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Published on 1 November 2003

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Advances in haematology: the challenge for pharmacy

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Nish Saini
PharmD BCOP MRPharmS
Haematology Pharmacist
Pharmacy Department
University College London Hospitals
London
UK
E:nishaat.saini@uclh.org

Contemporary haematology pharmacy practice is a vibrant, fascinating and dynamic specialty that offers a myriad of opportunities for pharmaceutical intervention, particularly in the setting of a large teaching hospital or tertiary referral centre. The demanding but rewarding educational and experiential challenges that accompany working in such an environment can be complicated by economic, logistical, regulatory and ethical controversies associated with the delivery of new technologies and treatment modalities. Examples of how these elements influence haematology pharmacy practice will be explored further in course of this article, which will focus on the provision of comprehensive pharmaceutical care to haemato-oncology patients, including individuals being treated using techniques in stem cell transplantation (SCT).

The ambitions of clinical excellence and cost-
effectiveness have never been mutually exclusive, and the financial pressures associated with many of the novel haematological therapies alluded to in this article mean that, today more than ever, pharmacoeconomic vigilance is an essential prerequisite to the delivery of rational pharmaceutical care.

Immunotherapy
Of major financial and therapeutic impact in the pharmacotherapy of haematological malignancies has been the increased availability and use of immunotherapy to target drug delivery. The use of monoclonal antibodies (MoAbs) is not a new concept, and modulation of the immune system is a technique that is increasingly being exploited in the battle against cancer. In being directed against tumour-specific cell-surface antigens, MoAbs can be considered analogous to stealth-like guided missiles, carrying payloads to precise targets, thereby reducing undesirable “collateral” damage.

Unconjugated monoclonal antibodies
“Naked” or unconjugated MoAbs are able to elicit cytotoxic effects via three different immune-mediated mechanisms: complement-dependent cytotoxicity (CDCC), antibody-dependent cytotoxicity (ADCC) and direct apoptosis. Alemtuzumab(1) (anti-CD52) and rituximab(2) (anti-CD20) are examples of two licensed products whose pharmacology reflects this mechanism of action, and they are indicated respectively for the treatment of refractory chronic lymphocytic leukaemia (CLL) and two specific histological subtypes of non-Hodgkin’s lymphoma (NHL).

The use of unconjugated MoAbs present unique pharmaceutical care challenges to the health professional. While infusion-related symptoms and allergic reactions have long been recognised as potential consequences of administering murine-derived MoAbs, the arrival of genetic engineering techniques to produce chimeric and humanised MoAbs has been a leap forward in reducing these complications. Nevertheless, appropriate premedication and controlled yet flexible infusion rates are still necessary prerequisites to minimising these side-effects and enhancing the patient experience.

Conjugated immunotherapy
An alternate method of evoking an antitumour effect is to conjugate an antibody with a cytotoxic agent, and this technology has been exploited in the development of gemtuzumab ozogomicin (GO). GO is  composed of a recombinant humanised monoclonal antibody (anti-CD33) conjugated with a cytotoxic antitumour antibiotic, calcheamicin.(3) CD33 is an antigen expressed by leukaemic blasts in approximately 90% of patients with acute myeloid leukaemia (AML).(4) After the administration of GO, the antibody component binds specifically to the CD33 antigen on AML blasts, forming a complex that the target cell internalises. Within the cell, the calicheamicin portion of the drug is released by hydrolysis, migrates to the cell nucleus, where it binds to DNA, and elicits double-stranded breaks that ultimately lead to cell death.(3) GO is not yet licensed in Europe, but it has been FDA approved in the USA, where open-label studies in patients with relapsed AML, traditionally considered a poor prognosis disease, have yielded promising response rates of approximately 30%.(3)

Handling and preparation
This is an appropriate juncture to address some of the logistical and practical controversies related to the handling and preparation of MoAbs. The allergic sensitisation associated with the handling of non-humanised MoAbs has been significantly reduced with the development of humanised or chimeric MoAbs.(5) Further, an expert panel convened to deliver opinion on the handling and manipulation of these agents has recommended that since unconjugated MoAbs currently used as anticancer agents do not represent a carcinogenic or teratogenic hazard, they can be handled in the same facilities as noncytotoxic aseptic products.(6) The scope of this recommendation is not inclusive of antibody–cytotoxic conjugates such as GO. Furthermore, there are pharmaceutical characteristics unique to GO that require innovative approaches to the drug preparation process: the conjugate is light-sensitive,(3) which necessitates preparation in a biological safety hood with any fluorescent light turned off. Manifestly, this can present a potential hazard to the operators, however, no viable alternative preparative technique is currently available. Following reconstitution, the diluted conjugate must be placed in an ultraviolet-protectant bag and infused immediately.(3) This means that close liaison with nursing and medical staff is necessary to coordinate the preparative and administrative times so as to minimise the possibility of expensive drug wastage.

Radioimmunotherapy
Exciting recent advancements resulting from an evolution and refinement in the development of MoAbs and techniques of drug delivery have culminated in the emergence of the radiolabelled MoAbs. Conjugating the MoAb with a radionuclide has been exploited with the arrival of two products that have exhibited efficacy in the treatment of indolent B-cell NHL. One of these, iodine-131 tositumomab, has obtained FDA approval for use in refractory or transformed low-grade NHL.(7) The conjugate consists of an anti-CD20 murine-derived MoAb coupled with a primarily beta-radiation-emitting isotope. The result is a dual-action product that binds to the target antigen CD20 found on NHL cells, thereby initiating an immune response against the cancer and concurrently delivering a dose of radiation directly to tumour cells.

The drug is associated with a complex administration schedule beyond the scope of this article, which is divided into “hot” and “cold” phases, each separated by one week. Coordinated multidisciplinary treatment planning is imperative to minimise patient and health-professional exposure to potentially harmful radioisotope emissions through the preparative, administrative and post-treatment phases. Specialist pharmacist participation is an essential component in this collaborative exercise.

Horizon scanning
The full therapeutic potential of MoAbs has still yet to be realised, and horizon scanning reveals a pipeline of products and proposed studies with the potential to expand the portfolio of haematological indications beyond the limits of cancer therapy to include the treatment and prevention of conditions such as post-transplant graft-versus-host disease (GVHD), immune thrombocytopenic purpurea (ITP) and thrombotic thrombocytopenic purpurea (TTP). The unique combination of clinical, logistical and economic insight makes the specialist haematology pharmacist a valuable consultant in the development of clinical trials and institution-specific protocols employing MoAbs, and his or her opinion and perspective should be sought at the inception of these ventures.

Supportive care
Over the last three decades the improved survival rates observed in patients with haematological malignancies, specifically those with acute leukaemias, has owed much to an enhancement of the available supportive-care armamentarium, particularly in relation to anti-infective strategies and growth factor support. With regard to the former, for more than 20 years the spectrum of systemic antifungal treatment has been largely limited to the ubiquitous use of azole antifungals, amphotericin-based products and 5-flucytosine. The last 12 months has seen the fruition of years of research with the launch within Europe of two new drugs, voriconazole and caspofungin, both possessing broader spectrums of antifungal activity than the older azoles, yet also devoid of the infusion- related reactions and nephrotoxicity associated with amphotericin-based products. While the side-effect profile and antifungal activity of these agents offer distinct advantages, the therapeutic conundrum introduced by the availability of these new therapies is twofold. First, in what context should these new antifungal agents be employed: as prophylaxis, empirical treatment, for refractory disease or solely for patients intolerant of existing agents? And what about combination treatment? The second issue complicates the first: pharmacoeconomic viability – the cost of these new agents to health systems may be prohibitive and result in a restrictive application of their full potential. The scenario depicted is one that is not unfamiliar to currently practising haematology pharmacists. Today, a pragmatic approach is essential to the development of a robust rational antifungal treatment strategy, requiring more than an isolated critical evaluation of the published evidence base, but also incorporating a clear understanding of the practical and economic considerations that will likely influence other stakeholders in the decision-making process. The challenge is onerous, but pharmacists have the skills, knowledge and vision to make them effective proponents in driving this negotiation forward.

Targeting signal transduction pathways
A greater understanding of the complex, intricate pathways and enzymes that constitute “signal transduction”, or the process by which a cellular stimulus is transmitted from one location within a cell to another,(8) has profoundly enhanced our understanding of the pathogenesis of malignancy and is now being increasingly exploited in the development of drugs that are able to act on specific molecular targets critical to these “signalling pathways”.

Archetypal within haematology is the use of imatinib mesylate for the treatment of chronic myeloid leukaemia (CML). Imatinib specifically targets a hyperefficient tyrosine kinase enzyme that elicits an unregulated “turn-on” of the cell signal pathway.(9) Undoubtedly, an evolution in our appreciation of other unique cellular targets will pave the way for the development of a wave of drugs with analogous pharmacology. What also makes imatinib unique is the fact that the drug is available in an oral formulation. Indeed, there has been increased availability of oral dosage forms within the haemato-oncology field, including the recent marketing approval of oral fludarabine. While these oral formulations improve patient convenience, it is imperative that pharmacists, as multidisciplinary team members, take shared responsibility for maintaining the same standards of vigilance that would be applied to the prescribing and handling of parenteral cytotoxics, including the monitoring of the individuals receiving them. Medication counselling is of particular importance in this context, and prospective outpatients need to be cognisant of the criteria they should use in being prompted to seek medical attention should they experience any significant adverse effects. In facilitating this process, haematology pharmacists have needed to play an active role in the development and implementation of protocols for patient education and counselling.

Regulatory and ethical issues
Having examined how economic, logistical and clinical challenges influence modern haematology pharmacy practice, the area that remains to be examined is that which is arguably the most controversial. The regulatory and ethical issues raised by the re-emergence of thalidomide as a potential treatment modality are a byproduct of the emotive history that clouds the drug’s past. Thalidomide has undisputable teratogenic effects, but its immunomodulatory (10) and antiangiogenic(11) properties make it an attractive proposition as salvage treatment for various haematological conditions, ranging from multiple myeloma to post-transplant GVHD. Patient advocacy groups, supported by legislative branches of government, have driven forward the development of programmes to ensure that there is a zero-tolerance policy for the exposure of pregnant women to thalidomide. In the USA, the STEPS(12) (System for Thalidomide Education and Prescribing Safety) programme has been in place for five years now, and its implementation was a prerequisite to FDA approval of thalidomide in that country. A similar exercise is already underway in Europe, where, although not yet licensed, one thalidomide manufacturer has already introduced a mandatory risk-management system for thalidomide that is being used in a myeloma trial for which the company is the single named source of the drug. The Pharmion Risk Management Programme (PRMP) mandates that prescriber, patient and pharmacy are all registered with the company.(13) Registration takes place via fax and phone communication and is structured in such a way as to ensure that patients have been fully consented, educated and made aware of the risks associated with treatment. Regular pregnancy tests form an integral part of the programme, and no more than 28 days’ supply of drug may be provided at any one time. The implementation of such a safety system is not inexpensive, and the result is likely to be a predictable rise in the cost of thalidomide. In addition, the increased administrative and logistical pressure placed on pharmacies will require already stretched resources to be further burdened. A real danger also exists that before European marketing authorisation is achieved by any single thalidomide manufacturer, the financial pressures of using the PRMP-associated product could lead to the creation of a two-tier approach to thalidomide prescribing: one that employs the PRMP system as mandated by a particular study; and the other using an alternative source of thalidomide for off-trial patients and for protocols that do not specify a particular brand of thalidomide. The ethical dilemma posed by this scenario is close to reality, and specialist haemato-oncology pharmacists will need to deal with the fallout in the immediate future.

The future is bright
This article has only scratched the surface of some of the contemporary issues challenging haematology pharmacy practice. Further discussion related to any one of a number of other novel treatment modalities could have also been introduced. The continuum of drug development will never be static, and the financial burden that parallels the discovery of new technology will ensure that this specialty is rarely short on controversy, challenge and, at the same time, opportunity. The future is bright, and specialist pharmacists are ideally placed to be key individuals in influencing the shape of future haematology practice.

References

  1. MabThera [SPC]. Welwyn Garden City, Herts: Roche; December 2002.
  2. MabCampath [SPC]. Burgess Hill, West Sussex: Schering; November 2002.
  3. Mylotarg [package insert]. Philadelphia (PA): Wyeth-Ayerst; May 2000.
  4. Sievers EL. Targeted therapy of acute myeloid leukaemia with monoclonal antibodies and immunoconjugates. Cancer Chemother Pharmacol 2000;46 Suppl:S18-22.
  5. Wood AM. Monoclonal antibodies: an overview. In: Monoclonal antibody therapy for non-Hodgkin’s lymphoma: a new therapeutic alternative. Bala Cynwyd (PA): Meniscus; 1999. p. 2-7.
  6. CIVAS group and BOPA joint statement on the handling of monoclonal antibodies. Hosp Pharm 2001;8:153.
  7. Bexxar [prescribing information]. Seattle (WA): Corixa; June 2003.
  8. Ross DW. Oncogenes: control of cell growth and senescence. In: Introduction to molecular cancer medicine. New York: Springer; 1998. p. 29-44.
  9. Seckl MJ. Growth factor and cell signalling inhibitors as novel anticancer agents. Cancer Topics 2000;11(3):1-4.
  10. Haslett PAJ, Corral LG, Albert M, Kaplan G. Thalidomide co-stimulates primary human T-lymphocytes, preferentially inducing proliferation, cytokine production and cytotoxic responses in the CD8+ subset. J Exp Med 1998;187:1885-92.
  11. D’Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci 1994;9:4082-5.
  12. Thalidomid (Thalidomide) clinical information and prescribing guidelines. Warren (NJ): Celgene; September 1998.
  13. Pharmion Risk Management Programme (PRMP) for patients taking Thalidomide Pharmion 50 mg hard capsules (thalidomide) [Information for healthcare professionals]. Great Abingdon, Cambridge: Pharmion; April 2003.


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