Medication Possession Ratio vs. Proportion of Days Covered
by Dr. Joseph Barone, BCOP
Onco360 recommends that we track compliance and persistency for each drug individually since they have unique frequencies of administration (e.g., twice daily continuous vs. twice daily for 14 days “on” followed by 7 days “off”). We can also employ medication possession ratio (MPR) or proportion of days covered (PDC) as adherence tracking and measuring components. Our MPR calculation is presented below:
MPR % = (sum of total days’ supply in period / (Last fill date – first fill date + Last fill days’ supply)) x 100%
PDC is very similar to MPR; however, it is capped at 100%. In MPR, a patient may have possession of more days of therapy than have existed. PDC on the other hand has a measure of one or zero; where a patient either has a drug available to take or does not. The excess number of tablets/caplets are ignored as a patient can either take the medicine or not. This results in a maximum result of 100% proportion of days covered. Our PDC calculation is presented below:
PDC = (Sum of the days covered / (Last fill date – first fill date + Last fill days’ supply)) x 100%.
First-line treatment generally includes induction chemotherapy, followed by consolidation therapy (this may involve chemotherapy or allogeneic stem cell transplantation). Generally, there is not a role for maintenance therapy in AML.
Induction (generally one cycle, goal is to obtain remission)
- The NCCN guidelines make a distinction regarding the patient’s age (<60 years old and >60 years old). For patients who are less than 60 years old, the “gold standard” induction regimen is the 7+3 regimen (either daunorubicin or idarubicin + cytarabine). For AML patients with FLT3 mutations, Rydapt® (oral TKI) is added to 7+3 induction treatment. For AML patients with CD33 positive disease, Mylotarg® (IV monoclonal antibody) is added to 7+3 regimen. For patients with therapy-related AML (AML arising following administration of cytotoxic chemotherapy) or AML-MRC (AML arising from MDS), Vyxeos® (liposomal daunorubicin/cytarabine combo) is the induction regimen of choice due to superior overall survival compared to 7+3.
- For patients who are >60 years old, the physician must first determine if the patient is medically fit for standard induction therapy as above. For patients >60 years old who are candidates for standard aggressive induction, they are treated the same as patients who are less than 60 years old (i.e., 7+3 +/- Rydapt if FLT3 positive). If the patient is not a candidate for standard induction, they most commonly receive treatment with a hypomethylating agent (intravenous) such as Vidaza® or Dacogen®.
- For patients who are not candidates for intensive induction and have certain mutations, Idhifa® (oral IDH2 inhibitor) and Mylotarg (CD33 antibody) are listed as induction options in the NCCN guidelines. If the patient has therapy-related AML or AML-MRC, Vyxeos is still your treatment of choice.
Consolidation (goal is to maintain remission)
- For patients who are less than 60 years old and have favorable cytogenetic risk, the HiDAC (high-dose cytarabine) regimen is the gold standard. This is usually given for 4-6 cycles. Patients who are CD33 positive may have Mylotarg added to their treatment.
- For those patients older than 60 years of age who have intermediate cytogenetic risk, they may receive an allogeneic stem-cell transplant as consolidation, or alternatively receive HiDAC as with favorable-risk patients. If the patient is FLT3 positive, Rydapt will be added to HiDAC.
- For those same patients who have poor cytogenetic risk, they may receive an allogeneic stem-cell transplant as consolidation, or alternatively, receive HiDAC as with favorable-risk patients. If the patient is FLT3 positive, Rydapt will be added to HiDAC.
- For those patients who also have therapy-related AML or AML-MRC, Vyxeos is used as consolidation.
- For patients who are greater than 60 years old and have demonstrated good performance status, intermediate-dose cytarabine is the gold standard. Patients may alternatively receive a reduced-intensity allogeneic stem cell transplant.
- For those patients who are older than 60 years of age who did not receive standard induction, hypomethylating agents (i.e., Vidaza, Dacogen) are continued if the patient is responding to treatment.
- For those patients older than 60 who have therapy-related AML or AML-MRC, Vyxeos is used for consolidation.
- Second-line and beyond therapy usually includes chemotherapy regimens not used during first-line treatment, as well as targeted therapy. NCCN usually recommends a clinical trial for relapsed/refractory AML patients.
- Chemotherapy options
- Cladribine + cytarabine + G-CSF support
- Fludarabine + cytarabine + G-CSF support +/- Idarubicin
- Clofarabine +/- cytarabine + G-CSF support +/- Idarubicin
- Low dose cytarabine
- Hypomethylating agents (Vidaza, Dacogen)
- Targeted agents
- Idhifa for IDH2 mutation AML
- Nexavar® or Rydapt for FLT3 AML
- Mylotarg for CD33 positive AML
- Chemotherapy options
How patients are managed from a clinical perspective
- AML has a significant amount of supportive care components. Due to the aggressive nature of induction chemotherapy, patients are at high risk for infections. Many patients end up on prophylactic antibiotics, antivirals, and/or antifungals due to the depth of neutropenia. With most antifungals, there is a significant risk of drug-drug interactions with concomitant oral oncolytics.
- Due to the emetic risk of cytotoxic chemotherapy administered, patients are at a high risk of chemotherapy-induced nausea/vomiting. Pharmacists must be well-versed in NCCN-recommended antiemetic prophylaxis. HiDAC (high-dose cytarabine) may cause chemical conjunctivitis, which requires prophylactic administration of corticosteroid eye drops +/- artificial tears. Anthracycline chemotherapy (daunorubicin, idarubicin, Vyxeos®) may result in cardiotoxicity (i.e. heart failure) and requires periodic ECG/EKG monitoring.
- Chemotherapy-induced mucositis is another common issue facing these patients, which often requires the administration of opioid analgesics as well as local therapy (e.g., Magic mouthwash). Depending on the severity, mucositis patients may end up requiring parenteral nutrition support.
- As the role of oral/IV targeted therapy emerges in AML, it is incumbent upon the pharmacist to confirm that the patient has an appropriate genetic mutation targeted by a given therapy.
So what does the payer landscape look like for AML self-administered therapies? What are common barriers/issues, and how are they mitigated? Regarding orally administered products for AML (e.g., Rydapt), we do not see many issues with PA denials. The denials we do see are generally resolved by submitting evidence that the patient has a genetic mutation (i.e., Rydapt – FLT3-ITD mutation).
How are manufacturers of AML therapies supporting patients (ex. HUB services, fee-for-service programs through SPs)? Manufacturers of AML products have standard services similar to non-AML products, such as Hub services, reimbursement assistance, patient support programs (manufacturer level), and patient support brochures. Regarding the oral targeted agents, no manufacturer in the AML marketplace executes a fee-for-service patient support program through an SP. This may be an area where you can set yourself apart from the crowd. As induction treatment universally starts inpatient, manufacturers for oral agents often have bridge-type programs to ensure the patient has a supply of medication when transitioning from inpatient to outpatient, which will help prevent any potential delay from an SP due to prior authorization requirements or the need for patient financial assistance.
What are other market trends associated with AML? In general, treatment is moving more toward oral targeted agents. Historically, AML has been a disease solely treated with intravenous agents.
Other Clinical Insights
There is also the consideration that some of these patients may transition from a hospital environment to an outpatient environment, which may require some coordination among the hospital, pharmacy, and oncologist. Onco360 seeks to understand how oncologists typically approach this coordination for AML patients. With the understanding that treatment for AML will likely begin in the inpatient setting, other manufacturers have instituted Quick-start/Bridge Supply-type programs to allow patients to appropriately transition from inpatient care to care at home regarding orally administered agents.
It is an unfortunate reality that there may be delays in terms of turnaround times (for first or subsequent fills) through an SP channel due to prior authorization needs or to acquire patient financial assistance. Following induction treatment, most patients go on to receive some form of consolidation treatment. If an SP is involved for dispensing the IV components of a regimen or is involved with dispensing an oral component of an AML regimen to be given in combination with buy-and-bill IV treatment, the SP will need to work in close coordination with the physician office to ensure that deliveries are made in a timely manner so as to not delay patient care.
Additionally, given the natural course of AML, patients may go in and out of inpatient care with an assortment of issues (e.g., febrile neutropenia), thus requiring clinical holds on treatment and potential dose reductions. At every transition in level of care (inpatient to outpatient, outpatient to inpatient, etc.), it is incumbent upon the SP to perform medication reconciliation to determine when the patient will restart therapy and at what dose. This is accurately performed by coordinating care directly with the prescribing physician.