EP 12B: Management of Chemotherapy Induced Myelosuppression (CIM) in ES-SCLC

In this Precision Medicine Perspectives series Addressing Myelotoxicity as a Consequence of Treatment for Extensive-Stage Small Cell Lung Cancer, experts consider key factors in the optimal management of patients with extensive-stage small cell lung cancer (ES-SCLC). Chemotherapy-induced myelosuppression (CIM) can impact the bone marrow resulting in decreased activity and reduced red/white blood cells in addition to platelets. Patients with extensive stage-small cell lung cancer (ES-SCLC) receiving chemotherapy can develop these conditions, resulting in poorer health outcomes. Luis E Raez, MD, Chief Scientific Officer, and Medical Director of the Memorial Cancer Institute, discusses chemotherapy induced myelosuppression (CIM) and its impact on blood cells. Dr. Raez highlights past and present obstacles faced by oncologists when treating CIM in patients with ES-SCLC. Lastly, Dr. Raez discusses the emergence of trilaciclib in patients who develop CIM for ES-SCLC and its clinical implications from recently published data.

Targeted Oncology™: Briefly define chemotherapy induced myelosuppression (CIM). How does it affect red blood cells, white blood cells and platelet production?

Dr Raez: Chemotherapy in small cell lung cancer is hard for the patients. We still use a very old regimen: carboplatin and etoposide. These agents were developed in the 1980s, more than 40 years ago. For that reason, it is no surprise that these drugs are very toxic for the bone marrow. There is a 50% chance or higher that patients will experience Grade 4 myelosuppression through either anemia, thrombocytopenia, or neutropenia. For this reason, we make myelosuppression into consideration each time that we treat patients with chemotherapy. According to current NCCN guidelines, the chance of myelosuppression in patients, specifically neutropenia, is more than 20%. Additionally, with the use of growth factor support, the risk of myelosuppression in patients on chemotherapy is between 10-20%. We must check the patient’s comorbidities to assess whether use of growth factor support is appropriate. Overall, these regimens will impact the patient’s bone marrow as a result.

Targeted Oncology™: HL is a 68-year-old woman who was recently diagnosed with extensive stage small lung cancer, and recently update with carboplatin and etoposide. After two cycles of treatment, she developed thrombocytopenia. How would you manage this patient’s thrombocytopenia and how do patients on chemotherapy typically develop thrombocytopenia?

Dr Raez: Managing thrombocytopenia in this specific case is a very common scenario seen in clinical practice. It is estimated that one-third of our patients with this treatment regimen will experience severe thrombocytopenia. Typically, we don't have a product that can protect patients from thrombocytopenia. In the last 20 years, we have made considerable attempts with several different growth factor drugs for managing thrombocytopenia. Prior to the recent approval of Trilaciclib, we didn't have a product that could be commonly used. The problem with thrombocytopenia is that it causes dose delays. Following chemotherapy, the patient comes for another cycle of treatment and if their platelet count is >100,000, there's going to be a dose delay. Typically, we don't transfuse platelets in patients until severe thrombocytopenia is present and as a result, platelets are not an option. If the patient, for example, has 70,000 platelets, they don’t need a transfusion, but we must delay chemotherapy and postpone treatment to allow for recovery. Another problem we face is inadequate management of thrombocytopenia. Due to mismanagement, we must begin dose reductions since we didn't effectively protect the patients. We don't want the patients to risk having severe thrombocytopenia and then worry that it could happen again. If we are unable to reduce the patient’s risk from thrombocytopenia, we will have to dose reduce chemotherapy. As a result, the intensity of chemotherapy decreases and ultimately may result in poorer outcomes.

Targeted Oncology™: What advice do you have for community oncologists who treat thrombocytopenia in patients receiving chemotherapy?

Dr Raez: Clinically, it has been very intriguing for us to learn about Trilaciclib with the recent publications. Interestingly, recent publications have shown that Grade 3/4 thrombocytopenia can be reduced in patients to nearly half [50%]. I think this product [Trilaciclib] is very valuable. The reduction in the number of platelet transfusions does not occur due to its uncommon use in patient. Overall, the best endpoint to measure is the reduction in severity of thrombocytopenia. Hopefully, this will allow us to timely administer chemotherapy in patients for their following cycles.

Targeted Oncology™: Please review the secondary myelosuppressive endpoints assessed in the pooled analysis of the impact of trilaciclib on CIM from the randomized trials in patients with extensive stage small cell lung cancer. How are they defined and what were the results of these endpoints?

Dr Raez: In a recent publication, a pooled analysis of three clinical trials were conducted with Trilaciclib. Of those trials, two investigated frontline therapy with carboplatin and etoposide while the other trial assessed second line therapy and beyond with topotecan. In this pooled analysis, the primary endpoint assessed was the duration of severe neutropenia. The duration and occurrence of severe neutropenia in Cycle 1 is the standard that was used in these studies to assess the utility of these drugs. Specifically, in the case of Trilaciclib, we see that the pooled analysis shows that the severity of neutropenia can be reduced from nearly 50% to about eleven or 12%, with tremendous statistical significance. Overall, the severity of neutropenia was the most significant endpoint. The secondary endpoint assessed related to white blood cells, red blood cells, and platelets. For white blood cells, the most important secondary endpoint was febrile neutropenia. Febrile neutropenia, in this study, decreased from 9-3% with very close statistical significance. However, the use of growth factor support in patients decreased from 55% to 28%. Since the use Trilaciclib in prophylactic treatment, the use of growth factor support has nearly halved which was statistically significant. Grade 3/4 anemia was also shown to decrease by 50%, from 30-20% which has lowered the rate of transfusions as well. Additionally, the administration of ESAs also decreased. Specifically for thrombocytopenia, 1/3 of patients experienced severe thrombocytopenia (Grade 3 and 4), with <75,000 platelets. Following the use of Trilaciclib, severe thrombocytopenia was shown to decrease by half, from around 36% to 19%. Platelet transfusions were no different in these studies, but as mentioned previously, it's not an endpoint that we look for. Typically, we only transfuse platelets in patients when their platelet count is <15,000. In the area of platelet transfusions, we do not expect much change. However, while most patients are in the platelet range of 70,000, this is still not good as it doesn't allow for the use of chemotherapy.

Targeted Oncology™: What were some adverse events seen in the publication of the pooled results of trilaciclib in CIM? What was the impact of trilaciclib on hospitalization rates and how are injection site reactions managed in patients?

Dr Raez: Regarding adverse events that we see with Trilaciclib, it’s difficult to evaluate while using chemotherapy concurrently. There are adverse events for both chemotherapy and Trilaciclib. It is challenging to differentiate the source of the adverse event. Certainly, you can see, for example, that the number of hospitalizations went down from 13% to four percent since using Trilaciclib. Averse events, like fatigue, are difficult to differentiate between Trilaciclib and chemotherapy. There are specific adverse events ones that originate from Trilaciclib. For example, injection site reactions were more commonly seen with Trilaciclib (13%) compared to placebo (2.5%). The chance of phlebitis was nine percent with 0.8 [percent]. Most of these adverse events were low grade, including hypersensitivity reactions (4% versus 3%). Even with placebo, it’s amazing that you can have reported hypersensitivity reactions. That's mainly the way that we saw specific adverse events and they usually do not prevent the use of the agent in the next cycle.

Targeted Oncology™: How does the safety and tolerability profile of trilaciclib factor into your decision when you initiate treatment? What other factors might you consider?

Dr Raez: Given all the data available, the deciding whether to use Trilaciclib is not a difficult choice, personally. I understand that these are small studies in only one tumor type, lung cancer, small cell lung cancer, but the current standard of care is very low realistically. Currently, we do not have a lot of standard of care options for patients. The only standard of care option that we have is to use growth factor support for patients that have >50% chance risk of severe neutropenia. That will only protect our white blood cell line and does not protect a patient’s platelets or anemia. I think that if physicians want to, based on the data, consider using Trilaciclib to protect not only the white blood cells, but also protect patients from the risk of anemia and thrombocytopenia. Given the data, it's very interesting that we see decreased occurrences of severe neutropenia and decreased usage of growth factor support to rescue patients. Ultimately, there are a lot of endpoints that I think very valuable.

Targeted Oncology™: What has been your experience with using trilaciclib in patients receiving chemotherapy? Do you foresee trilaciclib having a role in other tumor types?

Dr Raez: We have had the opportunity to use Trilaciclib and I think it's very interesting. With more than 20 years practicing with carboplatin/etoposide, there’s has never been a good agent to protect patients from anemia and thrombocytopenia. Presently, we have the option now. As I said before, we previously had options to protect patients from neutropenia, but now we have an option that can cover three blood cell lines for myelosuppression which is very interesting. While the drug’s approval is limited to small cell lung cancer, it is of my hope that further evidence is accumulated so that it [Trilaciclib] can be used in other tumor types. When we approved the use of growth factor support more than 20 years ago, we didn't test for every single tumor type to get approval. So, that is why we're looking forward for more data so our colleagues can benefit from this knowledge and these results. So far, I’ve seen many thoracic oncologists not only excited but interested in this agent as consideration for use in daily practice.