Samantha Hitchcock

live case-based peer perspectives program, Christopher Maisel, MD, recently discussed the treatment options and considerations he makes when treating patients with multiple myeloma. Maisel, a hematologist and oncologist at the Charles A. Sammons Cancer Center, Texas Oncology-Baylor, explained his treatment decisions and recent data that could impact his decisions based on 2 case scenarios.

A 77-year-old Caucasian man presented to his primary care physician complaining of fatigue. His past medical history revealed osteoarthritis with limited mobility. A physical exam showed pallor, hypertrophic changes at distal and proximal interphalangeal joints, poor grip strength, and bilateral swelling in shoulder joints.

His blood work indicated anemia (hemoglobin [Hb], 10.2 g/dL), hypercalcemia (corrected serum calcium [csCa]: 12.9 mg/dL), and slightly elevated creatinine (1.5 mg/dL); his creatinine clearance (CrCl) levels were 50 mL/min. Based on these findings, the patient was referred to hematology for further evaluation.

The patient&rsquo;s laboratory findings were notable for the following: peripheral blood smear showed rouleaux formation; Hb, 10.3 g/dL; creatinine, 1.3 mg/dL; CrCl, 61 mg/dL; M-protein, 1.4 g/dL; lambda free light chains, 4.43 mg/dL; lactate dehydrogenase, 186 U/L;

&beta;2 microglobulin (B2M): 3.8 mcg/mL; bone marrow biopsy showed 43% plasma cells; fluorescence in situ hybridization (FISH), t(14;16).

He was later diagnosed with multiple myeloma, high-risk and it was noted that he had an ECOG performance status of 1.

Based on the case, what are your initial concerns for this patient?

We see patients like this all the time at our practice. By modern American standards, we would not call him exceptionally elderly. The FISH t(14;16) for this patient concerns me because it is a high-risk cytogenetic feature. Additionally, his csCa is almost 13 mg/dL, which is an item of concern that needs to be immediately addressed. This patient needs treatment.

Can you identify the current treatment options for frontline multiple myeloma?

There is no right or wrong answer here, and it can be debated at some length. The category 1 preferred regimens from the National Comprehensive Cancer Network (NCCN) guidelines are: bortezomib (Velcade), lenalidomide (Revlimid), plus dexamethasone (RVD); lenalidomide plus low-dose dexamethasone (RD); bortezomib, cyclophosphamide, plus dexamethasone; and daratumumab (Darzalex) with bortezomib, melphalan, and prednisone (VMP). Other NCCN recommendations are a bit outside of label indications and they include: carfilzomib (Kyprolis), lenalidomide, and dexamethasone (KRD); carfilzomib, cyclophosphamide, and dexamethasone; and ixazomib (Ninlaro), lenalidomide, and dexamethasone.

Additionally, the doublet of bortezomib plus dexamethasone is used a fair amount in certain circumstances.

Would you consider a double or a triplet regimen for this patient?

The SWOG S0777 trial [considered this comparison] and mainly represented an older population, but all age groups were included.

The patients in the study had newly diagnosed multiple myeloma without the intention for immediate autologous stem cell transplant (autoSCT). This could include patients with comorbidities, as well as older patients. These are patients who fit our patient demographic. They were stratified 1:1 to receive induction with the triplet RVD versus RD. In the triplet regimen, the lenalidomide dose was 25 mg, which is our highest starting dose. Intravenous (IV) bortezomib was given, and this is something that we do not really do anymore. The comparative arm had the same doses of lenalidomide and dexamethasone. After 6 months of therapy, the patient went on to maintenance therapy until progressive disease or unacceptable toxicity. The maintenance therapy was also a very high dose of lenalidomide.

The primary endpoint was progression-free survival (PFS). The median PFS for the triplet regimen was 43 months versus 30 months for the doublet. That is a substantial difference, with a 2-sided

value of .004. In this trial, RVD significantly improved PFS. Additionally, overall survival (OS) was significantly improved, with a 2-sided

value of .03. In oncology, getting OS data in a study takes bigger power and a longer-duration follow-up. The median OS was 75 months with the triplet versus 64 months with the doublet. This tells us that the triplet up front seems to be have a better OS than the doublet.

What toxicities should oncologists be aware of with the triplet-regimen RVD?

In the SWOG study, rates of grade 3 or higher neurological toxicities for the RVD regimen were a lot higher, in addition to rates for pain, sensory, and gastrointestinal toxicities. This would be expected with the IV administration of bortezomib. With subcutaneous administration, neurotherapy and other associated toxicities are much less. In the case of our 77-year-old patient, using IV bortezomib twice a week could lead to a substantial change of neuropathy.

Could RVD-lite be a better option for this patient?

With RVD-lite, we are giving lenalidomide at a lower dose of 15 mg, and we are giving bortezomib once weekly subcutaneously. With RVD-lite there is an overall response rate (ORR) of 86% and a very good partial response (VGPR) or better rate of 66%.

This modified regimen seems to be less toxic, while preserving the ORR of the [full-dose] 3-drug regimen. With this regimen, I would say about 80% of my patients will experience fatigue; however, the peripheral neuropathy rate is only 2% grade 3 or higher. It is most likely the preferred option for this patient.

Are there other treatment regimens entering the landscape based on recent data?

The phase III MAIA study included transplant-ineligible newly diagnosed patients with multiple myeloma, with several stratifications.

The patients in this trial were randomized to either daratumumab, lenalidomide, plus dexamethasone or standard RD. There were about 370 patients in each arm, and the primary endpoint was PFS. In this study, the intent was that patients would not go on to autoSCT. The median age was 73 years, and more of these patients resided in Europe rather than the United States.

At 30 months, the PFS rate was 71% with the addition of daratumumab versus 56% for RD. The

value was statistically significant. These are very recent data supporting the use of daratumumab in the up-front setting without a melphalan-containing regimen. The median PFS was not reached with the triplet compared with 31.9 months [with RD]. We do not have enough data to determine OS; however, the ORR is 93% versus 81%, respectively, and there were more VGPRs and 3 times as much minimum residual disease (MRD) negativity among those treated with the triplet.

In terms of adverse events (AEs), there is a little bit more neutropenia, the same amount of anemia, and a little more lymphopenia, pneumonia, and potential for infection. This is not a significant difference compared to RD alone.

The phase III ALCYONE study was more recently published, and daratumumab plus VMP now has an FDA approval.

This study compared a very standard regimen of VMP, which is mostly used in Europe, with or without daratumumab in patients with untreated multiple myeloma who were not transplant candidates. We do not want to give melphalan for patients who may be collecting stem cells at some point. These patients had a good performance status and CrCl, with no preexisting neuropathy because they were going to get bortezomib.

Bortezomib was given subcutaneously in cycle 1 twice a week. Afterwards, it was given once a week. Melphalan and prednisone were given at the standard doses. The standard dose of daratumumab was also given at your standard dosing. It was given for 9 cycles and then it was either stopped or daratumumab was given for cycles 10 plus every 4 weeks until progressive disease.

The primary endpoint was PFS, and the secondary endpoints included OS. There was a fair number of patients who were included, with about 350 patients in each arm. The median PFS for the daratumumab-containing regimen was not yet reached. At 24 months, 63% of patients were progression free. This was compared to those who had VMP, where the median PFS was 19 months. This is a significant difference, with a median follow-up of 27.8 months. The

value was very statistically significant. All subgroups were favored, and the AEs were comparable in both arms, with more infection in the daratumumab arm.

Personally, I do not like giving melphalan and I find it to be challenging. I had a patient who was given a melphalan-containing regimen who experienced secondary myelodysplasia that was evolving in the leukemia. I think most American practitioners would agree with me that they do not use it. This is considered category 1 in the NCCN guidelines; however, it is a regimen that has not had a lot of uptake in the United States in the up-front setting.

How does MRD status affect your treatment decisions in multiple myeloma?

They briefly touched upon this in highlights of the American Society of Hematology, and MRD in myeloma is starting to get more traction. In the MAIA study, for patients who were MRD-negative, the percent surviving without progression is nearly 100% with the triplet regimen. In patients treated with RD who were MRD-negative, there was an 80% PFS rate up to 30 months. However, those who were MRD-positive at 30 months, the PFS rate is maybe 50%. Higher MRD-negativity rates are achieved with the triplet-containing regimen in the MAIA study.

The patient received continuous lenalidomide 15 mg plus low-dose dexamethasone. After 9 cycles of therapy, the M-spike plateaued at 0.6 g/dL and therapy with single-agent lenalidomide was continued.

Two years after diagnosis, the laboratory values were notable for the following: Hb, 11.4 g/dL; Creatinine, 1.0 mg/dL; M-protein rose from 0.6 g/dL to 1.2 g/dL to 1.5 g/dL. He also reported feeling tired. One month later, the patient complained of increasing back pain, fatigue, and weakness. Laboratory findings showed: M-protein, 2.1 g/dL; serum B2M, 6.2 mg/L; albumin, 2.1 g/dL; CrCl, 32 mL/min.

His PET/CT scan showed a new lytic lesion and new compression fracture in the L4/L5 vertebrae. Additionally, a bone marrow biopsy showed 30% involvement by abnormal-appearing plasma cells, confirmed by CD138+ immunohistochemistry stain. It was noted that he had an ECOG performance status of 2.

What factors do you consider when choosing the next therapy for this patient?

This patient received continuous RD. After 9 cycles of this doublet, his M-spike plateaued at 0.6. He achieved what we would call a PR, but not a VGPR. Then he was given single-agent lenalidomide. He [was] on this for 2 years after his diagnosis; however, his M-protein [rose] again and he reported feeling tired. I would have changed therapy at this point; however, they did not do this in this case. A month later, he [continued] to progress, and we [wanted] to give him new therapy. When deciding on my next choice of therapy, I would consider his renal function, performance status, the fact that he is lenalidomide-refractory, and he is now 80 years old.

Which backbone would you consider, and what AEs are of concern in an older patient such as this?

Infection is always a concern for the older population. We are probably less concerned about neuropathy. If we decide to treat this patient with bortezomib, we would use it once a week subcutaneously and it wouldn&rsquo;t be a problem. In general, this is someone who needs a proteasome inhibitor [PI]. He has had immunomodulatory therapy, he has become refractory to lenalidomide, and he has high-risk cytogenetics. A PI backbone would be the proper choice for this patient.

A 61-year-old Caucasian women was diagnosed with stage II multiple myeloma and her genetic testing showed t(11;14). At the time, she was treated with RVD induction therapy, followed by autoSCT. With this therapy, she achieved a complete remission and was placed on lenalidomide maintenance therapy.

Are you using MRD testing today, and if so, how do you use it?

I would like to use it; however, we do not yet have routine capability. There are data that show PFS and OS are significantly improved for patients who are MRD-negative versus MRD- positive.

This gives us further incentive for MRD testing, but we also should consider if insurance will pay for it.

On routine follow-up, the patient reported having mild fatigue, but continued to work full time. It was noted that she had grade 1 neuropathy. Her laboratory values showed: M-protein, 1.4 g/dL; light chain levels continued to rise; Hb, 10.3 g/dL; creatinine, 1.3 mg/dL.

Are you aware of any new data supporting regimens in the setting of relapsed disease?

Although it is not new, the phase III POLLUX trial studied the comparison of daratumumab, lenalidomide, and dexamethasone (DRd) versus RD in patients who were not lenalidomiderefractory.

There was a significant improvement in PFS for patients treated with DRd. It would not be an ideal regimen for this patient, however, because she had lenalidomide in the up-front setting, lenalidomide in the maintenance setting, and then progressed. For this patient, we would likely choose a PI as the backbone of therapy.

The phase III ARROW study compared once- versus twice-weekly dosing of carfilzomib plus dexamethasone in patients with relapsed/refractory multiple myeloma with 2 to 3 prior lines of therapy.

The once-weekly dose of carfilzomib was 70 mg after an initial dose of 20 mg. The twice-weekly dose of carfilzomib was the standard 27 mg after an initial dose of 20 mg. In the trial, the PFS was significantly improved with the once-weekly dosing, 11.2 months versus 7.6 months. The

value was also statistically significant.

If you look at the subgroup of this study, patients who were younger than 65 years seemed to benefit more in terms of PFS with the once-weekly dosing. For patients with high-risk cytogenetics, there was also a trend to benefit and patients who were refractory to lenalidomide also tended to benefit more than those who were not.

The ELOQUENT study compared elotuzumab (Empliciti), pomalidomide (Pomalyst), and dexamethasone versus pomalidomide and dexamethasone alone for patients who progressed on lenalidomide.

The drug was given 10 mg IV every week for cycles 1 and 2, and then every 4 weeks it was given at 20 mg. Pomalidomide was given at a dose of 4 mg orally on days 1 through 21, and dexamethasone was at a dose of 40 mg every week.

Articles

During a Targeted Oncology live case-based peer perspectives program, Christopher Maisel, MD, recently discussed the treatment options and considerations he makes when treating patients with multiple myeloma.

Maisel Reviews Treatment Options for Multiple Myeloma in 2 Case Studies

live case-based peer perspectives program, B. Douglas Smith, MD, discussed his clinical consideration for the management of acute myeloid leukemia (AML). Smith, professor of oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medicine, explained his treatment decisions during the dinner event in 2 case scenarios of patients with AML.

A 65-year-old woman presented to her primary care physician with bruising and fatigue from her daily 3-mile walk. His medical history revealed hypercholesterolemia, which was controlled with atorvastatin (Lipitor). She was diagnosed with acute myeloid leukemia (AML).

At this time, her laboratory findings revealed the following: white blood count (WBC): 2.8 x 10

/L; hemoglobin (Hb): 9.1 g/dL; platelets: 40 x 10

/L. She had an ECOG performance status of 0. Additionally, her bone marrow biopsy showed that her cytogenetics were normal; blasts percentage: 48%.

: What genetic and molecular tests are ordered routinely at your practice?

Everybody uses a slightly different platform. Unfortunately, some places might struggle with payment. In 2019, I think everyone should be getting some molecular testing on their patients with AML. On average, we know that there will be between 3 to 8 different mutations in every patient. I think there is valuable information there. This patient had

mutations3 mutations, which is very common in a newly diagnosed leukemia.

Next-generation sequencing (NGS) was completed, which revealed mutations in

What treatment options would you consider for this patient?

The first choice for someone like this is always a clinical trial. Chemotherapy cytarabine plus idarubicin (7 + 3) plus an inhibitor on a clinical trial would certainly be something worthwhile. It is closed now, but we did have it open. The 7 + 3 combination alone is also available, but it is not approved in the frontline setting for patients with

mutations. It is certainly not approved in combination yet, but those trials are currently being done.

In this situation, we would be thinking about traditional induction chemotherapy for a patient such as this. Her performance status is great, even if she is a little older. Her cytogenetics are normal and we don&rsquo;t have

mutations, simply because these drugs aren&rsquo;t indicated in the frontline setting at this point.

What are your expectations from traditional induction chemotherapy?

This patient was given 7 + 3. When you talk to a 60-year-old patient like this, [you tell them that] the likelihood that this regimen will work is two-thirds of the time. We don&rsquo;t know exactly what her mutations do individually, but we do expect the induction therapy to work.

What are the adverse events (AEs) associated with this regimen?

When you look at large, retrospective studies, the percentage of mortality ranges from a couple of percentage points to 18%, or even 20% for 30- to 60-day mortality for induction therapy in patients aged more than 60 years. For a patient with a good performance status, I tell people it is around 5%. Patients aged over 70 is when the percentage increases to 12%, 18%, and then 30%. We have significant mortality in that patient population.

The patient did have mucositis and febrile neutropenia, but she ended up getting a remission and went on to get 2 cycles of consolidation therapy. It was a fair success.

Her treatment course was complicated by mucositis and febrile neutropenia. After resolution of her complications, the patient received 2 cycles of intermediate-dose cytarabine consolidation.

Six months after initial diagnosis, she presented with fatigue, aches, and gum bleeding. Her laboratory findings were notable for the following: WBC: 22.8 x 10

/L; 20% circulating myeloblasts; absolute neutrophil count (ANC): 450 cells/mL. Her bone marrow biopsy showed hypercellular 80% blast; normal cytogenetics. NGS testing revealed the same mutations in

What treatment options would you consider for this patient after disease progression?

This person did not go on to transplant, and 6 months later she presented with bleeding. She relapsed pretty early, and the mutations have recurred with this relapse.

The recently approved drug for patients with

mutations in this setting is enasidenib (Idhifa). It definitely takes time to get, but we have not had any trouble getting it paid for. We know that between 10% to 15% of patients with AML will have&nbsp;

mutations. They are pretty common mutation, including in people whose disease comes out of myelodysplastic syndrome. You have to know that the mutation results in accumulation of 2-hydroxyglutarate, which blocks differentiation. It is epigenetically driven. The idea is that the cells don&rsquo;t differentiate normally when you have&nbsp;

drug is enasidenib. This was from a phase I/II study with an expansion arm that arrived at the idea that the best dose of this drug was 100 mg a day.

The drug was dosed continually for 28 days, and doses went from 50 mg upward.

Can you provide greater detail about this trial?

The patients on this trial had to have the

mutation. The majority of them had relapsed/refractory AML and were aged over 60. This was an alternative to reinduction with some chemotherapy-based regimen. When you look at the overall response rate, about 40% of patients responded.

Interestingly, it takes a couple of cycleson average, 2 cycles&mdash;until you get a first response. Best response might be closer to 3 or 4 cycles. This should remind you of hypomethylating agents. We used to tell physicians who gave these agents to go through 6 cycles with your patient until you could declare it didn&rsquo;t work. You had to get through multiple cycles. I tell people now, after 2, 3, or 4 cycles, you should be seeing some change in blood counts if you are headed in the right direction with the hypomethylating agents. I don&rsquo;t give up until 4 to 6 cycles, but if you see bad blood counts after 3 or 4 cycles, it is not clear that the patient will respond. It is the same with these drugs. You need multiple cycles to make sure you are going in the right direction. And you should be able to see some changes in blood counts by as early as a couple of cycles.

The chance of getting a remission here is probably better than with chemotherapy. That is why we are thinking about targeted therapy. The downside is that the median duration of response is 8 to 9 months. This doesn&rsquo;t fix everyone, but it does create a window where you can get someone who is in early relapse to stem cell transplant if you didn&rsquo;t transplant them at the beginning.

Enasidenib was initiated at 100 mg daily and after 3 cycles, the patient had stable disease. Then, after 5 cycles, laboratory results showed the following: peripheral blasts, 15%; ANC, 1.1/mm

Can you explain the outcome of stable disease in this patient after starting enasidenib treatment?

A key thing with these drugs is that sometimes you get stable disease. Now we have patients with stable disease with peripheral blasts for 6 to 15 months. They don&rsquo;t get worse, but they are not in a remission. That is not great for this person who is going to move to transplant, but for a 75-year-old patient who you are keeping stable, that is a reasonably good response. We believe that stable disease is important in these patients.

What are the AEs associated with enasidenib?

The majority of the AEs were grade 1 and grade 2 in the trial. But we think about gastrointestinal upsetincluding diarrhea, poor appetite, vomiting, hyperbilirubinemia&mdash;and liver function test abnormalities. Those tend to be some of the common treatment-related, single-agent AEs.

Two weeks later, she had dyspnea on exertion and mild swelling and a physical exam noted crackle bilaterally. Her Chest x-ray later noted bilateral infiltrates. Additionally, an increased indirect bilirubin of 1.9 mg/dL was noted.

What is the significance of the clinical symptoms experienced by this patient?

In [recent news], there have been 3 reported deaths from differentiation syndrome with this class of drugs. The FDA is up in arms about it. The drug is approved, but this is the number-1 issue. People actually die from it, and you have to be aware of that.

How is differentiation syndrome optimally managed?

Most of the time, you should probably stop the medication. You don&rsquo;t have to. If you have mild differentiation syndrome and you use steroids, you might be able to leave the patient on the drug. However, when you see this, a lot of people would recommend hospitalizing the patient and giving them a few days of steroids to make sure things normalize. Differentiation syndrome is a big deal and it is worth thinking about.

Dexamethasone 10 mg every other day and antibiotics were started, and her pulmonary symptoms resolved in 1 week. A bone marrow biopsy after 6 cycles showed: morphologic complete response (CR); 2% blasts by flow cytometry; persistence of IDH2 mutation by NGS.

After the patient goes into remission, what would you consider for the next step in treatment?

This patient should go on to an allogeneic stem cell transplantation (alloSCT). In my practice, we would start a donor while we were beginning treatment, and if the patient had an excellent response, the discussion would be: Should we continue therapywhere the responses last 8 to 12 months&mdash;or should we move on to transplant after 4 to 5 cycles? Transplant is the curative option for this disease.

A healthy 48-year-old man who was on no medication visited his primary care physician for flu-like symptoms lasting more than 2 weeks. His laboratory findings were notable for the following: WBC: 56,000 x 10

; liver and cardiac functions within normal limits; bone marrow 65% blasts.

His cytogenetics revealed normal cytogenetic risk by European LeukemiaNet classification. Additioanlly, molecular testing showed the following:

internal tandem duplication (ITD)positive (low allelic ratio);

What induction therapy would you offer this patient?

During a Targeted Oncology live case-based peer perspectives program, B. Douglas Smith, MD, discussed his clinical consideration for the management of acute myeloid leukemia. Smith explained his treatment decisions during the dinner event in 2 case scenarios of patients with AML.

Mutational Testing an Important Factor in AML Treatment Paradigm, Smith Explains

case-based peer perspectives program, Elias Jabbour, MD, discussed his clinical considerations for the management of chronic myeloid leukemia in chronic phase (CML-CP). Jabbour, a professor in the Department of Leukemia at the University of Texas MD Cancer Center, explained his treatment decisions during the live event based on a case scenario of a patient with CML-CP.

A 64-year-old man presented to his primary care physician with symptoms of fever, left upper-quadrant pain, and severe fatigue. In 2012, he fainted due to QT syndrome, which was managed with propranolol. In 2014, he was diagnosed with stage III kidney disease (glomerular filtration rate, 45 mL/min) and non

small cell lung cancer (NCSLC; stage IIa squamous histology), which was treated with resection and chemoradiotherapy; pleural effusion managed with thoracentesis.

His physical exam revealed that his spleen was palpable 1.5 inches below costal margin. The patient was referred to hematology based on his laboratory findings: white blood count (WBC), 172,000/

mcL (metamyelocytes, 3%; myelocytes, 6%; basophils, 6%; blasts, 2%); hematocrit (HCT), 30%; platelets, 536,000/

mcL; hemoglobin (Hb), 9.9 g/dL. His bone marrow evaluation showed Philadelphia chromosome positive (Ph+) in 20/20 metaphases. Additionally, a quantitative-polymerase chain reaction revealed his BCR-ABL1/ABL1 value was 90% IS. The patient was later diagnosed with CML-CP.

Describe the patient&rsquo;s risk status and how it affects your treatment decision.

This patient is asymptomatic and has a high WBC, and his spleen is 1.5 inches below the costal margin. With any score you use, this is going to be high-risk disease. Patients with CML are often asymptomatic. In the United States, 75% of patients will come in to see you with low-risk disease by any score. Few, such as this patient, will have a high WBC and high-risk disease.

All the scoring systemsSokal, Hasford, and European Treatment and Outcome Study&mdash;were established before the tyrosine kinase inhibitors (TKIs) were invented. However, we know that they do correlate with patient responses, which does affect your treatment decision. This man is a high-risk patient. What would you prescribe? You might decide to prescribe dasatinib (Sprycel) because of the risk features. The insurance will ask for a co-pay of $1000 per month. If you give him imatinib, however, they will not ask for anything. Does this justify your decision? Overall, there is no survival difference.

In my practice, I would try to convince the insurance company to cover dasatinib or nilotinib (Tasigna). There is an up-front risk of transformation, which is higher with imatinib (Gleevec) compared with the newer drugs. On a larger scale, the difference is not significant, and it does not affect overall survival. If I have to pay $1000, I cannot make the case to pay it because I want to avoid the 2% transformation rate with imatinib; however, all conditions equal, I would favor dasatinib, nilotinib, or even bosutinib in the frontline setting.

What challenges are presented when patients have multiple comorbidities?

This is not a typical patient. People may say that his multiple cancers may limit my options of TKIs. However, 1 thing that is for sure is that TKIs do no create an increase of other cancers. We look at the database as a whole, and there is no increase in incidences of cancer. The only TKI where you do not have to look at an electrocardiogram for QT syndrome is bosutinib (Bosulif). All the other TKIs&rsquo; package inserts will tell you to check for that.

In December 2014, the patient was started on therapy with imatinib 400 mg/day. In March 2015, his BCR-ABL1/ABL1 value was 10% IS and by June 2015, it decreased to 6% IS.  In September 2015, however, his BCR-ABL1/ABL1 increased to 9% IS.

In December 2016, his BCR-ABL1/ABL1 value was 75% IS and a bone marrow evaluation revealed Ph+ in 19/20 metaphases. His Sanger sequencing was negative for known TKI resistance mutations. Laboratory findings were notable for the following: WBC, 184,000/

mcL (metamyelocytes, 5%; myelocytes, 6%; basophils, 5%; blasts, 3%); HCT, 40%; platelets, 124,000/

How would you characterize the patient&rsquo;s response to imatinib?

Three months down the road, the BCR-ABL1/ABL1 is down to 10%, which is excellent. At 6 months, it is down to 6%. We continue to tell him to take his drugs and not miss a dose, but in September 2015, he comes in with 9% BCR-ABL1/ABL1. This may tell me that he is not taking his medicine. The first thing you should do when you see the BCR-ABL1/ABL1 going up is ask the patient if they are taking the drug. We waited it out, and the patient did well for a while.

In December 2016, he comes to see us and has a BCR-ABL1/ABL1 of 75%, and he has progressed. We should check for mutations at this point because when you fail, you can acquire change in the amino acid domain that the drug will not find. In this case, no mutations were detected. At this point, he has lost his response fully.

Does the fact that the patient has no known mutations affect your thinking about next steps?

Patients who don&rsquo;t have mutations tend to do worse than those that do. However, it does not affect anything. If the patient has the mutation, then you have to choose your drug based on the mutation profile. If there are no mutations, you can go with any agent based on the patient&rsquo;s comorbidities and your affinities.

How would the patient&rsquo;s medical history factor into treatment choice?

One thing to be careful about at this point is that he had lung cancer, and he had pleural effusions in his past medical history. Therefore, he may be at a higher risk of pleural effusion. We should keep that in mind, but it is not an absolute deprecation.

He had long QT syndrome, which does not make me comfortable with using nilotinib. He had kidney disease, which does not affect any TKI response. Bosutinib, however, can increase the creatinine levels a little bit at the beginning, and you can have diarrhea and/or dehydration. Dasatinib compared with nilotinib and imatinib can cause more thrombocytopenia. If this patient is on clopidogrel (Plavix), for example, you can have heightened bleeding.

What options are available&nbsp;for this patient?

In somebody who has a history of lung chronic obstructive pulmonary diseasebecause they were a smoker prior to their lung cancer&mdash;with a QT segment of concern, high-dose imatinib does not help. The right drug to prescribe is bosutinib, and you give loperamide (Imodium) with that because the rate of diarrhea is 80% in the first 2 days. But that is fine.

The patient was treated with bosutinib and at 3 months, he achieved a complete hematologic response (CHR) however, he lost his CHR at 6 months. No kinase domain mutation was encountered.

What would you do after he loses his response to

This man is truly resistant, and the best drug right now to get him to respond is ponatinib (Iclusig). For this scenario, to give dasatinib after failing bosutinib would produce an overall response rate (ORR) of just 20% or less. Additionally, the dasatinib profile is similar to that of bosutinib, from the perspective of molecular profiling. Nilotinib post bosutinib is the worst drug option. I would have given imatinib, nilotinib, dasatinibbut I would not have done the reverse.

There was a meta-analysis, and when you compare ORRs with a second-generation TKI, the best response rate is 24%. If you give ponatinib, you are at 56% to 60%. if you want the patient to live longer, your best bet is to give ponatinib. You are limited in your choices here.

The label is for 45 mg per day; however, I do not do this. This is 1 of the examples of where the FDA approves a drug and we do not use it as approved. I use it at 30 mg or possibly even 15 mg. The reason I use it at a lower dose is to avoid complicationsmainly, vascular events.

It is an expensive drug because when it was first approved, the company came with 15-mg and 45-mg pills and priced them the same. When vascular events started to happen [at the higher dose] and we started to dose reduce the patients, a lot of patients started using 30 mg, and that is when you take 2 tabs of 15 mg. In Europe, the government forced them to drop the price of the 30-mg tablets, which cost the same as the 15-mg and 45-mg tablets. In the United States, you can do whatever you want because it is a free market, and they priced the 15 mg pills the same as the 45-mg tablets because now we buy two 15-mg tablets. It becomes double the price. There was a bill that went to floor for Medicare, Medicaid, and other big payers to be able to negotiate with pharma to lower the prices; however, this bill did not get the vote.

What is the potential to transition to a lower dose based on achieving a long-term remission?

My goal when I&rsquo;m treating a patient who has a good response is to lower the dose and maintain them at 15 mg. Usually, this does happen within 3 months of therapy.

What would be your approach to next-line therapy if the CML relapses?

During a Targeted Oncology case-based peer perspectives program, Elias Jabbour, MD, discussed his clinical considerations for the management of chronic myeloid leukemia in chronic phase.&nbsp;Jabbour explained his treatment decisions during the live event based on a case scenario of a patient with CML-CP.

Jabbour Reviews TKI Options in Case Study of Chronic Phase CML

The healthcare community is still awaiting a response from the Centers for Medicare & Medicaid Services (CMS) to the opposition of the agency&rsquo;s proposal to substantially revise the Medicare Part D protected drug classes.

Protection of the 6 drug classes within the Part D prescription drug plan, which include antineoplastics such as chemotherapies, was instituted in 2006 to ensure that commercial health plan sponsors of the newly launched Medicare Part D program would make these drugs available to patients.

CMS contends that the protected-class categories were not intended to be permanent and that the protected status has caused the costs of these drugs to be higher for Part D coverage than for private plans. CMS states that the discounts on these drugs for private plans are in the range of 20% to 30%, versus 6% for Part D participants. &ldquo;The protected class policy is in need of an update to ensure that beneficiaries who depend on these drugs are getting the same discounts that other beneficiaries get,&rdquo; wrote Alex Azar, secretary of the Department of Health & Human Services (HHS), and Seema Verma, administrator of CMS, in a November statement.

Approximately 60 patient advocacy groups have joined the American Cancer Society Cancer Action Network&rsquo;s (ACS CAN) campaign to stop Medicare Part D health plans from scaling back coverage for these protected-class drugs, which also include anticonvulsants, antidepressants, antipsychotics, antiretrovirals, and immunosuppressants.3 The groups argue that the protections ensure patient access to a wide variety of nontherapeutically equivalent drugs within each class, which is essential because some available drugs work better than others for different patients, and doctors and patients need a choice, especially for chemotherapies. Without the protections, some of these drugs might drop off formularies, or step requirements and prior-approval processes could make accessing them more difficult, opponents argue.

A case in point, they say, is reflected in the subclass of antineoplastics known as tyrosine kinase inhibitors, &ldquo;which have been developed to treat cancer, but each drug within this category may target a different mutation that is relevant to a small subcategory of patients with a given disease,&rdquo; ACS CAN wrote in opposition to the proposed revision. The proposal for change was released by CMS in November 2018. The requirement to cover protected drug classes significantly lessens Part D plan sponsors&rsquo; negotiating power with drug providers such as manufacturers, according to CMS.

Opponents of the proposed change contend that within the existing protected-class framework, Part D plans can tier drugs, which does provide a form of leverage, and can allow management of these classes of drugs for savings.

They argue that &ldquo;generic utilization for drugs within the 6 protected classes is higher than [that of] other drug classes (92% vs 84%).&rdquo;

A similar effort to revise the protected-classes provision of Part D was attempted in 2014 but abandoned owing to contention among stakeholders. Verma and Azar have revived the effort under the drug-pricereduction banner raised by President Donald Trump in his &ldquo;blueprint&rdquo; for change. &ldquo;HHS has been hard at work to make the president&rsquo;s vision a realitybecause the status quo is simply unacceptable,&rdquo; Azar and Verma wrote.

Under the proposed revision to Part D, Part D plan sponsors would be required to keep a minimum of 2 drugs in their formularies for each of the 6 protected classes starting in 2020. CMS would allow the plans to exclude the remaining drugs with price increases greater than the rate of inflation, as well as new drug formulas that are not a significant innovation over the original products. The proposal also notes that plans would be allowed to exclude a newer formulation of an older drug, even if the older version is no longer on the market.

Additionally, the plans would be permitted to implement prior authorization or step therapy, the practice of using the most cost-effective drug therapy first and progressing to more costly or risky therapies only if needed. According to Azar and Verma, plan sponsor step therapy requirements would be fenced in by patient protections, which would include a CMS review on an annual basis and expedited appeals through which physicians could recommend an exception.

Opponents say that these reviews would be time-consuming and potentially perilous for patients whose health conditions require immediate action. &ldquo;Such policies may unnecessarily impede patient access to needed cancer care and lead to irreversible disease progression and other significant health risks,&rdquo; the American Society of Clinical Oncology (ASCO), which has joined the protest, said in a January 18th statement.

The Community Oncology Alliance has joined the struggle to prevent the policy change. Ted Okon, MBA, the group&rsquo;s executive director, said that care decisions based on cost are ultimately bad for patients and run counter to the principles of good medicine.

&ldquo;When it does not work, and the patient goes to the hospital because they are not getting the appropriate treatment, it is going to cost more. It is a very short-term strategy,&rdquo; he said.

In an interview with Targeted Therapies in Oncology, Jeffery C. Ward, MD, said that downsizing the protected-class policy would lead to negative health outcomes, increased costs for Medicare Part D health plans through increased morbidity, and higher beneficiary cost sharing. Starting patients on less-than-ideal drugs is a bad idea, he said.

&ldquo;With step therapy, for example, the cheaper drugs [used] may be more toxic,&rdquo; said Ward, a medical oncologist at the Swedish Cancer Institute and the current chair of ASCO&rsquo;s Government Relations Committee. &ldquo;With toxicities come increased supportive care costs [including] expensive emergency department visits and hospitalizations.&rdquo;

Similarly, ACS CAN said the requirements for step therapy and prior authorization would create unnecessary administrative challenges for physicians. The group said physicians report that prior authorization is behind most care delays, and these administratively burdensome processes are linked to patients abandoning prescribed treatments.

Okon contended that &ldquo;eliminating the protected classes would allow third-party entities to make the treatment decisions. They are going to include drugs that get the best deal for them, and it is questionable [whether] it will ever save money for Medicare or Medicaid patients.&rdquo;

Proposed changes to lower drug prices in Medicare Advantage and Part D. US Department of Health & Human Services website. hhs.gov/blog/2018/11/26/ proposed-changes-lower-drug-prices-medicare-advantage-part-d.html. Published November 26, 2018. Accessed February 25, 2019.

CMS takes action to lower prescription drug costs by modernizing Medicare [news release]. Baltimore, MD: US Centers for Medicare & Medicaid Services; November 26, 2018. cms.gov/newsroom/press-releases/cms-takes-action-lowerprescription- drug-costs-modernizing-medicare. Accessed February 6, 2019.

ACS CAN and nearly 60 patient advocacy groups send letter raising alarm over changes to Medicare Part D cancer drug coverage [news release]. Washington, DC: American Cancer Society Cancer Action Network; January 28, 2019. fightcancer.org/releases/acs-can-and-nearly-60-patient-advocacy-groups-sendletter- raising-alarm-over-changes. Accessed February 25, 2019.

Medicare&rsquo;s six protected classes explained. Fightcancer.org website. fightcancer. org/policy-resources/medicare%E2%80%99s-six-protected-classesexplained. Published July 20, 2018. Accessed February 25, 2019.

ASCO joins groups urging Congress to reject proposed changes to Medicare Part D. American Society of Clinical Oncology website. asco.org/advocacypolicy/ asco-in-action/asco-joins-groups-urging-congress-reject-proposedchanges- medicare. Published January 18, 2019. Accessed February 25, 2019.

The healthcare community is still awaiting a response from the Centers for Medicare &amp; Medicaid Services to the opposition of the agency&rsquo;s proposal to substantially revise the Medicare Part D protected drug classes.

Samantha Hitchcock | Authors

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