to radiation over the residual chloroma. Among CR patients, the average time to recovery of ANC to ≥1500/µl was 38 days, and platelets to ≥100000/µl was 30 days. Patients were observed too short a time to determine the duration of remission (mean time tracking 193 days).

The combination of citarabinom 100 mg/m²/day of daunorubicin 45 mg/m²and gemtuzumab ozogamicin 6 mg/m²was well tolerated at low hepatotoxicity and caused increased CR to 83%. These historical control Southwest Oncology group (SWOG) give the CR indicator 60% in the standard therapy citarabinom 100 mg/m²/day for seven days and daunorubicin 45 mg/m²within three days. The combination Citara is 100 mg/m ²/day of daunorubicin 45 mg/m²and gemtuzumab ozogamicin 6 mg/m²led to a noticeable improvement CR compared with standard therapy.

Example 2

The feasibility of the combination of gemtuzumab ozogamicin with intensive chemotherapy for induction and/or consolidation was evaluated in 67 patients in the safety study conducted in the United Kingdom before AML15 trial in a Medical research centre. The goal was a combination of gemtuzumab ozogamicin with the planned test of chemotherapy (DAT; daunorubicin, AraC, tioguanin, or DA; daunorubicin AraC; or FLAG-IDA; fludarabine, AraC, G-CSF, idarubitsin) course 1. Course 1 was performed with the introduction of gemtuzumab ozogamicin in the amount of 3 mg/m²on day 1 of chemotherapy in 55 patients. Thirty-three patients received gemtuzumab ozogamicin with DAT. Eight patients received gemtuzumab ozogamicin with the DA. Fourteen patients received gemtuzumab ozogamicin with FLAG-Ida. Of the 55 patients treated, 41 (85%) achieved a complete remission in course 1, raspredelyayas as follows: (1) DAT=26/32; (2) DA=7/8 and (3) FLAG-Ida=8/8. In previous experience with split testing indicated MRC AML12, in which 720 patients were treated only H-DAT in course 1, 64% of these patients achieved a complete remission. In this study, the average time to ANC recovery (1�D7; 10⁹/l) was 27 days (range 9-54), and platelet count >100×10⁹/l was 30 (range 21-48), which is within the average + ISD 720 patients treated only H-DAT in the test MRC AML12. Nahampoana toxicity was limited to the liver. Total maximum toxicity, corresponding to the degree 1=5 patients, grade 2=22 patients, grade 3=13 patients, and grade 4=10 patients. When the degree of toxicity 3 and 4 of the 7 cases were clearly associated with gemtuzumab therapy by ozogamicin. A possible contributing factor was the inclusion of Tg. Of the 39 recipients in the treatment regimen that was included tioguanin, 22 manifested toxicity 3 or 4 degrees in the liver compared with 1 to 16 recipients with schemes without Tg.

Nine additional patients received H-DAT with 6 mg/m²gemtuzumab ozogamicin, and 8 patients achieved a complete remission in course 1. Hematologic recovery was not renewed, but in 3 patients developed hepatotoxicity 3 or 4 degrees, from which 2 occurred VOD-like syndrome, which both managed to cure. It was recognized that the dose of 6 mg/m²gemtuzumab ozogamicin is unsuitable.

Fifteen patients received gemtuzumab ozogamicin dose of 3 mg/m²in courses 1 and 2 (DAT 3+10 and DAT 3+8). The ANC recovery was delayed in 5 patients, restoring trombi the tov - in 11 patients, and both indicators in 5 patients. The toxicity of 3 or 4 degrees in the liver was observed in 3 cases, of which 2 patients developed VOD-like syndrome.

Seventeen patients received gemtuzumab ozogamicin dose of 3 mg/m²in conjunction with chemotherapy in the course of 3 with MACE (MACE: amsacrine, AraC, etoposide or high dose AraC). Only one patient was observed hepatotoxicity above 2 degrees. Twelve patients were induced in the course of 1 gemtuzumab ozogamicin dose of 3 mg/m²and in the course of 3 gemtuzumab ozogamicin dose of 3 mg/m². Apparently, it is acceptable, but further study of this mode continues.

Overall survival of patients treated with gemtuzumab ozogamicin dose of 3 mg/m²in course 1, for 6 months, 73%, and in the last 12 months - 68%. For the patient receiving non-thioguanine induction with 3 mg/m²gemtuzumab ozogamicin, the survival rate for 6 months is 91%.

1. A method of treating acute myelogenous leukemia or myelodysplastic syndrome, including

(a) carrying out required treatment to the patient's first course of therapy, which includes the introduction

(i) gemtuzumab ozogamicin in number from 3 to 9 mg/m²a day for one day;

(ii) of daunorubicin in an amount of from 45 to 60 mg/m^{2 duration per day up to three days; and}

^{(iii) tsitarabina in the amount of from 100 to 200 mg/m2duration per day up to ten days;}

(b) carrying out required treatment to the patient a second course of therapy that includes the introduction

(i) gemtuzumab ozogamicin in number from 3 to 9 mg/m²a day for one day;

(ii) of daunorubicin in an amount of 45 mg/m²approximately 60 mg/m²duration per day up to three days; and

(iii) tsitarabina in the amount of from 100 to 200 mg/m²duration per day up to ten days;

(c) carrying out required treatment to the patient of the third course of therapy, which includes introduction;

(i) of daunorubicin in an amount of 45 mg/m²approximately 60 mg/m²duration per day up to three days; and

(ii) tsitarabina in the amount of from 100 mg/m²approximately 200 mg/m²duration per day up to ten days.

2. A method of treating acute myelogenous leukemia or myelodysplastic syndrome, including

(a) carrying out required treatment to the patient's first course of therapy, which includes the introduction

(i) gemtuzumab ozogamicin in the amount of 6 mg/m²a day for one day;

(ii) of daunorubicin in the amount of 45 mg/m²duration per day up to three days; and

(b) carrying out required treatment to the patient a second course of therapy that includes the introduction

(i) gemtuzumab ozogamicin in the amount of 6 mg/m²a day for one day;

(ii) of daunorubicin in the amount of 45 mg/m²duration per day up to three days; and

(iii) tsitarabina in the amount of 100 mg/m²duration per day up to ten days;

(c) carrying out required treatment to the patient of the third course of therapy, which includes the introduction

(i) of daunorubicin in the amount of 45 mg/m²duration per day up to three days; and

(ii) tsitarabina in the amount of 100 mg/m²duration per day up to ten days.