Journal Club

G U R U S U B R A M A N I A N G U R U M U R T H Y M D

P G Y - 3

I N T E R N A L M E D I C I N E

CHRONIC LYMPHOCYTIC LEUKEMIA“TOWARDS A NEW ERA IN THE MANAGEMENT”

Chronic Lymphocytic Leukemia

Indolent B-cell neoplasm characterized by the clonalproliferation and accumulation of mature, typically CD5-positive B-cells within the blood, bone marrow, lymph nodes, and spleen.

Epidemiology

Most common leukemia in the western world.

Age-adjusted incidence of 4.1/100,000 in the United States

Median age at diagnosis lies between 67 and 72 years.

More male than female patients (1.7:1)

Clinical Features

Around 25% of patients are asymptomatic

Constitutional: night sweats, fever, weakness, weight loss

Recurrent infections (bacterial, viral – Herpes Zoster, fungal)

Bleeding manifestations due to thrombocytopenia

Lymphadenopathy

Splenomegaly

Hepatomegaly

Autoimmune anemia and thrombocytopenia, PRCA.

Hypogammaglobulinemia

MPGN as a paraneoplastic manifestation

Diagnosis

Absolute B-lymphocyte count ≥ 5 x 10 9/L in the peripheral blood.

Clonality of the circulating B-lymphocytes needs to be confirmed by flow cytometry.

Small, mature lymphocytes positive for CD5, CD19, CD20, and CD23. The levels of surface immunoglobulin (Ig) are characteristically low compared to those found on normal B cells

Lymphocytosis and Smudge Cells

Staging

Staging

Chromosomal abnormalities in CLL

del(13q14) occurring in approx. 55%

del(11q) in 25% of chemotherapy-naïve

Trisomy 12 in 10–20% of patients

del(17p) in 5–8% of chemotherapy-naive patients. Show marked resistance against chemotherapies.

When to Treat CLL Patients

No advantage to treating CLL until symptoms develop irrespective of genomic features

IWCLL 2008 criteria for treatment

o Enlarging, symptomatic lymph nodes (> 10 cm)

o Enlarging, symptomatic spleen (> 6 cm)

o Cytopenias due to CLL (hemoglobin < 11, platelets < 100)

o Constitutional symptoms due to disease (fatigue, B symptoms)

o Poorly controlled AIHA or ITP

o Lymphocyte doubling time < 6 months or increase of 50% over a 2-month time period

History of CLL Therapy

Chlorambucil:

- well tolerated oral agent but low response

Fludarabine

- Higher response, longer remission but no major impact on survival; not beneficial to age >65 years

Fludarabine/cyclophosphamide

- Higher response, longer remission, but no major impact on survival

Antibody rituximab:

- well tolerated with low response

Rituximab addition to fludarabine ± cyclophosphamide(FCR):

- higher response, longer remission and overall survival .

CLL Therapy

FCR currently standard therapy for younger CLL patients

Bendamustine + Rituximab often substituted for FCR

Older patients (age > 65) are treated with chlorambucil/Rituximab or Bendamustine + Rituximab

How long do these therapies work ?

Six-year follow-up is available for 300 patients initially treated with FCR combination therapy as part of prospective phase II trials.

Six-year overall and failure-free survival rates were 77 and 51 percent, respectively, and the median time to progression was 80 months.

Relapse

Invariably occurs in all patients after stopping therapy.

Interval from last treatment to onset of relapse is important in determining the choice of further therapy.

Progressive disease occurring more than 12 months after the discontinuation of treatment can be retreated using the same medication, or by switching to other available treatments.

Relapse within 12 months or disease refractoriness would necessitate usage of alternative strategies.

Salvage therapy options for relapse

Fludarabine, Cyclophosphamide, and Rituximab

Bendamustine + Rituximab

High dose Solumedrol + Rituximab

Lenalidomide ± Rituximab

Ofatumumab—58% response but short PFS

Idelalisib

Alemtuzumab

Allogeneic stem cell transplantation

Difficult to treat groups

Short duration of response to initial therapy

Adverse cytogenetic abnormalities such as del 17p

Refractory CLL

B cell Receptor Signaling

Ibrutinib

Ibrutinib is a first-in-class, oral covalent inhibitor of Bruton’s tyrosine kinase, an essential enzyme in B-cell receptor signaling, homing, and adhesion.

Blocks survival signals transmitted from the microenvironment to CLL tumor cells through the B cell receptor signaling pathway

Phase 2 studies in relapsed or refractory CLL showed a response rate of 71%

FDA approved for CLL (in February 2014) who had received at least one previous therapy.

J O H N C . B Y R D , M . D . , J E N N I F E R R . B R O W N , M . D . , P H . D . , S U S A N O ' B R I E N , M . D E T A L .

N E N G L J M E D

V O L U M E 3 7 1 ( 3 ) : 2 1 3 - 2 2 3

J U L Y 1 7 , 2 0 1 4

Ibrutinib versus Ofatumumab in Previously Treated Chronic

Lymphoid Leukemia

Background

On the basis of the phase 2 trial, a multicenter, open-label, randomized, phase 3 trial was initiated -Ibrutinib versus Ofatumumab in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (RESONATE)

Overview

Period - June 2012 through April 2013

67 sites in the United States, Australia, and seven European countries.

Funded by Pharmacyclics and Janssen;

RESONATE ClinicalTrials.gov number NCT01578707.

Eligibility Criteria

Additional criteria

ECOG performance status of less than 2

Absolute neutrophil count of at least 750 cells per microliter

Platelet count of at least 30,000 cells per microliter

Adequate liver and kidney function.

Exclusion Criteria

Patients requiring warfarin or strong CYP3A4/5 inhibitors were excluded

Patients who did not meet the inclusion criteria

Therapy

Patients were randomly assigned to receive either

Oral ibrutinib at a dose of 420 mg once daily until disease progression or the occurrence of unacceptable toxic effects OR

Intravenous ofatumumab for up to 24 weeks at an initial dose of 300 mg at week 1, followed by a dose of 2000 mg weekly for 7 weeks and then every 4 weeks for 16 weeks.

End points

Primary end point - duration of progression-free survival, according to the criteria of the International Workshop on Chronic Lymphocytic Leukemia.

Secondary end points included the duration of overall survival and the response rate.

Followup

Patients were monitored weekly for the first 8 weeks, every 4 weeks until month 6, and then every 12 weeks, with full response assessments performed every 12 weeks.

CT to evaluate response and persistent improvement for at least 2 months to confirm response

Statistics

Primary analysis was a two-sided log-rank test stratified according to the presence or absence of the chromosome 17p13.1 deletion and the disease refractory status at randomization.

Type I error was controlled through adjustment of the significance level with the use of the O’Brien–Fleming boundary for the interim analysis

Hierarchical closed-testing procedure for primary and ordered secondary end points.

Results

PFS and OS

At a median follow-up of 9.4 months, ibrutinib significantly improved PFS.

Median duration was not reached in the ibrutinib group (PFS of 88% at 6 months), as compared with a median of 8.1 months in the ofatumumab group (hazard ratio in the ibrutinib group, 0.22; P<0.001).

Ibrutinib also significantly improved overall survival (hazard ratio for death, 0.43; P = 0.005). At 12 months, the overall survival rate was 90% in the ibrutinib group and 81% in the ofatumumab group.

Overall response rate was significantly higher in the ibrutinib group than in the ofatumumab group (42.6% vs. 4.1%, P<0.001).

17p deletion cohort

Median duration of progression-free survival was not reached in the ibrutinib group, as compared with a median of 5.8 months in the ofatumumab group (hazard ratio 0.25; 95% CI, 0.14 to 0.45).

At 6 months, 83% of the patients in the ibrutinibgroup, as compared with 49% of those with this deletion in the ofatumumab group, were alive with no disease progression.

Overall Survival

57 patients in the ofatumumab group had crossed over to receive ibrutinib after confirmed disease progression.

Survival effect was based on an analysis in which data were censored at the time of crossover.

At 12 months, the survival effect was also observed in the uncensored sensitivity analysis (hazard ratio 0.39; P = 0.001), with an overall survival rate of 90% in the ibrutinib group and 79% in the ofatumumab group

OS and PFS

Subgroup Analyses of Progression-free Survival

Overall Survival

Adverse Reactions

The most frequent non-hematologic adverse events were diarrhea, fatigue, pyrexia, and nausea in the ibrutinib group and fatigue, infusion-related reactions, and cough in the ofatumumab group.

Slightly higher incidence of AF, visual blurring and minor skin bleeds in ibrutinib group.

Adverse events

Conclusions

Ibrutinib significantly improves the overall response, PFS and OS as compared to ofatumumab in previously treated CLL patients.

Strengths

Phase III randomized study

Included the group of patients in whom the common treatment options did not work, hence addressed an unmet need.

Changes the landscape of CLL therapy

Weakness

Short follow-up period.

Did not include patients with poor performance status, liver dysfunction, renal dysfunction, and patients on warfarin.

Comparison against a new monotherapy

Future directions

Combination of Ibrutinib with other chemotherapy regimens

Role of ibrutinib in treatment naïve patients.

Points for Internists

Be aware of the side effects

Lymphocytosis during initial phase of treatment is common.

Not tested in patients taking warfarin.

Need to hold the drug before and after any elective surgical procedure with bleeding risk (1 week before and after).

References

Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 2008; 111:5446.

Tam CS, O'Brien S, Wierda W, et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood 2008; 112:975.

Uptodate – Chronic lymphocytic leukemia.