Chronic myeloid leukemia treatment

Busulfan was used for the treatment of chronic myeloid leukemia and polycytemia vera. 

The Italian Cooperative Study Group on Chronic Myeloid Leukemia., Interferon alpha-2a as compared with conventional chemotherapy for the treatment of chronic myeloid leukemia, N. Engl. J. Med., 330, 820, 1994. 

Imatinib mesylate (Gleevec, Novartis Glivec in countries other than the United States) is a drug for the treatment of chronic myeloid leukemia (CML). CML is a result of a chromosomal problem and gives rise to high levels of white blood cells. An enzyme called BCR-ABL is involved. The BCR-ABL gene encodes a protein with elevated tyrosine kinase activity (see Exhibit 7.3). 

In some circumstances, the FDA processes drug reviews under the accelerated scheme. This mechanism is to review and approve drugs speedily for cases where effective therapies are lacking or in situations of rare diseases. One of the fastest approval times to date is the case of imatinib mesylate (Gleevec, Novartis—Exhibit 7.3) for the treatment of chronic myeloid leukemia (CML) it was approved in less than 3 months after the filing of an NDA with the FDA. Another example is the new AIDS drug indinavir (Crixivan, Merck), which was approved in a mere 42 days. 

Goldman JM, Melo TV. Chronic myeloid leukemia advances in biology and new approaches to treatment. YAwg/JMed 2003 349 1451-1464. 

Roche-Lestienne C, Soenen-Cornu V, Grardel-Duflos N et al. Several types of mutations of the ABL gene ean be found in chronic myeloid leukemia patients resistant to STI571, and they ean pre-exist to the onset of treatment. B/oor/2002 100 1014-1018. 

In June 1999, phase I clinical trials of OTI-010 were initiated in cancer patients receivingchemotherapy and HSC transplantation for the treatment of high-risk hematological malignancies (including acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia and non-Hodgkin s lymphoma). The multicenter studies, conducted in seven US and European cancer centers, showed OTI-010 to be safe and efficacious, with 52% of patients ( 40 patients) responding positively to the therapy [327297], [495015]. 

Produced by recombinant DNA technology, IFN-a-2a is used for the treatment of chronic myeloid leukemia, Kaposi sarcoma, lymphoma, hairy cell leukemia, hepatitis B and C and cancer of the skin and kidney. It can only be administered by injection or into the bloodstream, and the most common method is subcutaneous injection. This cytokine can be injected every day however, commonly it is... 

Advice for treatment decisions based on specific genetic conditions were found in four Pis, namely that prolastin (a 1-proteinase inhibitor) is not indicated in patients with certain otl -antitrypsin deficiency phenotypes, trastuzumab indicated only in patients with overexpression of the HER2 protein, tretinoin, and imatinib are to be given only in patients with either a specific subtype of acute myelogenous leukemia or Philadelphia chromosome-positive chronic myeloid leukemia, respectively. 

Faber E et al (2010) Imatinib dose escalation in two patients with chronic myeloid leukemia, with low trough imatinib plasma levels measured at various intervals from the beginning of therapy and with suboptimal treatment response, leads to the achievement of higher plasma levels and major molecular response. Int J Hematol 91 897-902... 

This dynamic multidrug-targeted prevention technique has been proposed in the treatment of chronic myeloid leukemia and the positive results obtained with the newly introduced drugs nilotinib and dasatinib suggested that a combination of two or three kinase inhibitors, when carefully selected to cover all known resistant mutations, could shut off all mechanisms of escape. 

B. J. Druker, Imatinib mesylate in the treatment of chronic myeloid leukemia. Expert Opin. Pharmacother 4 (2003), 963-971. 

Luo CY, Tang JY, Wang YP. Homoharringtone a new treatment option for myeloid leukemia. Hematology 2004 9 259-270. Kantarjian HM, Cortes J. New shategies in chronic myeloid leukemia. Inti. J. Hematol. 2006 83 289-293. 

Savona M, Talpaz M. Chronic myeloid leukemia changing the treatment paradigms. Oncology (Williston Park). 2006 20 707— 711 discussion 712-704, 719, 724. 

Peggs, K. Mackinnon, S. Imatinib mesylate-the new gold standard for treatment of chronic myeloid leukemia. The New England Journal of Medicine 2003, 348, 1048-1050. 

Pericardial fibrosis has been reported after busulfan treatment in a man with chronic myeloid leukemia (3). Endocardial fibrosis has also been reported (4). 

The addition of cytarabine 10 mg/m /day subcutaneously for 10 days to interferon monotherapy more than doubled the incidence of gastrointestinal toxicity in the treatment of chronic myeloid leukemia in 139 patients (8). 

Rapid exacerbation (1-21 days) or delayed (3-38 months) de novo appearance of immune hemolytic anemia has been reported after initiation of interferon alfa treatment in nine patients with lymphoproliferative disorders (220). However, this rare event was identified in only 1% of 581 patients receiving interferon alfa alone or as part of a chemotherapeutic regimen for chronic myelogenous leukemia (221). A mechanism close to that observed with alpha-methyldopa has been thought to be involved (208). The direct antiglobulin test was positive in 32% of 28 chronic myeloid leukemia patients after a median of 1 year of treatment with interferon alfa (222). 

A review of 15 other available reports of renal insufficiency and proteinuria in patients with chronic myeloid leukemia or other malignancies confirmed that the histological spectrum of renal lesions associated with interferon alfa is varied, and includes membranous glomerulonephritis, minimal change glomerulonephritis, acute interstitial nephritis, hemolytic-uremic sjmdrome, and thrombotic microangiopathy. Renal comphcations were reversible in nine patients three patients had persistent proteinuria, and four had persistent renal dysfunction, of whom three required chronic hemodialysis. Two-thirds of the patients developed renal comphcations within 1 month of treatment with interferon alfa, and one-third had received a relatively low dosage of interferon alfa (9-15 MU/week). 

Two studies have provided insights into the incidence and risk factors of the immune-mediated comphcations of interferon alfa in patients with chronic myeloid leukemia. In the first study, 13 of 46 patients had autoimmune manifestations consisting of a combination of autoimmune thyroiditis in four, a direct antiglobulin test without hemolysis in eight, cryoagglutinins in one, Raynaud s phenomenon in two, and chronic autoimmune hepatitis in one (343). Overall, six patients had chnically symptomatic manifestations after a median of 15 months of treatment. In the second study, there were autoimmune diseases in seven of 76 patients after a median of 19 months of treatment, including hypothyroidism in one, immune-mediated hemolysis in two, systemic lupus erythematosus in two, Raynaud s phenomenon in one, and mixed connective tissue disease in one (344). In... 

The possibility that melphalan and busulfan may cause additive lung damage has been discussed in the light of a 59-year-old patient with chronic myeloid leukemia who developed severe interstitial lung fibrosis after short-term sequential treatment with the two drugs (7). 

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