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New Approvals in 2018 Change NCCN Guidelines for Hematologic Malignancies

Targeted Therapies in Oncology Staff Writer
Published Online: Dec 06,2018

Meletios A. Dimopoulos, MD
Recent FDA drug approvals in hematologic malignancies have changed the treatment paradigm of many diseases and resulted in necessary updates to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology.

Because they reflect clinical evidence and expert judgement, Targeted Therapies in Oncology summarized updates to the most recent clinical practice guidelines that are commonly used as a baseline in helping oncologists decide on which treatments are best for their patients.1
 

Waldenström Macroglobulinemia


The FDA recently approved ibrutinib (Imbruvica) plus rituximab (Rituxan) for the treatment of Waldenström macroglobulinemia (WM), or lymphoplasmacytic lymphoma, a rare form of B-cell lymphoma that is characterized by bone marrow infiltration by lymphoplasmacytic cells.2 The approval expands the label of ibrutinib in WM from its currently approved use as monotherapy to include the first nonchemotherapy combination in this malignancy.

Due to the rarity of this disease, there have only been a small number of studies that evaluate patients with this malignancy, and treatment strategies are relatively limited. New data from the phase III iNNOVATE trial, which evaluated the combination in 150 patients with both previously untreated or relapsed/refractory disease, has expanded the treatment options available for these patients.3

Patients were randomized to receive either ibrutinib or placebo, with all patients receiving rituximab. The 30-month progression-free survival (PFS) was significantly higher for the patients in the ibrutinib arm than for those receiving the placebo (82% vs 28%, respectively). The median PFS had not been reached for the patients in the ibrutinib arm by the median follow-up of 26.5 months, which was a improvement over the median PFS of 20.3 months experienced by the placebo group (P <.001). In addition, patients receiving the ibrutinib combination had an 80% lower risk of disease progression or death (P <.001).3 These data indicate the efficacy and superiority of the combination therapy over that of rituximab monotherapy in treatment-naive patients as well as those with recurring disease.

The lead author of the study, Meletios A. Dimopoulos, MD, chairman of the Department of Clinical Therapeutics at the National and Kapodistrian University of Athens School of Medicine, remarked, “We believe now that we have a new standard of care for the treatment of this disease.”

Prior to the introduction of this new therapy, the NCCN guidelines had recommended rituximab-based therapies for the treatment of WM.4 Rituximab is a monoclonal antibody that targets the lymphocyte antigen CD20, which is a protein that is expressed on the surface of infiltrating lymphoplasmacytic cells.

Rituximab has been somewhat successful as a monotherapy, with response rates between 25% and 45%. Combination therapies have resulted in improved outcomes, however, and preferred combination therapies include rituximab with bortezomib (Velcade) plus dexamethasone, rituximab with cyclophosphamide plus dexamethasone, and rituximab with bendamustine.

Ibrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor that has been effectively used as a single-agent therapeutic in this patient population.5 BTK is critical to the maturation of B cells and contributes to the proliferation of B-cell malignancies like WM. Previous NCCN guidelines considered single-agent ibrutinib to be in the category of “other recommended regimens” for primary treatment of WM and a “preferred regimen” for patients who received previous treatment for the disease.4 Two clinical trials in WM determined overall ibrutinib response rates between 70% and 100% in patients with mutations in MYD88 or CXCR4, 2 genes that are often mutated in the disease.6,7 Notably, patients in the iNNOVATE trial benefitted from ibrutinib/rituximab therapy regardless of MYD88 or CXCR4 mutational status.3

The ibrutinib/rituximab approval motivated updates to the NCCN guidelines for WM/lymphoplasmacytic lymphoma. These updates include the addition of ibrutinib plus rituximab as a category 2A therapy under “Other Recommended Regimens” for first-line therapy and in the “Preferred Regimens” category for patients who have received prior treatment.

The NCCN evidence blocks for this new recommended combination therapy indicate that although it is expensive, it is very effective, with a long-term survival advantage, mild or rare significant toxicities, and quality evidence supporting clinical use despite few trials.8 Evidence blocks are a visual representation of 5 key measures that provide important information about recommendations contained with the guidelines.9

Dimopoulos commented that future research in this area will focus on improving this treatment with additional therapies. “We need to add, in the context of trials, other agents to this backbone of [ibrutinib and rituximab], such as venetoclax [Venclexta] or bendamustine, or new proteasome inhibitors, such as carfilzomib [Kyprolis], to see whether…we may improve further upon these results.”

“In the future,” he adds “we would like to increase the depth of the response [… and] also, we would like to have regimens that will allow the patients to have a treatment-free interval.”
 

T-cell Lymphoma


Mycosis fungoides (MF) and Sézary syndrome (SS) are 2 subtypes of cutaneous T-cell lymphoma (CTCL) that were recently shown to benefit from mogamulizumab-kpkc (Poteligeo), a monoclonal antibody that targets CC chemokine receptor type 4 (CCR4).10 CCR4 is expressed on the surface of some malignant T cells. New clinical trial data regarding the use of this compound against cases of MF and SS have led to FDA approval and updates to clinical practice guidelines.

Patients with MF and SS make up approximately two-thirds of CTCL cases.11 A range of systemic treatment options exist for patients with one of these 2 subtypes, with variable data describing their efficacy. On August 8, 2018, the FDA announced the approval of mogamulizumab for the treatment of patients with relapsed or refractory MF or SS who have been previously treated with at least 1 other systemic therapy.12 Prior to this approval, the compound had been granted priority review and breakthrough therapy designations.

This approval was based on the results of the phase III MAVORIC trial, the largest randomized clinical trial that has ever been performed in patients with CTCL.13 This study evaluated the efficacy of mogamulizumab therapy in patients with relapsed or refractory MF or SS who had been treated with at least 1 other systemic therapy. The 372 patients enrolled were randomized 1:1 to receive treatment with mogamulizumab or vorinostat (Zolinza). Patients treated with mogamulizumab experienced a significantly longer PFS (median 7.7 months) compared with those in the vorinostat group (3.1 months; hazard ratio [HR], 0.53; 95% CI, 0.41-0.69; P <.0001). Adverse events (AEs) were similar in both arms.

Data from this study were published in The Lancet Oncology and Blood, where the authors state that mogamulizumab is “a valuable new therapeutic option in patients with MF and SS types of CTCL.”10,13

The NCCN guidelines for T-cell lymphomas have been updated to reflect this additional therapeutic option. Mogamulizumab has been added to the list of systemic therapies for patients with MF/SS as a category 2A recommendation.14 Mogamulizumab has also been added to second-line therapy and subsequent therapy options for adult T-cell leukemia/lymphoma with a category 2A designation.14

Mogamulizumab was also added to the list of preferred single-agents for adult T-cell leukemia/lymphoma. This addition contains a footnote that states important findings from a retrospective study indicated that patients who take mogamulizumab are at a higher risk for developing graft-versus-host disease when receiving an allogenic transplant within 50 days of treatment.15 This new approval and the subsequent updates to the NCCN guidelines provide an additional therapeutic option for patients with T-cell lymphomas, particularly those with MF and SS.
 

Hairy Cell Leukemia


Moxetumomab pasudotox (Lumoxiti) has been added to the list of therapies available for treating patients with hairy cell leukemia (HCL), a rare, slow-growing form of B-cell leukemia. HCL lymphocytes are characterized by cytoplasmic hair-like projections that give cells a distinct appearance.

The immunotoxin moxetumomab pasudotox consists of an anti-CD22 antibody fused to a truncated form of Pseudomonas exotoxin PE38.16 The antibody portion of the compound directs the toxin to CD22-expressing leukemia cells. Upon entry into the cytoplasm, the toxin inhibits protein synthesis and causes cell death.

A recent phase III study evaluated the efficacy of moxetumomab pasudotox in 80 patients with relapsed or refractory HCL. The objective response rate for these patients was 75% at 16.7 months, and 33 patients achieved a complete response.16 Peripheral edema (38.8%), nausea (35%), fatigue (33.8%), headache (32.5%), and pyrexia (31.3%) were the most frequent all-grade treatment-related AEs.

In response to these study results, the FDA approved the use of moxetumomab pasudotox for the treatment of patients with relapsed or refractory HCL who have been treated with at least 2 prior lines of therapy. Prior to this approval, moxetumomab pasudotox had been granted priority review, fast track, and orphan drug designations.17

These study results and subsequent FDA approval are encouraging, Javier A. Pinilla-Ibarz, MD, PhD, a hematologist/oncologist in the Department of Malignant Hematology at the Moffitt Cancer Center in Tampa, Florida, explained, “It’s quite exciting to finally have a drug approved for such a rare entity.”

Based on this new approval, NCCN guidelines have been updated to incorporate the newly available therapy. Moxetumomab pasudotox now has a category 2A recommendation for use in patients with relapsed or refractory disease who have been treated with at least 2 other agents.18

With this update comes a new section detailing special considerations for the use of moxetumomab pasudotox. This section explains that patients being treated with this therapy should be monitored for capillary leak syndrome (CLS) and hemolytic uremic syndrome (HUS). Patients who experience grade 2 CLS should be treated with corticosteroids and consider dose delay, and those with grade 3 or higher CLS should discontinue moxetumomab treatment. The guidelines recommend discontinuing moxetumomab in all patients with HUS.

According to the NCCN evidence blocks, this therapy is expensive, has a modest impact on survival, has a mild toxicity profile, and is supported by few clinical trials with variable outcomes.19

An additional approval for HCL for patients with progressive disease is promising for patient outcomes, said Pinilla-Ibarz, who further commented, “this approval, after 2 lines of therapy, is going to be really, really good news for patients who have had multiple relapses of hairy cell leukemia and are in need of other therapies,” as well as those “with a hairy cell leukemia variant that classically does not respond well to purine analogs.”
 

CLL/SLL and Follicular Lymphoma


September 2018 saw the FDA approve duvelisib (Copiktra) for use in patients with relapsed or refractory follicular lymphoma as well as relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL).20 Duvelisib is indicated in these populations for patients who have been treated with at least 2 prior lines of therapy. This approval was based on the results of 2 clinical trials: the phase II DYNAMO trial for follicular lymphoma and the phase III DUO trial for CLL/SLL.

DYNAMO evaluated 129 patients with indolent non-Hodgkin Lymphoma, including 83 with follicular lymphoma.21 The overall response rate for duvelisib in patients with follicular lymphoma was 41%, and the median overall survival was 18.4 months. The majority of AEs in the overall population were grade 1/2; neutropenia was the most common grade 3 AE, affecting 28% of patients. This study found duvelisib to be beneficial for patients treated with other regimens but who experienced refractory disease, and the relatively low toxicity makes it an option for many patients.

Ian W. Flinn, MD, PhD, director of Lymphoma Research at the Sarah Cannon Research Institute and lead investigator of the DYNAMO and DUO trials, explained the value of this new therapeutic option: “Unfortunately, our armamentarium is pretty small for patients with follicular lymphoma…Our options are very limited after chemoimmunotherapy, and so I think this is an important approval for these patients.”

Duvelisib has since been added to the NCCN guidelines, as a category 2A recommendation, as second-line therapy for patients with relapsed or refractory follicular lymphoma who have been treated with at least 2 other lines of therapy.22 The guidelines note that special considerations for the use of the small molecule inhibitor include avoiding the use of concomitant CYP3A inhibitors, inducers, and substrates. In the case of simultaneous administration with CYP3A inhibitors, however, the duvelisib dosage should be lowered to 15 mg twice daily, and patients should be monitored for signs of toxicity.

The DUO trial evaluated the use of duvelisib versus ofatumumab (Arzerra) in patients with relapsed or refractory CLL/SLL.23 In these patients, duvelisib significantly improved median PFS to 13.3 months with duvelisib versus 9.9 months with ofatumumab (P <.0001). The overall response rate for patients receiving duvelisib was 74%, which was significantly higher than the 45% response rate seen in patients who were treated with ofatumumab (P <.0001). Results of the trial supported duvelisib as a safe and effective treatment option.

The NCCN guidelines have been updated to reflect the addition of duvelisib for the management of patients with CLL/SLL without del(17p)/TP53 mutation. Duvelisib is now listed as a preferred regimen with a category 2A recommendation in most patients, including those considered frail with significant comorbidities and those older than 65 years.24 For patients with the del(17p)/TP53 mutation, duvelisib is now listed as a preferred regimen with a category 2A recommendation.

“Duvelisib is an inhibitor of both PI3K delta and gamma, so it is unique compared with other PI3K kinase inhibitors,” explained Flinn. “I think that having more options for these patients who are now progressing after other novel agents or after chemotherapy, is going to be an important new [treatment] for these patients.”
 

Tumor Lysis Syndrome


In addition to changes to the treatment regimen of CLL/SLL, the NCCN has made changes to the recommendations for the detection of tumor lysis syndrome (TLS) in this population. TLS, identified by laboratory hallmarks of high potassium, uric acid phosphorous, lactate dehydrogenase, and low calcium levels, occurs when large amounts of tumors cells undergo lysis and their contents are released into the bloodstream.

The explanation now specifies that TLS prophylaxis should be considered for patients with the following risk factors: renal disease or renal involvement by tumor, elevated white blood cell count, bulky lymph nodes, pre-existing elevated uric acid, progressive disease after small molecule inhibitor therapy, spontaneous TLS, or patients receiving treatment with venetoclax, chemoimmunotherapy, lenalidomide (Revlimid), or obinutuzumab (Gazyva).24

The guidelines further clarify the use of rasburicase (Elitek) as first-line therapy in treating patients with TLS by indicating its use for patients with the following risk factors: acute renal failure, situations in which hydration may be difficult, and high-bulk disease.
 

Chronic Myeloid Leukemia


Several changes to the latest version of the guidelines for the treatment of chronic myeloid leukemia (CML) relate to the use of second-generation tyrosine kinase inhibitors (TKIs) dasatinib (Sprycel), nilotinib (Tasigna), and bosutinib (Bosulif), as well as treatment response milestones.

In a statement regarding the use of second-generation TKIs, the FDA explains that, based on long-term follow-up data from the DASISION and ENESTnd trials and preliminary data from the BFORE trial, they are preferred for patients who exhibit intermediate or high-risk Sokal or Hasford scores.25 Previous recommendations suggest their use in this population whereas they are now considered preferred therapies. In particular, these therapies are recommended for women who aim to eventually discontinue the use of therapeutics for fertility purposes.

It is important for providers to consider the goals of each patient when recommending therapies like second-generation TKIs, said Jorge E. Cortes, MD, deputy chair and professor of medicine in the Department of Leukemia at MD Anderson Cancer Center in Houston, Texas. “…what we need to do is to have an honest conversation with the patient and see what the goals for each patient are…the goals for a young woman who wants to become pregnant…may be very different from an older gentleman who wants to just have minimum side effects, for example.”

Updates to the early treatment response milestones include the addition of a “concern” category to the color legend for disease considerations.25,26 Changes within the clinicalconsiderations added the recommendation to consider bone marrow cytogenic analysis to assess for major cytogenetic response at 3 months or complete cytogenetic response at 12 months in patients who fall in the yellow milestone category, which includes patients with a BCR-ABL1 >10% at 3 months or between 1% and 10% at 12 months.

Recommendations to consider treatment with the same TKI in second-line treatment of patients who fall into the yellow milestone category have been clarified to mean TKIs other than imatinib (Gleevec). A footnote was added to indicate that the continuation of 400 mg imatinib is not recommended for these patients. In the second-line treatment of patients in the yellow milestone category, the recommendation is to evaluate for allogenic hematopoietic cell transplantation (HCT). A footnote was added to the 12-month milestones that explains that BCR-ABL1 0.1% is associated with a high likelihood of achieving subsequent molecular response grade MR4.0, which may allow TKI therapy discontinuation.

Updates were also made to the clinical presentation decision tree. Under treatment considerations, “Treatment options are based on patient comorbidities and age” was removed and “allogenic HCT” was added as the final step following all treatment. A footnote was also added that explains that patients should be treated with a TKI if they present with accelerated-phase disease, and they should subsequently be evaluated for allogenic HCT.

In the definitions of blast phase, a footnote has been modified to indicate that criteria from the World Health Organization (WHO) are included in some reports, but the International Bone Marrow Transplant Registry criteria were used in most TKI clinical trials. The WHO criteria were moved from the figures to a footnote.

Under the criteria for cytogenetic response, the criteria for a minor cytogenetic response was updated to include responses from >35% Ph-positive metaphases to >35% to 65% Ph-positive metaphases.

Treatment-free remission (TFR) is an emerging topic of discussion for patients with CML and their healthcare providers, and in light of this new horizon, the criteria for TKI discontinuation were updated to include 2 footnotes. One footnote discusses the fact that TFR has not yet been evaluated in clinical trials, but based on data from studies in imatinib, dasatinib, and nilotinib, TFR following treatment discontinuation is anticipated to be similar irrespective of TKI in patients who have achieved deep molecular responses for more than 2 years.

An additional footnote was added to indicate that the EURO-SKI study found that the most significant predictor of successful imatinib discontinuation was MR4.0 for 3 or more years, and at least 6 years of imatinib therapy could also predict successful discontinuation. All were also reflected in changes in the discussion section to incorporate supportive data.

“We never thought we would be at this point, and some of us may have been actually skeptical even when we started hearing about these points. But it is real. It is here, and I think we need to help our patients get to that point,” explained Cortes.
 
 
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  20. Duvelisib Granted FDA approval for CLL and follicular lymphoma. Targeted Oncology™ website. targetedonc.com/news/duvelisib-granted-fda-approval-for-cll-and-follicular-lymphoma. Published September 24, 2018. Accessed November 10, 2018.
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New Approvals in 2018 Change NCCN Guidelines for Hematologic Malignancies
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