Chronic Lymphocytic Leukemia

Comanaging Chronic Lymphocytic Leukemia and Chronic Myeloid Leukemia: A Case Report

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Background

Agents that target B-cell signaling pathways, such as ibrutinib, idelalisib, and venetoclax, provide durable responses while drastically changing the adverse effect profile in the management of chronic lymphocytic leukemia (CLL).1–4 Ibrutinib is a first-generation Bruton’s tyrosine kinase inhibitor (BTKi) that has been shown to be effective in frontline and relapsed/refractory CLL, including in patients harboring a 17p deletion.2,5 Ibrutinib irreversibly binds to BTK, which is stimulated by the B-cell receptor and other cytokine receptors. Ibrutinib and other targeted agents have modified the landscape in the management of CLL.

Similar to CLL, the use of small-molecule tyrosine kinase inhibitors (TKIs) for the management of chronic myeloid leukemia (CML) has led to significant improvement in outcomes. These TKIs (eg, imatinib, dasatinib, nilotinib, bosutinib) have transformed CML from a fatal malignancy to a chronic disease with which most patients achieve a normal life expectancy.6–10 Despite the success of these therapies, some patients will either not tolerate first-line TKI or not achieve response milestones.11,12 Second- and third-generation TKIs (dasatinib, nilotinib, bosutinib, ponatinib, asciminib) have been shown to be efficacious for second and later lines of therapy, allowing patients to remain on oral therapy for long periods of time, even after other TKIs have failed.13–17 Nonetheless, these agents are affected by prevalent drug–drug interactions.18

One potential common target for both CLL and CML is inducing apoptosis through BCL-2.4,19 The BCL-2 family of proteins regulates the mitochondrial apoptotic response. Constitutionally elevated expression of BCL-2 leads to resistance to apoptosis. Venetoclax, a small molecular inhibitor, mimics BH3 and binds to the BCL-2 protein, causing a displacement of proapoptotic proteins, restoring apoptosis, and causing subsequent malignant cell death. Aberrant BCL-2 activity has been implicated in many types of cancer, including CLL, acute myeloid leukemia, and CML.4,19–27 Venetoclax is now an established therapeutic option in CLL, for use as first-line therapy or in relapsed/refractory disease.3,4,28–30 This report presents a case of concomitant use of venetoclax and imatinib for the comanagement of concurrent CLL and CML.

Case Report

The patient was a 73-year-old woman with a remote history of stage I breast cancer status post a partial mastectomy and brachytherapy in 2008, gastroesophageal reflux disease, dyslipidemia, and hypertension. She was diagnosed with CLL in 2012 at an outside facility, and initial immunophenotype, cytogenetics, indications for therapy, and staging were not known. She received one cycle of bendamustine + rituximab, which was complicated by severe anemia. She refused further bendamustine + rituximab therapy and was maintained on active surveillance. Her CLL remained quiescent until August 2018, when she was found to have a worsening WBC count of 31,000/mcL along with worsening lymphadenopathy of the neck, chest, abdomen, axilla, and pelvis. PET/CT imaging showed a new prevertebral soft tissue mass in the nasopharynx with a maximal standardized uptake value of 5.8. This mass was not biopsied. Flow cytometry on a bone marrow biopsy was variably positive for CD20 and CD23 (Figures 1 and 2). Fluorescence in situ hybridization (FISH) on bone marrow was positive for trisomy 12 and 14.q32.3, but negative for TP53 and ATM. It was determined that the patient had Rai stage I CLL. She was started on ibrutinib at 420 mg orally once daily, but the dose was reduced to 280 mg once daily shortly after initiation due to the development of skin rashes. After the dose reduction, her skin rashes resolved. Two years into therapy, restaging CT chest scan showed improvement but not resolution of lymphadenopathy, consistent with partial response.

Figure 1.

Figure 1.

Peripheral blood smear showing chronic lymphocytic leukemia/small lymphocytic lymphoma, August 2018. (A) Lymphocytes with numerous smudge cells are visible. (B, C) Bone marrow core biopsy shows diffuse infiltration of small lymphocytes with CD20 expression. On high magnification, a diffuse increase in small lymphocytes is seen.

Citation: Journal of the National Comprehensive Cancer Network 21, 2; 10.6004/jnccn.2022.7069

Figure 2.

Figure 2.

Bone marrow aspirate flow cytometry using CD45 versus side scatter (August 2018) separates the cells into regions: granulocytes (R4: 9%), monocytes (R3: 1.4%), and lymphocytes (R8: R2 + R5 + R7 = 83%). Within the lymphocyte population, 78% of clonal B cells (R2: green) represent lambda-restricted CD5(+) and CD23(+). Proliferation index showed 5% positivity.

Citation: Journal of the National Comprehensive Cancer Network 21, 2; 10.6004/jnccn.2022.7069

In October 2020, the patient presented to our lymphoma service for management and was found to have leukocytosis and mediastinal lymphadenopathy but no organomegaly, remaining Rai stage I. At presentation, the patient reported fatigue; otherwise the physical examination was unremarkable. She was found have a resolved hepatitis B infection, and tenofovir was initiated. A subcarinal lymph node biopsy was completed in January 2021 (Figure 3), which was positive for CD45, CD5 (dim), CD11c (dim), CD19, CD20, CD22, CD52, and monotypic surface lambda light chain, consistent with persistent CLL via flow cytometry. Due to worsening lymphadenopathy and flow cytometry results, a decision was made to change therapy to venetoclax with rituximab. Shortly before the initiation of venetoclax in late February 2021, the patient underwent a PET scan, but no PET-avid disease was identified. A FISH panel on peripheral blood was found to be normal.

Figure 3.

Figure 3.

Lymph node core needle biopsy from patient in January 2021 after 2 years of therapy using ibrutinib, 280 mg once daily. (A, B) Hematoxylin-eosin staining from subcarinal lymph node biopsy reveals effacement of the lymph node architecture by medium-sized CD20-positive lymphocytes.

Citation: Journal of the National Comprehensive Cancer Network 21, 2; 10.6004/jnccn.2022.7069

At the initiation of venetoclax in early March 2021, the patient’s WBC count was 66,900/mcL. After completing only week 1 of venetoclax at 20 mg once daily, her WBC count increased to 74,400/mcL, with increases in neutrophils and metamyelocytes (Table 1). Given her peripheral blood FISH and PET scan results and increasing absolute neutrophil count and basophilia during week 2 of venetoclax at 50 mg once daily, a bone marrow biopsy was performed. Results showed hypercellular bone marrow (95%) with CML with 1% blasts, and flow cytometry showed residual low-grade B-cell lymphoma (<5%) (Figure 4). A karyogram of this sample showed 46,XX,t(9;22)(q34;q11.2), and FISH identified 182/200 nuclei positive for BCR::ABL1 fusion (Figure 5). The final diagnosis was confirmed as chronic phase CML, in addition to the already known CLL. When the ramp-up phase was completed, ibrutinib was stopped, imatinib was started at a dose of 400 mg daily, and venetoclax was continued at a maintenance dose of 200 mg daily, given that imatinib is an inhibitor of cytochrome P450 3A4 (CYP3A4).

Table 1.

Blood Counts

Table 1.
Figure 4.

Figure 4.

Peripheral blood smear, bone marrow biopsy, and aspirate particles in March 2021. (A, B) Leukocytosis with granulocytic left shift, nontoxic neutrophilia, and basophilia (inset, A) and rare blast (inset, B) are the classic features of BCR::ABL1–positive chronic phase CML. (C) Megakaryocytes in CML are small and hypolobated in contrast to other classic myeloproliferative neoplasms. (D) Low- and high-power magnification of hypercellular bone marrow core biopsy with increased myeloid-to-erythroid ratio. MPO staining highlights left-shifted myeloid element (inset, D).

Abbreviations: CML, chronic myeloid leukemia; MPO, myeloperoxidase.

Citation: Journal of the National Comprehensive Cancer Network 21, 2; 10.6004/jnccn.2022.7069

Figure 5.

Figure 5.

Karyogram and FISH studies from bone marrow sample, March 2021. Karyogram highlights the classic chromosome 22 (Philadelphia) in CML. (A) The reciprocal translocation involves 9q34 and 22q11.2 juxtaposing the ABL1 and BCR genes at the molecular examination. (B) FISH using dual-fusion probe shows the presence of a BCR::ABL1 gene fusion (arrows).

Abbreviations: CML, chronic myeloid leukemia; FISH, fluorescence in situ hybridization.

Citation: Journal of the National Comprehensive Cancer Network 21, 2; 10.6004/jnccn.2022.7069

Rituximab was added to venetoclax therapy, with the last rituximab dose being given in November 2021. She is currently continuing imatinib and venetoclax therapy for comanagement of her CML and CLL. She has tolerated both imatinib and venetoclax very well with only mild leukopenia, anemia, neutropenia, and nausea managed with ondansetron. At the time of writing, her response to venetoclax therapy is unknown because restaging imaging has not occurred. Regarding her CML, she has experienced a major molecular remission (Table 2).

Table 2.

BCR::ABL Transcript-Level Trends and Response to Imatinib Therapy

Table 2.

Discussion

Several aspects of this case report are noteworthy. Venetoclax dosing with imatinib requires consideration. After daily administration under fed conditions, the venetoclax maximum concentration is reached within 5 to 8 hours and is oxidized by cytochrome P450 3A to its inactive metabolite.31 After single and multiple doses, strong inhibitors of CYP3A4 have resulted in a 2.3- to 2.4-fold increase in maximum concentration and a 6.9- to 8.1-fold increase in the area under the curve.31–33 Imatinib is a known substrate and a moderate inhibitor of CYP3A4 and cytochrome P450 3A5.34,35 For this reason, the venetoclax dose was chosen to be 200 mg once daily for this patient. To date, she has tolerated concomitant therapy well.

Synchronous occurrence of CLL and CML is rare. Although secondary malignancies with CLL are common, most are found to be skin, prostate, and breast cancers.36 In addition, malignancy post-BTK therapy can also be problematic in CLL.37,38 Secondary CML has been reported, but it does not have additional cytogenetic abnormalities typically found with other secondary cancers, such as acute myeloid lekemia.39 A handful of concurrent CML and CLL cases have been reported in the literature spanning 30 years that have successfully been comanaged.40–44 Targeted therapies have also been used successfully in a few cases, strengthening the argument that combination therapies can be safely and effectively administered in these rare patients.45,46

The most compelling component of this case report is that it highlights the safety and efficacy of concomitant venetoclax and imatinib. Both are well-established therapies in their respective diseases; however, concurrent CML and CLL are exceptionally rare. In preclinical models, venetoclax and navitoclax have activity in CML.19 Venetoclax activity is related directly to the expression of BCL-2 in CML but is modest at best as a single agent in several CML cell lines. When combined with imatinib, venetoclax enhanced imatinib-induced apoptosis in cell lines higher in BCL-2 expression. The present case report also corroborates a reported case series demonstrating that the concomitant use of venetoclax and TKIs is safe and effective.47 In addition, venetoclax has been shown to target leukemia stem cells,48,49 which are believed to be responsible for the initiation and perpetuation of leukemias and are known to be resistant to traditional chemotherapy and TKIs. And finally, adding TKIs to venetoclax has been shown to overcome venetoclax resistance through inducing Lck/Yes-related novel tyrosine kinase–mediated proapoptotic BCL-2–like protein 11 expression and inhibiting the upregulation of antiapoptotic MCL-1.50

Given all of this information, a compelling argument can be made for combination therapy using venetoclax plus TKIs as a novel and attractive approach for CML to obtain treatment-free remission and potentially a cure. However further studies, particularly prospective in nature, are needed to evaluate this combination from a treatment perspective and for treatment-free remission attempts.

Conclusions

This case report represents the second report on the use of venetoclax plus TKIs for CML and is the first report on the use of venetoclax plus TKIs for concomitant CLL and CML. Concomitant oral BCL-2 and TKI therapy was shown to be safe and efficacious, but given the unique pharmacokinetic and pharmacodynamic profiles of these drugs, careful monitoring and management of adverse events with this combination is warranted. Future studies of this novel treatment combination are needed.

FDA Approves Zanubrutinib in Treatment of CLL or SLL

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U.S. Food and Drug Administration (FDA) approved the kinase inhibitor zanubrutinib (Brukinsa) in the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

Efficacy in patients with treatment-naive CLL or SLL was evaluated in the SEQUOIA trial (ClinicalTrials.gov identifier NCT03336333). In the randomized cohort of the SEQUOIA trial, including patients without 17p deletion, a total of 479 patients were randomly assigned 1:1 to receive either zanubrutinib until disease progression or unacceptable toxicity or bendamustine plus rituximab (BR) for six cycles. The median progression-free survival was not reached in the zanubrutinib arm and was 33.7 months in the BR arm (hazard ratio = 0.42, 95% confidence interval [CI] = 0.28–0.63; P < .0001). Estimated median follow-up for progression-free survival was 25.0 months.

In a separate nonrandomized cohort of SEQUOIA, zanubrutinib was evaluated in 110 patients with previously untreated CLL or SLL with 17p deletion. The overall response rate per independent review committee was 88% (95% CI = 81%–94%). The median duration of response was not reached after a median follow-up of 25.1 months.

Efficacy in patients with relapsed or refractory CLL or SLL was evaluated in the ALPINE trial (NCT03734016). A total of 652 patients were randomly assigned 1:1 to receive either zanubrutinib or ibrutinib. The median number of prior lines of therapy was one (range, 1–8). The overall response rate was 80% (95% CI = 76%–85%) with zanubrutinib and 73% (95% CI = 68%–78%) with ibrutinib (response rate ratio, 1.10, 95% CI = 1.01–1.20; P = .0264). The median duration of response was not reached in either arm, after a median follow-up of 14.1 months.

Across clinical trials of zanubrutinib, the most common adverse reactions (≥ 30%) were neutrophil count decreased (42%), upper respiratory tract infection (39%), platelet count decreased (34%), hemorrhage (30%), and musculoskeletal pain (30%). Second primary malignancies, including non-skin carcinomas, developed in 13% of patients. Atrial fibrillation or flutter was reported in 3.7% of patients, and grade 3 or higher ventricular arrhythmia was noted in 0.2% of patients.

The recommended zanubrutinib dosage is 160 mg taken orally twice daily or 320 mg taken orally once daily until disease progression or unacceptable toxicity.

Ibrutinib and Rituximab for Untreated CLL: ‘Practice Changing’

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The combination of ibrutinib (Imbruvica, Pharmacyclics/Janssen) and rituximab (Rituxan, Roche/Genentech) beat the current gold standard of fludarabine, cyclophosphamide, and rituximab (FCR) for young, fit patients with untreated chronic lymphocytic leukemia (CLL) in a large trial funded by the National Cancer Institute (NCI).

Ibrutinib plus rituximab showed superior progression-free survival (PFS) and overall survival (OS) compared with FCR, and was also less toxic.

Tait D. Shanafelt, MD

These results from the E1912 study were presented here at the American Society of Hematology (ASH) 2018 Annual Meeting.

“These findings have immediate practice-changing implications and establish ibrutinib as the single most effective first-line therapy for patients with CLL,” lead author Tait D. Shanafelt, MD, from Stanford University, California, told Medscape Medical News.

“These definitive results show why large trials like this that test new therapies in an effort to achieve clinically meaningful benefit for patients are so important,” said Richard F. Little, MD, of the Cancer Therapy Evaluation Program at NCI in a statement.

Shifting Landscape

How these new findings fit alongside other recent results with ibrutinib in CLL is now a matter for consideration.

As reported by Medscape Medical News, data from another large NCI-sponsored trial, the ALLIANCE study, also presented at ASH, showed that ibrutinib alone was superior to the combination of bendamustine-rituximab in elderly patients ≥ 65 years of age with CLL. The investigators concluded that ibrutinib alone is appropriate as initial treatment of CLL in this patient population.

Additionally, results from an industry-sponsored study, the phase 3 iLLUMINATE trial — also presented at ASH (abstract 691) and submitted for approval of an additional indication — showed that the combination of ibrutinib and obinutuzumab (Gazyva, Roche/Genentech) provided a 77% reduction in risk of progression or death compared with chlorambucil and obinutuzumab (HR: 0.23; 95% CI: 0.15 – 0.37; P < .0001).

Aaron T. Gerds, MD

So three trials presented at the meeting suggest, in turn, that ibrutinib alone, ibrutinib plus rituximab, or ibrutinib plus obinutuzumab, should be the new standard for CLL. How are clinicians to choose between these regimens when treating patients with CLL?

“This is an embarrassment of riches,” commented Aaron T. Gerds, MD, of the Cleveland Clinic Taussig Cancer Institute, Ohio, who moderated an ASH press briefing during which the new results were discussed.

Ultimately, clinicians will have to weigh all the factors before deciding on the choices before them, he observed.

He also said that E1912 and ALLIANCE, large cooperative group studies, are important and unbiased, adding they are trials that industry is not likely to conduct. The iLLUMINATE study is industry sponsored and supports a US Food and Drug Administration (FDA) label — another way to pursue a treatment option, he pointed out.

Shanafelt pointed out although the E1912 study is not industry sponsored, it is registered with and has endpoints approved by the FDA. The study met all its endpoints, he noted, and hopes this new partnership between the cooperative groups and the FDA will get a nod for non-industry sponsored treatment options.

With ibrutinib approved as a single agent to treat newly diagnosed CLL, the E1912 study is the first trial in younger patients in which an ibrutinib regimen (ibrutinib plus rituximab) was compared with the gold-standard FCR regimen, and shows that for most patients an ibrutinib regimen should be preferred, lead author Jennifer A. Woyach, MD, of the ALLIANCE study, told Medscape Medical News.

“With these data it is probably appropriate to treat patients with either ibrutinib or the combination of ibrutinib and rituximab,” said Woyach, who is at Ohio State University Comprehensive Cancer, Columbus.

After the ASH meeting, practicing clinicians are likely to offer ibrutinib monotherapy first-line to treatment-naive CLL patients, commented Kanti R. Rai, MD, from the Feinstein Institute of Medical Research at Hofstra/Northwell, Hempstead, New York.

“It is a game changer,” he said and added that physicians are experienced with and comfortable using ibrutinib.

Rai believes data from the ALLIANCE study are more likely to inform clinical practice and ibrutinib monotherapy will be the standard in treatment-naive CLL. “Physicians, patients, and society have become sensitive to the cost of therapy, and with single-agent ibrutinib one is likely to avoid unnecessary expense,” he said.

“The age group difference [younger versus older] between E1912 and ALLIANCE is not likely to be critical,” Rai observed.

“We do not know for sure whether the data from ibrutinib-rituximab versus ibrutinib in older patients [ALLIANCE population] is generalizable to the entire CLL population, and I do not believe this comparison will ever be repeated in younger patients, so I think it is probably reasonable to choose either ibrutinib alone or in combination with rituximab in younger patients,” Woyach told Medscape Medical News.

Shanafelt indicated that the ongoing FLAIR trial is likely to provide a more definitive answer. FLAIR, which is enrolling patients with treatment-naive CLL aged 18 to 75 years, is evaluating four treatment regimens: FCR, ibrutinib-rituximab, ibrutinib-venetoclax, and ibrutinib alone.

Both Rai and Woyach predict that FCR will be used less but is appropriate for certain patients, such as those with mutated IGVH disease (low risk). “Long-term data from the FCR studies shows that a proportion of low-risk patients have the potential for very long-term remission and even cure. We will have to see with long-term follow-up from the E1912 study whether ibrutinib-rituximab is superior to FCR in IGVH mutated patients because that is not clear at this time,” Woyach said.

Shanafelt told Medscape Medical News that both E1912 and ALLIANCE are cooperative group studies and were designed simultaneously prior to the approval of ibrutinib (in 2014). E1912 was conducted in patients ≤ 70 years of age and ALLIANCE in those ≥ 65 years of age. “There was an intentional overlap because some patients have robust health and can tolerate FCR,” he said. “Both trials met their endpoint at the same time and based on the age category, ibrutinib-based therapy is the most effective compared with the best historic regimens,” he said.

“For all comers independent of age, ibrutinib-based treatment is the standard of care based on data from the two studies,” Shanafelt told Medscape Medical News.

The E1912 Study Results

The E1912 trial was a randomized phase 3 study that enrolled 529 patients (2:1) to ibrutinib plus rituximab (n = 354) or standard FCR therapy (n = 175). Patients enrolled were ≤ 70 years of age and those with 17p deletion were excluded because of poor disease response to FCR.

Patients treated with the combination of ibrutinib and rituximab received ibrutinib daily on days 1-28 for each cycle until disease progression or unacceptable toxicity. Rituximab was given in cycles 1-7. Patients in the FCR group were given the drugs over 6 cycles, as is typical in clinical practice.

Median age of patients was 58 years and 41% were ≥ 60 years; 75% of patients had IGVH unmutated disease.

Results were presented for the first interim analysis performed September 2018. Median follow-up was 33.4 months.

For the primary endpoint of PFS, the combination of ibrutinib and rituximab was associated with a 65% reduced risk for progression or death (hazard ratio [HR], 0.35; 95% CI, 0.22 – 0.5; P < .00001). Three-year PFS was 89% for the ibrutinib-rituximab combination and 73% for FCR.

OS was also superior for the combination of ibrutinib and rituximab (HR, 0.17; 95% CI, 0.05 – 0.54; P < .0003).

The superiority of the combination of ibrutinib and rituximab was seen regardless of age, performance status, disease stage, or presence or absence of del11q23. The superiority was also established for IGVH unmutated but not IGVH mutated disease.

Grade 3/4 treatment-related adverse events were reported for 58% and 72% of patients receiving the ibrutinib regimen and FCR, respectively. Compared with ibrutinib plus rituximab, FCR was associated with a significantly higher incidence of grade 3/4 neutropenia (22.7% vs 43.7%), anemia (2.6% vs 12.0%), thrombocytopenia (2.9% vs 13.9%), and infectious complications (7.1% vs 19.0%).

Duvelisib Approved for Certain Lymphomas

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A new oral drug for use in patients with certain blood cancers has been approved by the US Food and Drug Administration (FDA).

The drug, duvelisib (Copiktra, Verstem Oncology), is an oral inhibitor of phosphoinositide 3–kinase (PI3K) and is the first to act as a dual inhibitor of PI3K-delta and PI3K-gamma.

The FDA granted approval for use of duvelisib in adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (CLL/SLL) who have received at least two prior therapies. This approval was based on data from the DUO trial, which showed a benefit in progression-free survival.

The FDA also granted an accelerated approval for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) who had undergone at least two prior systemic therapies. This accelerated approval was based on overall response rate from the DYNAMO clinical trial. Further data showing clinical benefit are required.

These three disorders — CLL/SLL and FL — are common types of indolent non-Hodgkin lymphomas. It is estimated that 681,000 people are living with non-Hodgkin lymphoma in the United States, including nearly 350,000 patients with CLL/SLL or FL, notes the manufacturer. Many of these patients will eventually experience relapse or develop refractory disease, it adds.

The drug has orphan drug designation and was approved after a priority review.

“Duvelisib is an important addition to the evolving treatment paradigm for patients with CLL/SLL and FL,” said Ian Flinn, MD, PhD, director of the Lymphoma Research Program at Sarah Cannon Research Institute. He was lead investigator of the pivotal studies that led to this approval. Together, the studies involved more than 400 patients.

“I believe [it] will address an unmet need for patients who have limited options once they have progressed after two prior therapies,” he said in a company press release.

Boxed Warning and Adverse Effects

The product carries a boxed warning for four fatal and/or serious toxicities: infections, diarrhea or colitis, cutaneous reactions, and pneumonitis. The manufacturer is implementing an informational risk evaluation and mitigation strategy to provide appropriate dosing and safety information to physicians.

The drug is also associated with adverse reactions that may require dose reduction, treatment delay, or discontinuation. These may include infections, diarrhea or colitis, cutaneous reactions, pneumonitis, hepatotoxicity, neutropenia, and embryo-fetal toxicity.

The most common adverse reactions (reported in ≥20% of patients) were diarrhea or colitis, neutropenia, rash, fatigue, pyrexia, cough, nausea, upper respiratory infection, pneumonia, musculoskeletal pain, and anemia.

Clinical Trial Data

The approval for use in refractory or relapsed CLL/SLL was based on results from a subset of patients who took part in the DYNAMO trial.

This trial compared duvelisib to ofatumumab (Arzerra, Genmab/Novartis) in 319 adult patients with CLL (n = 312) or SLL (n = 7) who had received at least one prior therapy.

The approval was based on a subset of these patients — those who had received at least two prior therapies — because “the benefit:risk appeared greater in this more heavily pretreated population compared to the overall trial population,” the manufacturer explains.

In this subset of patients (95 received buvelisib, 101 received ofatumumab), the median age of the patients was 69 years (range, 40 to 90 years). Among these patients, 46% had received two prior lines of therapy, and 54% had received three or more prior lines.

Efficacy was based on progression-free survival (PFS), as assessed by an independent review committee. The median PFS was 16.4 months with develisib and 9.1 months with ofatumumab (hazard ratio, 0.40).

The accelerated approval for use in patients with previously treated FL was based on the single-arm, multicenter DYNAMO trial, conducted in 83 patients whose conditions were refractory to rituximab and to either chemotherapy or radioimmunotherapy.

This trial excluded patients with grade 3b FL, large cell transformation, prior allogeneic transplant, and prior exposure to a PI3K inhibitor or to a Bruton’s tyrosine kinase inhibitor.

These patients had undergone a median of three prior lines of therapy (range, 1 to 10).

Efficacy was based on overall response rate (35 patients, 42%) and duration of response — 15/35 (43%) maintained the response at 6 months, and 6/35 (17%) maintained the response at 12 months.

The US has given fast-track approval to a surprising new cancer drug

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“Even when it’s killing cells, you feel great.”

A new cancer drug called Venetoclax is causing quite a stir in the medical community, with the announcement that the US FDA has given it fast-track approval for the treatment of patients with chronic lymphocytic leukemia (CLL).

CLL is one of the most common types of leukemia in adults, and during a recent clinical trial, 80 percent of patients treated with Venetoclax experienced complete or partial remission of their cancer.

Developed in Australia over several decades, Venetoclax is taken in pill-form, and of the small sample of patients who have been treated with it so far, some reported no adverse side-effects at all.

“It causes no side-effects. Nothing, absolutely nothing,” Robert Oblak, who had recurring CLL when he was selected to participate in the trial in 2013, told the ABC. “Quite amazing. So even when it’s killing cells, you feel great.”

Oblak estimates that he was just the 11th person in the world to be treated with Venetoclax, and within a year of treatment, he went into remission.

The phase II trial involved 107 patients aged 18 or older with CLL, who had undergone at least one type of treatment already.

The patients also had to have a particular chromosome abnormality in their leukemia cells called 17p deletion, which means they’re lacking a portion of the chromosome that acts to suppress cancer growth.

They were asked to take one Venetoclax pill per day for five weeks straight, with doses starting at 20 mg and gradually increasing to 400 mg.

At the end of the trial, which involved patients and researchers from 31 centres in the US, Canada, the UK, Germany, Poland, and Australia, four out of five patients experienced a positive result, with complete remission reported for one in five.

“These patients now have a new, targeted therapy that inhibits a protein involved in keeping tumour cells alive,” Richard Pazdur from the FDA’s Centre for Drug Evaluation and Research, announced back in April. 

“For certain patients with CLL who have not had favourable outcomes with other therapies, Venclexta may provide a new option for their specific condition.”

The results of the trial, which were published in The Lancet in June, informed the FDA’s decision to fast-track approval of the drug and make it available to patients in the US.

Despite being developed by researchers at Australia’s Walter and Eliza Hall Institute of Medical Research, it’s not yet been approved for use by Australian patients, but an application has been made.

So, how does the drug work? Venetoclax is one of a new generation of immunotherapy cancer drugs that are designed to address certain failings of a person’s own immune system – such as missing portions of chromosomes that inhibit the cells’ ability to fight the spread of cancer.

In CLL patients with 17p deletion, malignant cells don’t proliferate all that much, but they don’t die, because the body’s immune response has been hindered, and abundant levels of a protein called BCL2 helps keep them alive.

“Cells, when they are born, are destined to die and cancer cells and particularly leukaemia cells delay that death by using a protein called BCL2 that stops the normal time of death,” John Seymour from the Peter MacCallum Cancer Centre in Melbourne, who helped oversee the trial, told the ABC.

“Venetoclax works by specifically blocking the action of that BCL2, and allows the cells to die in the way that they were destined to.”

venetoclax-actionVenetoclax

So rather than killing off the cancer cells – and a bunch of healthy cells in the vicinity – like current treatments like chemo and radiotherapy do, the drug reestablishes the balance of the body’s immune system, and effectively allows the cancer cells to die on their own.

This explains why some patients, like Oblak can undergo treatment with no discernible side-effects. But let’s be clear – Oblak was very lucky.

The FDA reports that, depending on the patient, side-effects from Venetoclax include low white blood cell count, diarrhoea, nausea, anaemia, upper respiratory tract infection, low platelet count, and fatigue. Serious complications can include pneumonia, fever, and death.

During the Venetoclax trial, of the 107 patients, 11 ended up dying, seven because of the progression of their cancer, and four from adverse side-effects.

Similar results were seen in a separate trial of a similar immunotherapy cancer drug, Ipilimumab, which has recently been approved for the Australian market.

While Australian patient Greg Lawson was declared free from melanomas 12 months after treatment, and reportedly suffered “virtually no side-effects”, his wife, who was treated with a different melanoma immunotherapy drug at the same time, died when her body could not tolerate the treatment.

“She had two sets of the treatment, but was so ill from the side-effects that the decision was made to take her off it,” Lawson told the ABC.

But with immunotherapy drugs seeing “extraordinary” results in other trials this year, and with the possibility of a ‘universal cancer vaccine’ hanging in the air, this is just the beginning for the next generation of cancer treatment.

 

FDA Expands Approved Use of Imbruvica for Chronic Lymphocytic Leukemia

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The U.S. Food and Drug Administration today expanded the approved use ofImbruvica (ibrutinib) to treat patients with chronic lymphocytic leukemia (CLL) who carry a deletion in chromosome 17 (17p deletion), which is associated with poor responses to standard treatment for CLL. Imbruvica received a breakthrough therapy designation for this use.

The FDA is also approving new labeling to reflect that Imbruvica’s clinical benefit in treating CLL has been verified. In February 2014, Imbruvica received accelerated approval to treat CLL based on its effect on overall response rate. New clinical trial results examining progression-free survival and overall survival have confirmed the drug’s clinical benefit.

A type of non-Hodgkin lymphoma, CLL is a rare blood and bone marrow disease that usually gets worse slowly over time, causing a gradual increase in white blood cells called B lymphocytes, or B cells. The National Cancer Institute estimates that 15,720 Americans will be diagnosed and 4,600 will die from CLL in 2014. Imbruvica works by blocking the enzyme that allows cancer cells to grow and divide.

“We continue to see advances in the availability of therapies to treat chronic lymphocytic leukemia, especially for difficult-to-treat patient populations,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Imbruvica is the fourth drug approved to treat CLL that received a breakthrough therapy designation, reflecting the promise of the breakthrough therapy designation program and demonstrating the FDA’s commitment to working cooperatively with companies to expedite the development, review and approval of these important new drugs.”

The other three drugs approved to treat CLL that received breakthrough designations are Gazyva (obinutuzumab) in November 2013, Arzerra (ofatumumab) in April 2014 and Zydelig (idelalisib) in July 2014. Imbruvica’s application for accelerated approval to treat CLL did not receive breakthrough therapy designation.

Today’s approval actions for Imbruvica are based on a clinical study of 391 previously treated participants, 127 of whom had CLL with 17p deletion. Participants were randomly assigned to receive Imbruvica or Arzerra until disease progression or side effects became intolerable.

The trial was stopped early for efficacy after a pre-planned interim analysis showed Imbruvica-treated participants experienced a 78 percent reduction in risk of disease progression or death (progression-free survival). Results also showed a 57 percent reduction in risk of death (overall survival) in participants treated with Imbruvica. Of the 127 participants who had CLL with 17p deletion, those treated with Imbruvica experienced a 75 percent reduction in risk of disease progression or death.

The most common side effects associated with Imbruvica observed in the clinical study include low levels of platelets in the blood (thrombocytopenia), a decrease in infection-fighting white blood cells called neutrophils (neutropenia), diarrhea, low red blood cells (anemia), fatigue, pain in the muscles and bones (musculoskeletal pain), upper respiratory tract infection, rash, nausea and fever (pyrexia).

Imbruvica’s new use is being approved more than two months ahead of the product’s prescription drug user fee goal date of Oct. 7, 2014, the date the FDA was scheduled to complete review of the drug application. The FDA reviewed Imbruvica’s application for this new use under the agency’s priority review program, which provides for an expedited review of drugs that are intended to treat a serious disease or condition and, if approved, would offer significant improvement compared to marketed products.

Imbruvica also received accelerated approval in November 2013 for the treatment of patients with mantle cell lymphoma who have received at least one prior therapy. Clinical studies to verify and describe Imbruvica’s clinical benefit in mantle cell lymphoma are ongoing.

Imbruvica is co-marketed by Pharmacyclics, based in Sunnyvale, Calif., and Janssen Biotech, based in Horsham, Penn.

Source: FDA

 

Ibrutinib versus Ofatumumab in Previously Treated Chronic Lymphoid Leukemia.

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Chronic lymphoid leukemia (CLL) is characterized by a variable natural history that is partly predicted by clinical and genomic features.1 Therapy for CLL has evolved from monotherapy with alkylating agents to chemoimmunotherapy.2,3 Each of the combination regimens has shown prolonged rates of progression-free survival, as compared with similar regimens that do not contain antibodies.
Treatment of patients with relapsed CLL often includes regimens such as bendamustine and rituximab,4ofatumumab,5 or investigational agents.6-8 Ofatumumab was approved by the Food and Drug Administration (FDA) and the European Medicines Agency on the basis of a single-group study involving patients who had resistance to fludarabine and alemtuzumab therapy; with an overall response rate of 58%,5 ofatumumab has been recommended in international consensus guidelines as a therapeutic option for patients with previously treated CLL.9,10
A short duration of response to initial therapy or adverse cytogenetic abnormalities have been associated with a poor outcome among patients receiving conventional therapy.9,11,12 Identifying new therapies that prolong survival remains an important need for these patients.
Ibrutinib (Imbruvica, Pharmacyclics and Janssen) is a first-in-class, oral covalent inhibitor of Bruton’s tyrosine kinase, an essential enzyme in B-cell receptor signaling, homing, and adhesion.13-15 On the basis of response rates in single-group, phase 2 studies, ibrutinib was recognized by the FDA as a breakthrough therapy and was granted accelerated approval for patients with mantle-cell lymphoma (in November 2013) and CLL (in February 2014) who had received at least one previous therapy. Among patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL), those who received ibrutinib had a response rate of 71%, according to investigator assessment, and a progression-free survival rate of 75% at 2 years.13 In this study, drug toxicity did not result in the discontinuation of ibrutinib in most patients. On the basis of early results of the phase 2 trial, we initiated a multicenter, open-label, randomized, phase 3 trial, the Study of Ibrutinib versus Ofatumumab in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (RESONATE), to compare once-daily oral ibrutinib with an active control single-agent therapy, ofatumumab, in patients with relapsed or refractory CLL or SLL.
DISCUSSION
Among patients with relapsed CLL or SLL, including those who had a short duration of response to prior therapy or who had adverse cytogenetic abnormalities, ibrutinib was superior to ofatumumab with respect to progression-free survival, overall survival, and response rate at a median follow-up of 9.4 months. The positive effect of ibrutinib was observed in subgroups of patients with a high-risk chromosome 17p13.1 deletion and with resistance to previous purine analogue therapy. Similar benefits with respect to progression-free survival were observed regardless of age, clinical stage, and factors such as status with respect to mutations in IGHV. The effect of ibrutinib on overall survival was significant, an effect that was robust despite the crossover of 57 patients to the ibrutinib group after they had disease progression while receiving ofatumumab; this effect was also observed in subgroup and sensitivity analyses.
Except for a few differences, our findings are largely similar to those of other trials of ibrutinib or ofatumumab. In each of the two groups in our study, the response rate as determined by independent assessors was lower than the response rate as determined by investigators. In the phase 2 study of ibrutinib monotherapy,13 in which response was assessed by investigators, the response rate was 71%, which is similar to the 70% response rate assessed by investigators in our study. The independently assessed response rate in the ofatumumab group in our study appears to be lower than that in the pivotal study that was based on 1996 National Cancer Institute guidelines for CLL,23 which did not require CT scanning to confirm response.24 This difference may be due in part to the requirement in our study for serial CT scanning, which was performed every 12 weeks, to confirm response. Another ofatumumab study that compared response assessment between patients who underwent CT scanning and those who did not undergo CT scanning showed substantial differences in the rates of response between the two subgroups, with lower response rates seen in the group that underwent CT scanning.25 Furthermore, the investigator-assessed response rate among patients in the ofatumumab group in our study (21%) was similar to the rate (23%) in a recent study that used 2008 criteria of the International Workshop on Chronic Lymphocytic Leukemia.26 Reassuringly, the results with respect to progression-free survival in the ofatumumab group in our study (median, 8.1 months) are similar to those in historical reports (median, approximately 6 months).5
Previous reports of ofatumumab therapy showed that patients with refractory CLL had a median survival of 12 months26 and 15 months,5 with no plateau in deaths. With a median follow-up of 9.4 months in our study, an early separation in the curves for overall survival favored ibrutinib; however, the median was not reached in either study group. At later time points, the survival curve for ofatumumab began to flatten, which may in part be a reflection of the influence of ibrutinib on patients in the ofatumumab group who crossed over to ibrutinib therapy.
Ibrutinib was associated with toxic effects that were expected on the basis of the results of phase 2 studies. It appears that the drug can be safely administered even in a heavily pretreated and elderly population with baseline coexisting conditions, such as the one in our study. In the ibrutinib group, 32% of the patients had a decreased creatinine clearance, 64% had cytopenias, and 32% had a score on the Cumulative Illness Rating Scale of more than 6 (ranging from 0 to 52, with higher scores indicating worse health status). Toxic effects did not result in frequent dose reductions or treatment discontinuations.
One strength of a randomized, controlled trial is that background disease-related complications may be differentiated from a treatment effect with a new agent. However, it is important to note that patients in the ibrutinib group had a reporting period for adverse events that was more than 3 months longer than that in the ofatumumab group (median duration, 8.6 months vs. 5.3 months), and no exposure-adjusted analysis of adverse events was performed.
The frequencies of renal complications and increased creatinine levels were similar in the two study groups. Although the overall rate of infections was higher in the ibrutinib group, the frequency of infections of grade 3 or higher did not differ significantly between the two groups. Ocular symptoms were collected proactively and were reported more frequently among patients in the ibrutinib group, including a small proportion of patients who reported blurred vision. The development of cataracts in 3% of the patients receiving ibrutinib (as compared with 1% in the control group) bears noting, since longer exposure may be associated with an increased risk.
Atrial fibrillation of any grade was noted in 10 patients in the ibrutinib group, as compared with 1 patient in the ofatumumab group, and led to the discontinuation of ibrutinib in 1 patient. Potential reasons for the higher rate of atrial fibrillation among patients receiving ibrutinib are being explored. In clinical studies in which serial electrocardiographic studies were performed, no evidence of arrhythmias was observed among patients receiving ibrutinib.13,27
An adverse event of interest with ibrutinib from early studies was major hemorrhage, including subdural hematoma. In our study, we excluded patients requiring warfarin but not those requiring other forms of anticoagulation. The rate of major hemorrhage was similar in the two study groups, with one subdural hematoma noted in a patient receiving ibrutinib. Although mild bleeding episodes were more common in the ibrutinib group, adherence to appropriate drug-withholding guidelines perioperatively and precautions regarding the use of antiplatelet agents and anticoagulants resulted in no unexpected major bleeding complications in the ibrutinib group. Further studies of the mechanism of bleeding, including bruising, that was observed among patients receiving ibrutinib have been conducted28 or are planned.
In conclusion, ibrutinib was superior to ofatumumab in difficult-to-treat patients with relapsed or refractory CLL or SLL, as measured by progression-free survival, overall survival, and response. The improvement was observed across all subgroups that were examined, including patients who were resistant to chemoimmunotherapy and those with a chromosome 17p13.1 deletion, which confirms single-agent ibrutinib as an effective therapy for CLL or SLL. Phase 3 studies examining the effect of ibrutinib in previously untreated patients with CLL or SLL are ongoing

Source: NEJM