Medical Pharmacology Chapter 33-34:  Anticancer Drugs

• Alkylating Agents

  • Alkylating Agents in Chemotherapy³⁰

    Attribution: Vincent Lecture#2 Alkylating Agents for Cancer https://www.youtube.com/watch?v=UWLmu6BI2Cw (30) The author, Vincent, discusses alkylating agents used in cancer, reviewing mechanisms of action, side effects, indications and management of adverse effects. An overview of the cell cycle and apoptosis is provided. Drugs discussed are: cyclophosphamide, ifosfamide, chlorambucil and bendamustine.

   

  • Classification⁸

    • Alkyl Sulfonates

      • Busulfan

        • Busulfan (Busulfex, Mykeran)

      • Overview: 

        • The main pharmacological action of busulfan (Busulfex, Mykeran) is myelosuppression at typical doses⁴  in the context of bone marrow transplantation, most typically for treating chronic myelogenous leukemia²⁸.

          • The principal benefit of allogenic stem cell transplantation is the reduction in disease relapse or cure potential due to graft versus tumor reactions in those patients whose presentation makes cure unlikely or even impossible using standard chemotherapy by itself.  

            • Prior to allogenic stem cell transplantation, a reduction in disease burden is required.

              • For example, in leukemias a 5% blasts value represents a transplantation threshold, although more recently the threshold is evolving to an absence of residual disease with an absence of cytogenetic abnormalities.

              • In the case of lymphomas, a negative positron emission tomographic/computed tomographic (PET/CT) scan or objective data showing lymph node size reduction with disease-free marrow represent the standard. 

          • Generally, the presence of more pronounced disease prior to allogenic stem cell transplant is associated with elevated relapse rates.

          • Alternatively, patients who demonstrate no apparent residual disease exhibit improved outcomes²⁸.

            • Busulfan (16 mg/kg) in combination with cyclophosphamide is considered myeloablative while providing a moderate degree of immunosuppression.

        • Before the introduction of imatinib mesylate (Gleevec),  busulfan was a frequently used drug in treating patients during the chronic phase of myelocytic leukemia.

          • Such treatment resulted in extended pancytopenia (pancytopenia:  deficiency in red cells, white cells and platelets) in some individuals.⁴ 

          • The degree and time course of bone marrow suppression exhibit notable differences between patients.

            • Compared to some other alkylating agents, such as cyclophosphamide, busulfan is especially toxic to bone marrow stem cells.⁸

          • Recovery from busulfan-induced pancytopenia may be prolonged, lasting up to 2 years.¹²  

          • Busulfan is now mainly used in high-dose protocols and as such organ system toxicities are to be expected.

            • For example, some noteworthy toxicities include pulmonary fibrosis, gastrointestinal mucosal pathology and hepatic venoocclusive disease (VOD).⁴ 

      • Pharmacokinetics:

        • Busulfan is well-absorbed following oral administration.¹   

          • The plasma half-life (t_½) is about 2-3 hours.

          • Busulfan metabolism involves both conjugation (GSH catalyzed by glutathione-S-transferase A1A) and inactivation by the liver microsomal enzyme system (cytochrome P450).

            • Drug clearance is higher in children (<18 years of age).

            • Generally, busulfan clearance is variable between patients.

        • Busulfan is also available for IV administration, useful in preparative conditioning prior to stem cell transplantation.

          • Furthermore, in the presence of venoocclusive disease (VOD), both a high area-under-the-curve (AUC) and slow busulfan clearance have been shown.¹ 

            • VOD (venoocclusive disease) is also called SOS (sinusoidal obstruction syndrome).²⁰

      • Clinical Uses:

        • For use in chronic myelogenous leukemia (CML) busulfan initial oral dosing takes into account both total leukocyte counts as well as disease severity.¹ 

          • Following the initial doses, dose adjustments factor in both hematological as well as clinical responses.¹  

            • An important endpoint is a reduction of total leukocyte counts to ≤ 10,000 cells/mm³.

            • A reduction in leukocyte counts may not be observed for the first two weeks; however, the absence of a change in leukocyte count or even an increase does not suggest drug resistance or provide a basis for increasing dose.

            • Following cessation of busulfan administration, total leukocyte counts may continue to decline for >1 month.

              • Therefore, to hit the target of ≤ 10,000 leukocytes /mm³, busulfan should be discontinued when the leukocyte count is ~15,000 cells/mm³.

              • Normal leukocyte levels are typically achieved within about 12-20 weeks.

            •  For "high-dose" protocols, anticonvulsive drugs should be used along with with busulfan to counteract CNS toxicities which may include tonic-clonic seizures.¹  

              • For patients already requiring phenytoin as an anti-seizure agent an alternative drug, perhaps lorazepam, would be more appropriate.

                • This change may be required since busulfan increases phenytoin metabolism.¹

        • Although busulfan is not the current first-line treatment for chronic myeloid leukemia (CML), the agent remains an important option for high-dose chemotherapy (HDC) associated with hematopoietic progenitor cell (HPC) transplantation (stem cell transplantation).²⁰

          • Hematopoietic Progenitor Cell (Stem Cell)²³

            "Hematopoietic stem cell (HSC) surface markers and typical cytokines that regulate "HSCs.Stem cell factor (SCF) promotes the proliferation and differentiation of HSCs. "Thrombopoietin (TPO) and its receptor, c-Mpl, play important roles in early hematopoiesis, especially self-renewal. "Signals from angiotensin-1 via Tie2 and transforming growth factor -β via its receptors regulate HSC dormancy. "(This figure is based on the illustration by BioLegend, Inc. San Diego, CA, U.S.A. http://www.biolegend.com/cell_markers)" Tsuruta T Recent Advances in Hematopoietic Stem Cell Gene Therapy.  Chapter 5 in Innovations in Stem Cell Transplantation (Demirer T, ed) 2013 http://www.intechopen.com/books/innovations-in-stem-cell-transplantation/recent-advances-in-hematopoietic-stem-cell-gene-therapy

          •  

            Stem Cell Transplantation²¹    

            Attribution:  Talebi T Stem Cell Transplantation (2/2015) https://www.youtube.com/watch?v=_Y-P6mJ2ncY Tony Talebi Youtube Channel https://www.youtube.com/channel/UC6CFAGOplTIod22Pg48SZog

           

          • High-dose chemotherapy (HDC) in combination with autologous hematopoietic progenitor cell (HPC) transplantation is an effective treatment approach both for some hematologic malignancies and some solid tumors.

          •  

            Hematopoiesis²²

            A Rad Hematopoiesis (human) diagram https://commons.wikimedia.org/wiki/File:Hematopoiesis_simple.svg

          • Both high-dose chemotherapy and high-dose radiation administration have limitations due to normal tissue toxicity, particularly referable to bone marrow suppression.

          • However, chemotherapy doses and radiation doses can be significantly increased if they are to be followed by either autologous or allogeneic transplantation which restores hematopoiesis.

          • The pluripotent HPC progenitor cells following infusion both divide and differentiate leading to mature blood and immune cells.²⁰  

            • Several steps are involved in autologous transplantation.²⁰

              • (1) Collection: Most often hemopoietic progenitor cells (HPC) are collected from peripheral blood. Increasing the number of the cells in blood may be accomplished through the administration of granulocyte colony-stimulating factor (G-CSF) in addition to the inherently elevated HPC levels following chemotherapy. By contrast to bone marrow HPC collection, HPCs from peripheral blood appear to engraft more quickly.²⁰  

                (2) Processing: Following HPC collection, the stem cells are concentrated and purified.

                (3) Cryopreservation: The concentrated HPC sample is then preserved for later use by freezing (cryopreservation).

                (4) Chemotherapy: High-dose chemotherapy (± radiation) is administered to the patient.

                • Autologous hematopoietic progenitor cell transplants appear most efficacious in those malignancies in which a 3-5 fold increase in myelosuppressive drug dose or radiation is accompanied by a substantial increase in cytotoxicity against tumor cells.²⁰  

                • To achieve such high dose effects, alkylating agents are most commonly used.

                • Should autologous HPC transplantation failure occur, the most likely reason is reemergence of the underlying malignant disease.

                  • Factors that predispose to failure include suboptimal reduction in cancer cell number or reintroduction of malignant cells as a contaminant in the HPC reinfusion.

                  • The best high-dose chemotherapy protocol depends on the disease and various approaches are being considered in efforts to improve outcome.²⁰  

          • Numerous complications of high-dose chemotherapy have been identified.

            • Infection represents a significant complication during the neutropenic phase following chemotherapy (HDC) administration.²⁰  

              • During this period complications due to infection can range from "febrile neutropenia" to "life-threatening septic episodes." ²⁰

              • For half a year or more following transplant the patient remains at risk for Pneumocystis jiroveci, herpes zoster reactivation, and fungal infections.

              • To mitigate these adverse effects,  prophylaxis may be initiated beginning at stem cell infusion and continuing until the neutropenic phase has resolved.

                • For example, bacterial prophylaxis may be achieved with a fluoroquinolone-type drug; whereas antifungal prophylaxis may be accomplished with fluconazole.

                • Prevention of viral infection in this setting may involve administration of acyclovir/valacyclovir.²⁰

            • SOS/VOD:

              • Sinusoidal obstruction syndrome (SOS) originally described as "venoocclusive disease" (VOD) is a serious hepatic injury that can occur following drug administration.²⁴

                • This syndrome can be a life-threatening complication following hemopoietic stem cell transplant.

                • Sinusoidal endothelial cells and hepatocytes of the hepatic acinus zone 3 become damaged by toxic metabolites resulting from the conditioning regimen.

                • Hepatic Lobule Organization²⁶

                  Yager JD Hepato and Renal Toxicology Johns Hopkins Bloomberg School of Public Health http://ocw.jhsph.edu/courses/publichealthtoxicology/PDFs/Lecture6_Yager.pdf (2008)

                • SOS can occur following even a single infusion of drug and presents in the acute setting within 1-3 weeks of exposure.

                • Both chronic and subacute forms of SOS have been described and can become apparent in the weeks to years.

                • Diagnosis of SOS depends on clinical criteria that can include weight gain, ascites, tender hepatomegaly and jaundice.²⁴  

              • In the context of hemopoietic stem cell transplant (HSCT), SOS/VOD is more likely to occur in the first month.²⁵  

                • There is a wide incidence range associated with SOS (5%-60%).

                  • This range depends  not only on risk factors, transplant types, conditioning regimens but also on the clinical basis used for diagnosis.

                • At this time (2015) SOS is more common following allogenic HSCT a.k.a. allo-HSCT following conditioning with myeloablative protocols.

                  • Here, the incidence appears around 10%-15%.²⁵  

                  • Other estimates suggest that about 3%-10% of patients will develop SOS, depending on the conditioning regimen intensity.²⁷  

                    • Peak incidence during the first month occurs at day 16.

                    • Factors that increase the likelihood of SOS include:

                      • Previous treatment with intensive chemotherapy protocols

                      • Pretransplant hepatitis, and

                      • Drug protocols involving more intense conditioning approaches.²⁷  

                  • The overall mortality rate of SOS is estimated at 30%. Progressive liver failure results in a "terminal hepatorenal syndrome."²⁷

                  • By contrast, reduced intensity conditioning and autologous HSCT (auto-HSCT) is associated with an incidence of <5%.²⁵  

              • Severity of SOS is highly variable. In the mild form the syndrome may resolve within a few weeks.²⁵  

                • In a severe presentation, which includes multiorgan failure, mortality rates may exceed 80%.

              • Early morphological change in SOS is noted in sinusoidal endothelial cells resulting in hepatic sinusoids zone 3 obstruction in the hepatic acinus.

                • Sinusoidal Obstruction Syndrome²⁴

                  "This biopsy was taken from a 48 year old man who developed signs of sinusoidal obstruction syndrome following bone marrow transplantation. "There is congestion and hemorrhage in zone 3 with spillage of red blood cells in between hepatocytes. "This change is associated with hepatocyte necrosis (arrow). "The central vein is not clearly seen, but the location is indicated (V). "The portal area (P) is also marked for reference."24   Kleiner DE Histologic Image:  Sinusoidal Obstruction Syndrome, Laboratory of Pathology National Cancer Institute. 24  o

                •  

                  Sinusoidal Obstruction Syndrome²⁴ 

                  "Here a central vein (V) is clearly seen. There is hemorrhage in the vein wall and narrowing of the lumen by loose connective tissue.24   Kleiner DE Histologic Image:  Sinusoidal Obstruction Syndrome, Laboratory of Pathology National Cancer Institute. 24

                • Endothelial pathology following HSCT is not limited to sinusoidal lining and can result in many endothelial syndromes following transplant including “capillary leak syndrome, engraftment syndrome, transplant-associated microangiopathy or diffuse alveolar hemorrhage.”²⁵  

                 

                • Case example: "Mild sinusoidal obstruction syndrome after hematopoietic cell transplantation." (Case study provided by Dr. George B. McDonald from the files of the Fred Hutchinson Cancer Center)²⁴ 

                  "A 56-year-old woman with myelofibrosis and agnogenic myeloid metaplasia underwent allogenic hematopoietic cell transplantation after the conditioning regimen of oral busulfan (16 mg/kg with therapeutic drug monitoring), followed by intravenous cyclophosphamide (120 mg/kg) and prophylactic ursodiol therapy.  One week later she became jaundiced and had mild hepatic tenderness. She gained approximately 10% of her initial body weight. Liver enzyme levels did not change and serum creatinine was stable (0.7 to 1.0 mg/dL). She had complications of staphylococcal bacteremia and pulmonary fungal infection and was treated for gastrointestinal graft-vs-host disease, but responded to antibiotic and antifungal therapy and was discharged 28 days after the transplant at which time her weight was back to baseline."24  Laboratory Values for the Case Above24

                 

            (5) Reinfusion: Frozen concentrated hemopoietic progenitor cell sample stored earlier is then thawed and infused into the patient.²⁰  

            Hemopoietic response occurs within a few weeks and occurs most rapidly following high doses of CD34 ⁺ cells.

            • Neutrophil levels recover in 7-10 days with platelets recovering in about 10-14 days after reinfusion.²⁰  

      • Toxicities:

        • Pulmonary:

          • Long-term treatment with busulfan may result in slow fever onset with nonproductive cough and dyspnea.⁸ 

            • With time tachypnea and cyanosis may develop with progression to significant pulmonary insufficiency and death.

              • Cessation of busulfan therapy prior to these clinical symptoms may allow stabilization of pulmonary function.

              • Unfortunately, should clinical symptoms present, death may rapidly ensue.⁸ 

                • "Pulmonary Busulfan Cells"¹⁹

                  "Pulmonary busulfan cells with large, distinctive, hyperchromatic nuclei (X480).

            • Comparable pulmonary toxicities may also be seen with cyclophosphamide, some nitrosoureas, in circumstances of high cumulative doses.⁸   

            • Administration of other alkylating drugs such as chlorambucil, mitomycin C, and melphalan may also cause post-treatment pulmonary fibrosis.

              • Pulmonary fibrosis in this circumstance is likely due to direct drug cytotoxicity targeting the pulmonary epithelium resulting in both alveolitis and fibrosis.⁸ 

         

        • Chemotherapeutic Applications

          Primary Chemotherapeutic applications Chronic myelogenous leukemia Busulfan is not a current standard of therapy agent. Current role is part of a conditioning protocol in allogeneic stem cell transplantation (SCT)13 Conditioning refers to either chemotherapy or radiation with the purpose of eliminating patient disease prior to hematopoietic stem cell transplantation.  Another reason for conditioning is suppression of the immune reaction. First-line therapy for chronic myeloid leukemia (CML) often involves a BCR-ABL tyrosine kinase inhibitor such as the first-generation agent imatinib mesylate, dasatinib, or nilotinib.13 Imatinib (Gleevec)16 Top:  Imatinib Bottom:  "Imatinib in its binding site.  Amino acids with major interactions displayed.  Dotted lines represent hydrogen bonding." https://commons.wikimedia.org/wiki/File:Imatinib_in_its_binding_site.svg Imatinib (Gleevac) as a Paradigm of Targeted Cancer Therapies17 Attribution: Druker BJ Imatinib (Gleevec) as a Paradigm of Targeted Cancer Therapeies (Part I:  Imatinib (Gleevec:  A Targeted Cancer Therapy)  https://www.youtube.com/watch?v=d6xU3bgBLIw  March 29, 2010 "Imatinib (Gleevec) has become a paradigm for targeted cancer therapies. "The first part of this lecture will describe the clinical features and the molecular pathogenesis of the disease for which imatinib was developed, chronic myeloid leukemia (CML). "This overview will trace the history of the identification of the target of imatinib, BCR-ABL. "The preclinical development of the BCR-ABL kinase inhibitor, imatinib and highly successful clinical trials of this agent for patients with CML will be reviewed along with the most up-to-date follow-up on these studies."17 iBiology Youtube Channel:  https://www.youtube.com/channel/UCsvqEZBO-kNmwuDBbKbfL6A These agents control both thrombocytosis and leukocytosis.13  Administration of the first-generation agent imatinib usually results in both a complete hematologic and cytogenetic response.13   The associated estimated 8- to 10-year survival rate is about 85% (all causes) or about 93% for chronic myeloid leukemia-related deaths. Second-generation tyrosine kinase inhibitors such as nilotinib or dasatinib use appear associated with better results compared to imatinib. Furthermore, following imatinib failure (loss of clinical effectiveness) the second-generation agents (dasatinib, nilotinib, ponatinib, bosutinib) are active.13   Dasatinib (Sprycel)   Nilotinib (Tasigna)   Ponatinib (Iclusig)   Bosutinib (Bosulif)   Another, nonpharmacologic approaches allogenic stem cell transplantation.13   This treatment may be curative but is accompanied by notable morbidity and mortality.13 Most cases of CML result from the formation of the "Philadelphia chromosome", a chromosomal abnormality.14,15  The abnormality occurs because of a fusion between the Abelson (ABL) tyrosine kinase gene located on chromosome 9 and a breakpoint cluster (BCR) gene located on chromosome 22. This interaction produces a chimeric oncogene (BCR-ABL) which in turn appears responsible for the constitutively active BCR-ABL tyrosine kinase.14 Bone marrow transplantation8

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Kirschner RH Esterly JF Pulmonary lesions associated with busulfan therapy of chronic myelogenous leukemia Cancer 27:  1074-1080 May 1971. http://onlinelibrary.wiley.com/doi/10.1002/1097-0142(197105)27:5<1074::AID-CNCR2820270511>3.0.CO;2-G/pdf EL Fakih R Shah N Nieto Y Chapter 12:  Autologous Hematopoietic Progenitor Cell Transplantation in The MD Anderson Manual of Medical Oncology (Kantarijian HM and Wolff RA, eds; Shpall EJ Section ed) 3e McGraw-Hill Eduation 2016. 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