Virginia Powers, PhD

Bruton tyrosine kinase (BTK) inhibitor acalabrutinib (Calquence) demonstrated a high rate of response, prolonged survival, and high tolerability in patients with chronic lymphocytic leukemia (CLL) who demonstrated intolerance to ibrutinib (Imbruvica). Findings were presented at the 15th International Conference on Malignant Lymphoma.

Following acalabrutinib treatment, the investigator-assessed overall response rate (ORR; partial response [PR] or better) was 72% in ibrutinib-intolerant patients with relapsed or refractory (R/R) CLL; the ORR plus late partial response with lymphocytosis (PRL) was 77% (

). The complete response (CR) rate was achieved by 5% of patients, 67% had a PR, 5% had PRL, and 8% had stable disease (SD). Progressive disease occurred in 2% of patients, another 2% had unknown response, and 12% were not evaluated.

Patients with dell(17p) demonstrated an ORR (&ge; PR) of 71% (91% Cl, 44%-90%).

&ldquo;The primary reason patients discontinued the trial was intolerance in 50% to 63% of patients,&rdquo; said lead study author Kerry A. Rogers, MD, assistant professor of internal medicine in the Division of Hematology at The Ohio State University College of Medicine in Columbus.

Both ibrutinib and acalabrutinib target BTK, which plays a key role in B-cell receptor signaling and has become a well-validated therapeutic target in CLL.

&ldquo;Acalabrutinib is a highly selective, potent, covalent BTK inhibitor with minimal off-target activity; given the in vitro selectivity of acalabrutinib, we hypothesized that it would be tolerable in patients with CLL who were intolerant to ibrutinib,&rdquo; Rogers said.

On the heels of the conference, the FDA granted a breakthrough therapy designation to single-agent acalabrutinib for the treatment of adult patients with CLL.

The designation was given based on the results of interim analyses from 2 phase III trials: ELEVATE-TN and ASCEND.

Rogers reported findings from this phase II trial evaluating acalabrutinib in ibrutinib-intolerant patients with R/R CLL who had received &ge;1 prior therapy. The study population had a median age of 70 years (range, 43-88), 63% were men, 97% had an ECOG performance score &le;1, 32% had bulky disease &ge;5 cm, and 52% were Rai stage III/IV. Patients had also been treated with chemotherapy, rituximab (Rituxan), lenalidomide (Revlimid), and other agents. Regarding genetic mutations, 28% of patients had del(17p), 23% had del(11q), 79% had unmutated

, and 95% had available baseline samples that were wild-type for

Eligibility criteria required patients to have progressive disease after discontinuing ibrutinib, and treatment discontinuation was due to grade 3/4 adverse events (AEs) or persistent/recurrent grade 2 AEs. The median duration of prior ibrutinib therapy was 6 months (range, <1-55). The most commonly reported AEs leading to ibrutinib discontinuation were atrial fibrillation/flutter (25%), diarrhea (12%), arthralgia (10%), and rash (12%). The median time from the last ibrutinib dose to acalabrutinib initiation was 9.2 months (range, 0.8-31.1). Sixty patients received oral acalabrutinib at 100 mg twice daily in 28-day cycles until progressive disease or unacceptable toxicity. The primary endpoint was ORR, and key secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response (DOR), time to next treatment, and safety. At a median follow-up of 19 months (range, 1-31), PFS was not reached; the 18-month rate was 73.5% (95% CI, 59.2%-83.4%). Among patients who responded to acalabrutinib, the median DOR was not reached and the 21-month rate was 77.1% (95% CI, 59.1%- 87.9%). The median OS was not reached; the 18-month rate was 89.7% (95% CI, not estimable), according to investigators.

At a median follow-up of 23 months (range, 1-36), 62% of patients remained on acalabrutinib and 80% remained on the study. Acalabrutinib discontinuations occurred in 38% of patients and were due to progressive disease (16%); AEs (12%); and patient withdrawal, investigator decision, or other (7% each). AEs leading to acalabrutinib discontinuation included pneumonia (n = 2) and diarrhea, subdural hematoma, endometrial cancer, headache, and arthralgia (n = 1).

The most common grade &ge;3 AEs occurring in &ge;5% patients with acalabrutinib were pneumonia (10%), neutropenia (8%), decreased lymphocyte count (7%), lymphocytosis (7%), and decreased platelet count and anemia (3% each).

Bleeding events occurred in 37 (62%) patients, and 2 (3%) patients had major hemorrhage. Hypertension was seen in 7 (12%) patients; 1 (2%) patient experienced it as a grade 3 event.

Eight (13%) deaths occurred on study, and of the 4 grade 5 AEs, none were considered treatment related.

&ldquo;Acalabrutinib is tolerable and effective in ibrutinib-intolerant patients; these data suggest that acalabrutinib may provide a potential strategy for retreatment with BTK inhibitor therapy after intolerance to ibrutinib,&rdquo; said Rogers.

Rogers KA, Thompson PA, Allan JN, et al. Phase 2 study of acalabrutinib in ibrutinib (IBR)-in- tolerant patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL).

. 2019;37(suppl 2; abstr 029). doi: 10.1002/hon.29_2629.

Calquence granted US breakthrough therapy designation for chronic lymphocytic leukaemia [news release]. Kenilworth, NJ: AstraZeneca; August 14, 2019. bit.ly/2MfbCja. Accessed August 14, 2019.

Articles

Bruton tyrosine kinase inhibitor acalabrutinib demonstrated a high rate of response, prolonged survival, and high tolerability in patients with chronic lymphocytic leukemia who demonstrated intolerance to ibrutinib. Findings were presented at the 15th International Conference on Malignant Lymphoma.

Acalabrutinib Shows High Response, Prolonged Survival in Ibrutinib-Intolerant R/R CLL

Rate of response and progression- free survival (PFS) were superior with venetoclax (Venclexta) versus chlorambucil in patients with chronic lymphocytic leukemia (CLL) who also received obinutuzumab (Gazyva), and this trend was observed across all genetic subgroups.

Findings from this analysis of genetic aberrations and mutations in patients with CLL who participated in the CLL14 trial were presented at the 15th International Conference on Malignant Lymphoma.

Eugen Tausch, MD, of Ulm University, Germany, explained: &ldquo;Genomic aberrations,

-mutation status, and mutations in genes such as

are established prognostic factors in CLL in the context of chemoimmunotherapy. Their role is [not as] well established when using chemotherapy- free treatments.&rdquo;

Overall results from the open-label phase III CLL14 trial were presented at the 2019 American Society of Clinical Oncology Annual Meeting and published simultaneously in the

.2 The data from the trial also served as the basis of the May 2019 FDA approval of venetoclax for the frontline treatment of patients with CLL or small lymphocytic lymphoma.

The CLL14 study enrolled 432 patients with previously untreated CLL and relevant comorbidities, including those with a chronic inflammatory response syndrome score greater than 6 or kidney disease represented by creatinine clearance of less than 70 mL/min. The patients were randomized into 2 equal groups to receive 6 cycles of obinutuzumab plus 12 cycles of either venetoclax or chlorambucil. The median patient age was 72 years (range, 41-89 years), the median chronic inflammatory response syndrome score was 8, and the median creatinine clearance was 66.4 mL/min.

The venetoclax combination treatment reduced the risk of disease progression or death by 65% versus obinutuzumab plus chlorambucil (HR, 0.35; 95% CI, 0.23-0.53;

<.001). The objective response rate (ORR) was 85% with venetoclax/ obinutuzumab versus 71% in the control arm. The complete response or complete response with incomplete hematologic recovery rates were 50% versus 23%, respectively.

Tausch and colleagues assessed the incidence of genomic aberrations and evaluated their impact on outcomes in the CLL14 trial. Across all genetic variants assessed, the approximate ORRs for the venetoclax and chlorambucil arms were 80% and 60%, respectively.

The investigators used fluorescence in situ hybridization to determine the cytogenetics in 418 patients and the

status with <98% homology cutoff in 408 patients, and they used a custom next-generation sequencing panel to evaluate the mutations in 13 genes in 421 of 432 patients in the intention-to-treat population.

The ORR was lowered in patients with deletion of 17p (del[17p]), deletion of 11q (del[11q]), or

mutations who were treated with the chlorambucil combination. None of these alterations affected the venetoclax ORR.

The ORR was approximately 82% in patients with unmutated

who received the venetoclax combination. In multivariate analysis, the HR was 3.475 (95% CI, 1.96-6.15;

<.001) for the relationship between unmutated

. In the venetoclax arm, the HR was 1.16 (

<.001) for the same comparison in the chlorambucil arm.

&ldquo;Venetoclax was particularly effective in patients with

unmutated disease; these findings establish

as a predictive rather than prognostic marker,&rdquo; Tausch commented.

The incidence of genomic aberrations were del(17p) in 7% of patients, del(11q) in 18%, trisomy 12q in 18%, and deletion of 13q in 53%. Unmutated

was detected in 61% of patients. The incidence of the following gene mutations was determined:

PFS was assessed according to the genetic variables. With median follow-up of 29 months, 107 PFS events and 37 overall survival events had occurred in the intention-to-treat population.

mutations remain adverse prognostic factors for PFS with venetoclax/obinutuzumab treatment,&rdquo; Tausch said.

Del(17p) significantly impacted PFS with both venetoclax and chlorambucil: in the venetoclax arm, the HR was 4.42 (

= .001) for the comparison of no del(17p) versus del(17p), and in the chlorambucil arm the HR was 4.64 (

mutations also affected PFS with both treatments: for patients without and with

who were treated with venetoclax, the HR was 3.08 (

= .01); for patients with the same characteristics treated with chlorambucil, the HR was 2.74 (

The PFS of chlorambucil was adversely affected by mutated versus nonmutated

= .06); however, these mutations did not significantly affect PFS with venetoclax. Mutations in the other investigated genes had no effect on the efficacy of either venetoclax or chlorambucil.

All of the genetic subgroups showed more favorable PFS outcomes with venetoclax than with obinutuzumab; these subgroups included patients with del(17p), del(11q), and

mutations. High coincidence was found for del(17p) and

&ldquo;These data demonstrate that PFS and response are superior in patients receiving venetoclax/ obinutuzumab and support unmutated

as a predictive factor for increased benefit from venetoclax,&rdquo; Tausch concluded.

Tausch E, Bahlo J, Robrecht S, et al. Genetic markers and outcome in the CLL14 trial of the GCLLSG comparing front line obinutuzumab plus chlorambucil or venetoclax in patients with comorbidity. Hematol Oncol. 2019;37(suppl 2; abstr 047). doi: 10.1002/hon.53_2629.

Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225- 2236. doi: 10.1056/NEJMoa1815281.

FDA approves venetoclax for CLL and SLL. FDA website. bit.ly/2wgFCRI. Published May 15, 2019. Accessed August 21, 2019.

Rate of response and progression-free survival were superior with venetoclax versus chlorambucil in patients with chronic lymphocytic leukemia who also received obinutuzumab, and this trend was observed across all genetic subgroups.<br />
&nbsp;

Genetic Analysis Provides Insight Into Venetoclax/Obinutuzumab Benefit in Frontline CLL

Lenalidomide (Revlimid) plus standard R-CHOP immunochemotherapy may help select patients with activated B-cell (ABC)-type diffuse large B-cell lymphoma (DLBCL) who have a poor prognosis, based on data from the phase III ROBUST trial presented at the 2019 International Conference on Malignant Lymphoma (ICML).

In the overall ROBUST patient population, there was a not a significant improvement in progression-free survival (PFS) with the R2CHOP regimen of lenalidomide plus R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, prednisone) compared with R-CHOP alone. The median PFS was not reached in either arm (HR, 0.85; 95% CI, 0.63‐1.14;

However, nonstatistically significant trends favoring R2CHOP were observed in subgroups of patients with disease stage III/IV (HR 0.81; 95% CI, 0.60‐1.10) and patients having an IPI score &ge;3 (HR, 0.74; 95% CI, 0.53‐1.05).

&ldquo;Overall, the ROBUST study did not meet the primary endpoint of PFS for lenalidomide/R‐CHOP versus placebo/R‐CHOP in previously untreated patients with ABC‐DLBCL, although a positive trend favoring lenalidomide/R‐CHOP has been observed in advanced stage and higher risk patients,&rdquo; said Umberto Vitolo, MD, Citt&agrave; della Salute e della Scienza, University-Hospital, Torino. &ldquo;Future direction of our study will be to evaluate the promising preclinical data of immunomodulatory agents in DLBCL.&rdquo;

Vitolo explained that &ldquo;Approximately one-third of patients with newly diagnosed DLBCL are of the ABC type, which is less likely to respond to standard therapies. Despite attempts to improve the outcome following R-CHOP by adding different agents, the ABC subtype of DLBCL continues to convey inferior survival, making a need to find new therapies.&rdquo;

ROBUST was the first study to directly compare R2CHOP with placebo/R‐CHOP in patients with previously untreated, prospectively selected, CD20+ ABC‐type DLBCL. The study enrolled 570 adult patients with ABC‐DLBCL, Ann Arbor stage II to IV disease, IPI score &ge;2, and ECOG PS &le;2.

All patients underwent an investigational gene-expression profile test to identify the gene of origin, specifically, patients with ABC-type DLBCL. Formalin-fixed paraffin-embedded excisional and surgical or core needle biopsy samples were analyzed by central pathology using the NanoString Lymphoma Subtyping Test based on the Lymph2Cx GEP assay. Within a mean turnaround time of 2.4 days, the investigators were able to establish the rates of ABC-type DLBCL rate among successfully tested samples as 60% from China/Japan/South Korea/Taiwan, 40% from Russia/Europe/Middle East, and 37% from North America/Australia/New Zealand.

Prior to randomization, the patients were stratified by IPI score (2 versus &ge;3), bulky disease (<7 cm versus &ge;7 cm) and age (<65 versus &ge;65 years); 285 patients per arm were randomly assigned to receive 6 cycles of oral lenalidomide at 15 mg on days 1 to 14 or placebo, both administered with R-CHOP-21 (n= 285 per arm).

The primary endpoint was PFS assessed by independent central radiology per 2014 NHL IWG criteria, and defined as time from randomization to disease progression or death from any cause. Secondary endpoints included complete response (CR) rate, duration of response, time to next lymphoma treatment, objective response rate (ORR), event-free survival (EFS), overall survival (OS), and health-related quality of life.

In the overall population, analysis of the secondary endpoints also showed little difference between the 2 treatments. The ORR was 91% for both arms and the rates of CR were 69% with R2CHOP compared to 65% with placebo/R‐CHOP. EFS rates at 1 year were 68% versus 71% and 2-year EFS rates were 59% versus 61%, respectively. PFS rates at 1 year were 77% versus 75% and 2-year PFS rates were 67% versus 64%, respectively.

In the R2CHOP arm, 57 deaths occurred compared with 62 deaths in the placebo arm. The 1-year OS rates were 91% versus 90% and 2-year OS rates were 79% versus 80%, respectively. The median OS was not reached for either arm (HR, 0.93; 95% CI, 0.65-1.32;

The most common grade 3/4 AEs occurring in &ge;10% of for R2CHOP versus placebo/R‐CHOP were neutropenia (60% vs 48%), anemia (22% vs 14%), thrombocytopenia (17% vs 11%), leukopenia (14% vs 15%), febrile neutropenia (14% vs 9%), and lymphopenia (11% vs 8%).

With the respective treatments, 74% and 84% of patients completed 6 cycles of treatment. Treatment discontinuation was due to AEs (primarily neutropenia).

Vitolo&rsquo;s presentation was immediately followed by discussion of the phase II ECOG-ACRIN 1412 trial, which, in contrast to ROBUST, demonstrated a positive improvement in PFS with R2CHOP versus R-CHOP in newly diagnosed patients with DLBCL and either ABC or germinal center B-like (GCB) subtypes.

The 2-year PFS rate was 76% for the R2CHOP arm compared with 70% for the R-CHOP arm (

Invited discussant, Margaret Shipp, MD, Dana Farber Cancer Institute, focused on the important differences between the 2 trials that may have produced the different results. Aside from the patient population, which was exclusively ABC subtype in ROBUST, and both ABC and GCB in ECOG-ACRIN 1412, the respective trials also used different dose levels of lenalidomide of 15 mg (days 1 to 14) versus 25 mg (days 1 to 10). She also highlighted that treatment was within 31 days of diagnosis in ROBUST, whereas patients were treated more rapidlywithin 21 days&mdash;in ECOG-ACRIN 1412.

&ldquo;Possible explanations for the different trial outcomes may include the different dose, eligibility criteria, and time to treatment,&rdquo; Shipp concluded.

Vitolo U. ROBUST: first report of phase III randomized study of lenalidomide/RCHOP (R2-CHOP) vs placebo/R-CHOP in previously untreated ABC-type diffuse large B-cell lymphoma. Presented at: 2019 International Conference on Malignant Lymphoma; June 18-22, 2019; Lugano, Switzerland. Abstract 005.

Nowakowski GS. Addition of lenalidomide to R-CHOP (R2CHOP) improves outcomes in newly diagnosed diffuse large B-cell lymphoma (DLBCL): first report of ECOG-ACRIN 1412 a randomized phase II US Intergroup study of R2CHOP vs R-CHOP. June 18-22, 2019; Lugano, Switzerland. Abstract 006.

Lenalidomide plus standard R-CHOP immunochemotherapy may help select patients with activated B-cell-type diffuse large B-cell lymphoma who have a poor prognosis, based on data from the phase III ROBUST trial presented at the 2019 International Conference on Malignant Lymphoma.<br />
&nbsp;

Frontline Treatment With Lenalidomide Plus R-CHOP May Benefit Select Patients With DLBCL

Significant activity was observed when ibrutinib (Imbruvica) was administered concurrently with CD19-directed CAR T-cell therapy compared with separately in patients with high-risk relapsed/refractory chronic lymphocytic leukemia (CLL) who had progressed on or were intolerant of ibrutinib.&nbsp;Data presented at the 15th International Conference on Malignant Lymphoma show a high response rate with this concurrent treatment.&nbsp;

Results showed that high rates of response by 2018 International Workshop Group CLL criteria were seen in 18 evaluable patients at 4 weeks after CD19-targeted CAR T-cell therapy and concurrent ibrutinib. The objective response rate (ORR) was 83%, which included 4 (22%) complete responses in the marrow (CRi) and 11 (61%) partial responses (PR). In patients who did not receive concurrent ibrutinib, the ORR was 65%.

No patients had stable disease and 3 (17%) patients had disease progression. Regarding the marrow response, no detectable disease was detected by flow cytometry in 13 (72%) patients or by IGH sequencing in 11 (61%) patients.

Lead study author Jordan S. Gauthier MD, MSc, a senior fellow in the Clinical Research Division at Fred Hutchinson Cancer Research Center, discussed the unmet need for treatments in patients with high-risk CLL due to a complex karyotype (CKT) or ibrutinib failure; this subgroup demonstrates decreased survival.

"We previously reported that CD19 CAR T cells could lead to durable responses in relapsed/refractory CLL in patients who had previously failed ibrutinib therapy," he explained. "However, preclinical studies showed that ibrutinib might improve CAR T-cell antitumor efficacy and reduce cytokine release syndrome (CRS)."

Therefore, Gauthier and colleagues explored the safety and efficacy of CD19-directed CAR T cells with concurrent ibrutinib administration in a pilot cohort of a phase I/II trial (NCT01865617). The cohort comprised 19 patients with high-risk relapsed/refractory CLL. The patients were required to be beyond first remission and to have received or been ineligible for chemoimmunotherapy containing a purine analogue and a CD20-targeted antibody, plus no response to or progression on ibrutinib.

Among the baseline demographics, Gauthier highlighted that 89% of patients had high-risk cytogenetics, including del(17p) in 74%, and a CKT in 74% of patients. The median number of prior therapies was 5 (range, 1-10), which included venetoclax (Venclexta) in 58% and idelalisib (Zydelig) in 21% of patients, and 10% had shown ibrutinib intolerance. Overall, the median age was 65 years (range, 40-71), 63% of patients were male, and all patients had an ECOG performance status of 0 or 1. All patients had failed treatment with ibrutinib prior to study entry.

In the concurrent ibrutinib cohort, patients received concurrent administration of ibrutinib at 420 mg daily at least 2 weeks before leukapheresis and continuously though leukapheresis and lymphodepletion, as well as with infusion of a defined composition of 2 x 105 or 2 x 106/kg CD4+ and CD8+ CD19-directed CAR T cells subsequent to lymphodepletion chemotherapy. Ibrutinib was continued for 3 months after CAR T-cell infusion.

Most patients (68%) in this cohort tolerated ibrutinib and continued with treatment as planned. However, 7 patients discontinued ibrutinib or required dose reductions due to disease progression, thrombocytopenia, intravascular coagulation during CRS, or microembolic stroke, which each occurred in one patient, and CAR T-cellrelated toxicity in 2 patients. One patient died 4 days after infusion.

At a median follow-up of 12 months (range 4-17), durable responses were observed in the patients showing response by day 28; the 1-year OS rate was 72% (

<.001). In patients achieving minimal residual disease (MRD) by IgH sequencing on day 28, the 1-year OS and PFS rates were 86% (

The study also contained a cohort of 24 patients with high-risk relapsed/refractory CLL and detectable disease after initial ibrutinib treatment who received an infusion of up to 2 x 106 CAR T cells but no ibrutinib. A retrospective comparison of the 2 cohorts indicated that the rates of any grade CRS (74% vs 92%) severe CRS (0% vs 25%), and grade &ge;3 cytotoxicity (26% vs 29%) favored the concurrent ibrutinib cohort over the no-ibrutinib arm.

"All grade 1 through 4 CRS and neurotoxicity events were reversible," he said.

One patient in each cohort died; in the concurrent ibrutinib arm, the death occurred on day 4 in a patient with cardiac history and grade 2 CRS on the day of death. In the no-ibrutinib arm, the death was due to CRS and neurotoxicity on day 11.

"Close cardiac monitoring using telemetry might be considered in patients developing CRS due to the potential risk of cardiac arrhythmia," he advised. "Despite robust CAR T-cell expansion the levels of cytokines associated with severe CRS were lower in the concurrent ibrutinib cohort."

For the comparison between the concurrent and no ibrutinib arms and MCP-1 (

Further comparison of the concurrent and no ibrutinib cohorts showed high rates of response at 4 weeks post CAR T-cell infusion (83% vs 65%), marrow response by flow cytometry (72% vs 74%), marrow response by IGH sequencing (85% vs 50%), nodal CR/PR (71% vs 64%), and PET CR/PR by Lugano criteria (80% vs 69%), respectively.

"CD19 CAR T cells with concurrent ibrutinib leads to high response rates without severe CRS in ibrutinib-refractory CLL," commented Gauthier. "Concurrent administration of ibrutinib is feasible in most patients, and provides high rates of MRD-negative responses."

The therapy is now being prospectively explored in the phase I/II TRANSCEND-CLL 17004 trial (NCT03331198).

Gauthier J. Durable responses after CD19-targeted CAR-T cell immunotherapy with concurrent ibrutinib for CLL after prior ibrutinib failure. Presented at: 15th International Conference on Malignant Lymphoma; June 18-22, 2019; Lugano, Switzerland. Abstract 120.

Significant activity was observed when ibrutinib was administered concurrently with CD19-directed CAR T-cell therapy compared with separately in patients with&nbsp;high-risk relapsed/refractory chronic lymphocytic leukemia who had progressed on or were intolerant of ibrutinib.&nbsp;Data presented at the 15th International Conference on Malignant Lymphoma show a high response rate with this concurrent treatment.&nbsp;

Virginia Powers, PhD | Authors

Articles

Acalabrutinib Shows High Response, Prolonged Survival in Ibrutinib-Intolerant R/R CLL

Genetic Analysis Provides Insight Into Venetoclax/Obinutuzumab Benefit in Frontline CLL

Frontline Treatment With Lenalidomide Plus R-CHOP May Benefit Select Patients With DLBCL

High Response Rate Seen With Concurrent Ibrutinib Plus CAR T-Cell Therapy in High-Risk CLL