By Talal Hilal, MD - Division of Hematology/Oncology, University of Mississippi Medical Center, Jackson, Mississippi, USA

Toxicity in oncology can be both financial and physical. Often, patients incur physical toxicity with the hope that the benefit of treatment outweighs the risk. However, increasingly, the benefit of many practices in haematology and oncology is marginal (1), and based on improvements in surrogate endpoints, which may not always translate to meaningful gains for patients (2). Furthermore, aside from physical toxicity, patients are commonly incurring financial toxicity with escalating drug prices that is leading to their inability to continue a prescribed drug or seek ongoing treatment, leading to worse outcomes (3, 4). 

Insurance companies, pharmacy-benefit managers (PBMs), drug manufacturers, and government policies are key players that often have variable priorities and incentives (5). The issue of increasing drug prices requires all stakeholders to reach an agreement that does not leave patients and health care systems financial strain. Until that happens, haematologists/oncologists at the forefront of care are having to make diagnostic and treatment decisions that are under constant influence by marketing forces, regulatory approvals, and guidelines. Keeping the patient’s well-being as the main goal, many treatment decisions are increasingly leading to more toxicity, both physical and financial, with questionable added benefit.

Here, I aim to present a few examples of practices from haematology disciplines that should be heavily scrutinised before they are adopted by practicing haematologists.  Some of these have been highlighted by national campaigns, such as the Choosing Wisely campaign by the American Society of Haematology (ASH) (6), while others may not be frequently discussed.

1. Fresh frozen plasma in patients with cirrhosis and coagulopathy

Abnormal coagulation tests in patients with cirrhosis is common and does not accurately reflect coagulation status and tendency to bleed. In fact, it has been shown that patients with cirrhosis and coagulopathy have a balance between pro- and anticoagulant factors (7). Despite this, it is common practice to transfuse fresh frozen plasma (FFP) to correct coagulation factors before invasive procedures. A recent study that examined the endogenous thrombin potential with thrombomodulin (ETP-TM), a surrogate of thrombin generation, showed that FFP enhanced ETP-TM by only 5.7%. In 94% of patients, ETP-TM was normal or high, indicating adequate thrombin generation in most patients with an INR >1.5 (8).  FFP is associated with increased risk of alloantibody formation and infection, and should be avoided.

2. Blood transfusions in sickle cell disease with pain crisis and chronic anaemia

Patients with sickle cell disease (SCD) are chronically anaemic with elevated reticulocyte counts leading to moderate compensation. They are typically not symptomatic from their anaemia, and do not require prophylactic transfusions without a clear indication (e.g. previous stroke). The most common misuse of transfusion is in patients who are hospitalised for acute pain episodes. Studies have shown that correcting anaemia in patients with acute pain may worsen pain (9). Limiting liberal use of blood products in patients with SCD is essential to prevent alloimmunization since many will require blood transfusions for other indications.

3. Using 2nd generation tyrosine kinase inhibitors for newly diagnosed chronic myeloid leukaemia

Three 2nd generation tyrosine kinase inhibitors (TKIs) have been approved for first-line use for chronic myeloid leukaemia (CML); dasatinib, nilotinib, and bosutinib. All three agents were approved based on achieving their ability to achieve a faster major molecular response at 12 months compared to imatinib. However, none of them has shown improved long-term outcomes, including overall survival compared to imatinib. Furthermore, these agents appear to be more toxic than imatinib. For example, dasatinib is associated with pleural and pericardial effusions, nilotinib is associated with vascular events and metabolic syndrome (10) while bosutinib is associated with more diarrhoea and transaminase elevations (11). Furthermore, the price difference of 2nd generation TKIs is substantially higher than generic imatinib (12).

4. Adding rituximab to ibrutinib in first-line chronic lymphocytic leukaemia

Ibrutinib has become standard of care in the first-line treatment of chronic lymphocytic leukaemia (CLL) in the majority of patients. A cooperative group trial compared ibrutinib with rituximab to chemoimmunotherapy in patients younger than 70 years and showed improved overall survival with the ibrutinib combination (13). However, another cooperative group trial, which randomised patients older than 70 years to single-agent ibrutinib, ibrutinib plus rituximab, or chemoimmunotherapy, failed to show an improvement in outcomes with the rituximab combination compared to single-agent ibrutinib (14). Furthermore, the addition of the CD-20 antibody, rituximab, to ibrutinib did not provide additional benefit in another randomised single-center trial (15). Rituximab is associated with increased toxicity in the form of neutropenia, as well as cost, and does not seem to improve outcomes of patients with CLL treated with ibrutinib.

5. Using obinutuzumab in place of rituximab in first-line follicular lymphoma

Obinutuzuma is a humanised type 2 antibody that is Fc-optimised allowing for longer persistence on B-cells and enhanced antibody-dependent cytotoxicity (16). In the pivotal GALLIUM trial, obinutuzumab’s added benefit to a chemotherapy backbone (including CHOP, CVP, or bendamustine) for induction and maintenance was marginal and came at the cost of increased toxicity in the form of neutropenia and infections, especially when paired with bendamustine in the maintenance phase (17). The efficacy data showed an absolute benefit of 7% in progression-free survival, while failing to show an OS benefit compared to rituximab added to a backbone of chemotherapy (17, 18). Given its indolent nature, an OS benefit in follicular lymphoma may be a difficult endpoint to achieve as was found in the PRIMA trial of rituximab maintenance (19), but in a malignancy that is incurable, one wonders if a delay in progression ultimately affects a patient’s quality of life?

6. Using brentuximab vedotin in place of bleomycin in advanced Hodgkin’s lymphoma

Brentuximab vedotin (BV), a CD30 antibody-drug conjugate, was evaluated in the ECHELON-1 trial for advanced Hodgkin’s lymphoma (20). The addition of BV to doxorubicin, vinblastine, and dacarbazine (AVD) failed to show an improvement in OS compared to standard of care AVD with bleomycin. Some criticisms of the ECHELON-1 trial included the use of a Deauville score of 3 as a marker of residual disease, the use of a modified PFS endpoint which added more patients with progression to the ABVD arm, and lack of PET-guided approach to therapy to discontinue bleomycin after 2 cycles of chemotherapy (21).

7. Using denosumab in place of zoledronic acid in multiple myeloma

The US Food and Drug Administration (FDA) approved denosumab based on the XGEVA 20090482 (‘482) randomised, non-inferiority trial that showed denosumab was noninferior to zoledronic acid in preventing skeletal-related events (SREs) in patients with newly diagnosed multiple myeloma. An unplanned post hoc analysis of the trial showed a PFS benefit for denosumab compared to zoledronic acid, especially in patients with intent to proceed with autologous stem cell transplantation (22). This may have driven the rapid uptake in the market within 2 years of FDA approval, approaching 40% of the bone-modifying agent market based on Medicare claims data (23). Although a potential option for patients with chronic kidney disease (CKD) and a creatinine clearance between 30 – 60 mL/min, its use in those without CKD was substantial. This comes with a significant price difference (e.g. Medicare Part B Average Sales Price in January 2020: $2,312 per 120 mg dose of denosumab vs $43.2 per 4 mg dose of zoledronic acid (www.cms.gov)), and without clear superiority of standard of care bisphosphonate therapy.

Conclusion

This list is by no means all-inclusive but aims to highlight some common practices in haematology with questionable added benefits that can be influenced by aggressive marketing and guidelines that may limit valid options. Methods of limiting toxicity for patients are plentiful but require a careful evaluation of the evidence while maintaining a position that is not easily swayed by small gains and financial incentives. In an a field that is increasingly complex and ever expanding, reliance on a single source of information that often propagates a view that may be self-serving can restrict a multitude of reasonable approaches to treatment that may be associated with less physical and financial toxicity.

References

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