Evolving Treatment for CLL, Small Molecule Inhibitors May Become Standard

^{By Edan Stanley}

Robert Greer, RPh, BCOP, senior director of clinical strategy and programs at Magellan Rx Management, discusses the use of ibrutinib compared with traditional immunochemotherapy, and small molecule inhibitors in the treatment of chronic lymphocytic leukemia.

Please introduce yourself and briefly explain your background.

My name is Robert Greer, RPh, BCOP, senior director of clinical strategy and programs at Magellan Rx Management. I’ve been a pharmacist for 19 years, 13 of which have been in the managed care space.

What are some of the challenges in treating chronic lymphocytic leukemia?

This is predominantly a disease of the elderly and as such comorbidities and performance status often limit the few treatment options. Most trials do not include patients >65 years.

Mutations and karyotype impact prognosis (eg, immunoglobulin heavy-chain variable (IGHV) unmutated has poorer survival than IGHV mutated; del(17p), loss of TP53, is associated with poorer response rates to chemoimmunotherapy and shorter median survival, etc). These come into play mainly for risk stratification, though some do impact treatment decisions.

Other challenges treating CLL are infection (herpes, PJP, etc) and viral reactivation (HBV, HCV, CMV, etc) require prophylaxis and monitoring.

Another potential challenge during treatment is managing tumor lysis syndrome (TLS) with certain agents, such as venetoclax, necessitating hyperuricemia management, as well as hydration prior to administration.

We also have limited data on overall survival (OS) comparing different therapies. Most data use a surrogate endpoint.

Can you explain some of the benefits of using Ibrutinib compared to chemotherapy?

Historically, chlorambucil and FC (fludarabine/cyclophosphamide) were standard therapies. That changed with the approval of the CD20+ MoAbs as well as bendamustine. Now we are moving into a new era of small molecule inhibitors, such as ibrutinib, venetoclax, etc.

In this population in particular, transportation and general caregiver assistance can be a challenge. Provider administered infusions require a port, pretreatment labs (with potential for treatment delay necessitating rescheduling), and time in the infusion center. Traditional chemotherapy (ie, purine analog) is also quite toxic with a litany of adverse drug reactions. An oral option can be useful here, assuming there are no adherence issues.

Chlorambucil monotherapy is the typical “straw man” used as the active comparator in clinical trials. We do know that ibrutinib demonstrated improved OS compared to ofatumumab in R/R disease. Front-line data used PFS comparing it to chlorambucil both in combination with obinutuzumab.

In terms of the Oncology Care Model, what course of treatment is more cost effective for payers? For patients?

The information presented in First Report Managed Care’s article is intriguing and does show a net benefit to using ibrutinib from an overall cost containment standpoint. I would like to see another layer to the analysis factoring in response to therapy as well. This would require a cross-benefit approach to institute.

What potential changes do you anticipate in treatment for Front-line CLL?

Small molecule inhibitors will become the standard of care. There is data supporting efficacy for venetoclax+obinutuzumab > chlorambucil+obinutuzumab with regard to progression-free survival (PFS). There is also data supporting efficacy of ibrutinib+obinutuzumab > chlorambucil+obinutuzumab with regard to PFS. Obinutuzumab has data showing improvement in OS compared to chlorambucil in the front-line setting.

Do you have anything to add?

CLL is diagnosed based upon ≥50,000 monoclonal B-lymphocytes in the peripheral blood

CLL and small lymphocytic lymphoma (SLL) are the same disease and both are a type of B-cell Non-Hodgkin's lymphoma (NHL). CLL has lymphocytes predominantly in the blood vs SLL in the lymph nodes. Both will have lymphocytes in the lymphoid tissues and bone marrow. Richter’s transformation to DLBCL can occur

CD20+ MoAb treatment can result in B-cell aplasia necessitating treatment with immunoglobulin. BTK inhibitors and PI3K inhibitors can cause transient increases in lymphocytes due to redistribution and should not be confused with progression

When switching off of a BTK, the interval between therapies should be as short as possible as progression may acceleration after discontinuation.