A satellite meeting sponsored by Teva at the 18th Congress of the European Haematology Association in June 2013 examined how to raise the standards of care in the management of haematology patients
Hospital Pharmacy Europe
The symposium began by examining whether it is possible to further improve success in the treatment of acute promyelocytic leukaemia (APL). This disease is characterised by the morphology of blast cells (M3 in the French–American–British classification of AML), the t(15;17) chromosomal translocation that fuses the PML gene on chromosome 15 to the retinoic acid receptor alpha (RARα) gene on chromosome 17, and by a coagulopathy combining disseminated intravascular coagulation and fibrinolysis. White blood cell (WBC) count has been shown to be a main pre-treatment prognostic factor, with poorer prognosis if WBC count is >10 x 109/l. APL is sensitive to chemotherapy associating an anthracycline and cytarabine, all-trans retinoic acid (ATRA) and, more recently, arsenic trioxide (ATO) or gemtuzumab. The simultaneous administration of ATRA and anthracycline-based chemotherapy is currently considered the standard induction treatment in newly diagnosed patients.(1) However, this approach requires a very rapid onset of ATRA, based on morphological diagnosis, massive platelet transfusions, early addition of anthracycline-based chemotherapy to ATRA, and early management of differentiation syndrome if it occurs with rapid onset of high-dose steroids. Controversial topics are related to the use of cytarabine, probably dependent on APL risk, type of anthracyclines (idarubicin better than daunorubicin?), the role of low-dose maintenance chemotherapy, and the importance of CNS prophylaxis.
Initial findings reported from China, and more recent studies from the US, demonstrate the beneficial effects of ATO in the treatment of APL. Trisenox® (ATO) is licensed in the EU for the treatment (induction or remission and consolidation) of adults with relapsed or refractory APL. Previous therapy should have included a retinoid and chemotherapy. It has also been studied in newly diagnosed APL. In combination with ATRA and chemotherapy, ATO significantly improves event-free and disease-free survival.(2) ATO has shown very encouraging results as a single agent, and it has a synergistic effect when combined with ATRA, said Professor Pierre Fenaux (Avicenne Hospital, France). As an alternative to chemotherapy, the association of ATRA and ATO gives good results for standard-risk patients, but high-risk patients may need further chemotherapy.(3) The combination ATRA + ATO has been compared with ATRA + chemotherapy during a Phase III trial in low-to-intermediate risk APL. Two-year event-free survival rates and overall survival were better in the ATRA + ATO arm, which was associated with less haematological toxicity and fewer infections but with more hepatic toxicity and QTc prolongation.(4) ATO may be crucial in patients needing lower toxicity, such as the elderly and children. ATO may also replace cytarabine to reduce myeloid toxicity, for example, during the consolidation phase: this question is being addressed in the ongoing APL2006 trial.
Dr Jens Hasskarl (University Medical Centre Freiburg, Germany) started by presenting the results of the LNH 98-5 trial that introduced rituximab associated with CHOP (R-CHOP) as the new standard for newly diagnosed non-Hodgkin’s lymphoma (NHL) in elderly patients.(5) Several trials have studied the possible benefit of dose intensification by comparing R-CHOP every two weeks (R-CHOP14) or three weeks (R-CHOP 21). Both regimens are similar in efficacy, and R-CHOP21 remains the standard of care as R-CHOP14 may lead to higher haematological toxicity, with mandatory granulating colony-stimulating factor (G-CSF) support and transfusions.(6) Numerous trials are ongoing with maintenance treatment (everolimus, lenalidomide) or evaluation of small molecule inhibitors and new monoclonal antibodies (mAbs) including improved anti-CD20 mAb obinutuzumab (GA101). Neutropenia and consequent infections are highly prevalent in elderly patients under treatment, and this needs proactive management with assessment of individual risk for febrile neutropenia, and compliance to G-CSF guidelines. Current practices should be improved because data show that an insufficient number of patients receive adequate G-CSF support.
Professor Arnon Nagler (Chaim Sheba Medical Center, Tel Hashomer & Tel Aviv University, Israel) presented a clinical overview of biosimilar G-CSF in stem-cell mobilisation. G-CSF is the backbone for mobilisation of haematopoietic stem cells. Recently, CXCR4 antagonists (for example, plerixafor) are being used in conjunction with G-CSF in patients in whom mobilisation fails with G-CSF alone. Two studies have evaluated the use of biosimilar G-CSF for chemotherapy-based peripheral blood stem-cell (PBSC) mobilisation.(7,8) Both have concluded that the biosimilar G-CSF is comparable to original filgrastim for peripheral blood stem-cell mobilisation and collection after chemotherapy. Publicover et al showed that engraftment did not differ, and the use of biosimilar G-CSF could produce a significant cost saving (£930 per autograft).(8) The combination of Tevagrastim and plerixafor has been studied as a first-line PBSC mobilisation strategy in multiple myeloma and lymphoma patients who are candidates for autograft. The regimen allowed a collection of the target dose of CD34+ cells in a maximum of two procedures in 100% of the cases.(9)
Tevagrastim has also been studied in the post-autograft setting in comparison with historical controls with rhG-CSF(10): results showed a comparable efficacy, and possible cost-savings (–50%). Allogeneic stem-cell transplantation (AlloSCT) is a well‑established, potentially curative, therapy for patients with acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS). About 70% of AlloSCTs for AML and MDS in Europe are performed with G-CSF-mobilised peripheral blood stem cells (MPBSC). Growth factors such as rhG-CSF (original filgrastim) are routinely used in normal donors to mobilise haematopoietic progenitor cells from the bone marrow into the peripheral circulation.
Adverse events data from donors mobilised using rhG-CSF are being collected by the WMDA, EBMT and NMDP (all established large databases). Concerns have arisen over biosimilar G-CSF in normal healthy volunteer donors for the mobilisation of stem cells, owing to very short follow-up times and minimal data in the normal donor setting. EBMT and WMDA stated that biosimilar G-CSF should not be used for mobilisation in normal donors, except in clinical trials when both the donor and patient consent. To address this issue, several studies have been performed, including 154 normal donors. Schmitt et al compared Tevagrastim versus original filgrastim used as historical control.(11) Authors found a comparable efficacy and safety of biosimilar G-CSF when compared with reference G-CSF. Professor Nagler presented satisfying results from two unpublished studies (submitted as abstracts to ASH) using Tevagrastim for mobilisation from normal sibling donors. Another study by Becker et al showed that biosimilar (ZARZIO®) G-CSF-based mobilisation of haematopoietic stem cells from unrelated registry normal volunteer donors was effective with minimal side effects.(12) WBC/biochemistry and acute toxicity were consistent with reported data, both in frequency and severity. Relevant issues to be addressed in the future are related to long-term effects, rare serious adverse events and immunogenicity of biosimilars.
Professor Heinz Ludwig (Wilhelminenspital, Vienna, Austria) discussed the main complications that are encountered in the treatment of patients with lymphoma and myeloma, and their management by adequate supportive care. Haematological toxicity, and especially febrile neutropenia, impairs quality of life, and is associated with treatment delays, life-threatening infections and increased mortality. Risk factors for febrile neutropenia are related to the patient (age ≥ 65 years, poor performance status, co-morbidities, anaemia), the tumour (type and progression) and the treatment (dose, type, length of chemotherapy and combination with radiotherapy). Mortality from febrile neutropenia can rise up to 50% if associated to four major co-morbidities.(13) Combination of lenalidomide and dexamethasone can lead to consequent febrile neutropenia: in this regard, recommendations for G-CSF use have been proposed by Palumbo et al.(14) EORTC and ASCO have published guidelines for risk assessment for febrile neutropenia.(15,16) Prophylactic G-CSF is recommended if chemotherapy-related risk of febrile neutropenia is ≥ 20%, and should be considered if other risk factors increase probability of febrile neutropenia. G-CSF should be administered 1–4 days after chemotherapy. Viral infections in patients with haematological malignancies are also to be prevented or diagnosed as early as possible. Prevention includes the use of acyclovir regarding herpes zoster reactivation, and vaccination for influenza before therapy. Diarrhoea is a common toxicity because of mucosal damage by chemotherapy.(17) Symptomatic treatment includes loperamide, antisecretory agents, such as atropine and budesonide, somatostatin (especially analogues with long half-lives), and rehydration and electrolyte supplementation in patients with significant fluid loss and in elderly patients. Thrombocytopenia occurs frequently, and could require platelet transfusions. Prophylactic platelet transfusion may be avoided during autologous stem cell transplant when platelets < 1 x 109/l if no signs of bleeding, with the exception of AML patients.(18)
Professor Anders Österborg (Karolinska University Hospital, Stockholm, Sweden), moderating the symposium, concluded: “Through the introduction of active, supportive care, along with effective treatment for the haematological malignancy, the aim is to avoid or limit the quality of life impairment associated with long-term use of chemotherapy, and to enable the patient to continue treatment as long as necessary to achieve maximum benefit”.
- Sanz MA et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2009;113(9):1875–91.
- Powell BL et al. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood 2010;116(19):3751–7.
- Estey E et al. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood 2006;107(9):3469–73.
- Lo-Coco F et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 2013;369(2):111–21.
- Coiffier B et al. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d’Etudes des Lymphomes de l’Adulte. Blood 2010;116(12):2040–5.
- Cunningham D et al. Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles. Lancet 2013;381(9880):1817–26.
- Lefrere F et al. First experience of autologous peripheral blood stem cell mobilization with biosimilar granulocyte colony-stimulating factor. Adv Ther 2011;28(4):304–10.
- Publicover A et al. Use of a biosimilar granulocyte colony-stimulating factor for peripheral blood stem cell mobilization: an analysis of mobilization and engraftment. Br J Haematol 2013;162(1):107–11.
- Laszlo D et al. The more effective and the more (bio) similar: Plerixafor and filgrastim XM02 (tevagastrim) as first line PBSC mobilization strategy in patients with multiple myeloma and lymphomas candidate to ABMT. Blood (ASH Annual Meeting Abstracts) 2011;118:Abs 2994.
- Sammassimo S et al. Biosimilar G-CSF in post-autologous stem cell transplantation setting: preliminary results. Haematologica 2011;96(Suppl 2):Abs 1487.
- Schmitt M et al. Mobilization of PBSC for allogeneic transplantation by the use of the G-CSF biosimilar XM02 in healthy donors. Bone Marrow Transplant 2013;48(7):922–5.
- Becker PSA et al. Biosimilar filgrastim mobilises haematopoietic stem cells in healthy volunteer donors with expected efficiency and typical acute adverse events: interim results of a post-authorization safety study. Bone Marrow Transplant 2013;48(Suppl 2):S28(0177).
- Kuderer NM et al. Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients. Cancer 2006;106(10):2258–66.
- Palumbo A et al. Practical recommendations on the management of VTE patients with relapsed/refractory multiple myeloma who are treated with lenalidomide and dexamethasone. Haematologica 2007;92(Suppl 1):96:Abs 0264.
- Aapro MS et al. EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphomas and solid tumours. Eur J Cancer 2006;42(15):2433–53.
- Smith TJ et al. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006;24(19):3187–205.
- Ludwig H et al. Advances in the treatment of hematological malignancies: current treatment approaches in multiple myeloma. Ann Oncol 2007;18 Suppl 9:ix64–70.
- Wandt H et al. Therapeutic platelet transfusion versus routine prophylactic transfusion in patients with haematological malignancies: an open-label, multicentre, randomised study. Lancet 2012;380(9850):1309–16.
Raising the Standards of Management of Haematology Patients
An official satellite symposium sponsored by Teva at the 18th Congress of the European Haematology Association, 13 June 2013, Stockholm