How frequent are chromosomal aberrations detected in CLL?
What is the most frequent genetic aberrations?
1) 13q deletion (50%) 2) 11q deletion (20%) 3) 12q Trisomy (15%) 4) 17p deletion (7%) 5) 6q deletion (6%)
How do chromosomal aberrations in CLL correlate with survival ?
17p deletion - 30m 11q deletion - 80m 12q deletion - 114m Normal karyotype - 110m (9years) 13q deletion - 120months
What contributed to the prognosis of CLL?
Presence/absence of 17p deletion Presence/absence of 11q deletion Age Binet stage Serum LDH WCC
What can Binet and Rai staging NOT do?
Cannot predict individual risk of disease progression and survival in the early stages of CLL (I.e. Binet stage A or Rai stage 0-2 disease)
What is the immunophenotyping of CLL?
CD19+ CD20+ CD23+ CD5+ CD10- BCL6+
What is the difference between CLL and SLL?
CLL (Chronic Lymphocytic Leukemia) is identical to SLL (Small Lymphocytic Lymphoma). CLL = disease manifests primarily in the bloods SLL = disease is mainly nodal. Treatment of early stage has some differences. Treatment of advanced stage is the same.
What are the initial treatment options available?
Purine analogs (Fludarabine, pentostatin) Alkylating agents (Chlorambucil, cyclophosphamide, Bendamustine) Monoclonal Ab (Rituximab, Ofatumumab, Obinutuzumab) Bruton's tyrosine kinase inhibitor (Ibrutinib)
What is the estimated median OS of CLL with modern regimens?
What is the preferred treatment for those
Regimen that contains both Fludarabine and Rituximab 1) FCR is used (Fludarabine, Cyclophosphamide, Rituximab) 2) FR (Fludarabine, Rituximab)
What is the preferred treatment of CLL For >70yo?
1) Single agent Ibrutinib 2) Chlorambucil + Obinutuzumab (or Ofatumumab) *Fludarabine not commonly used in this age group due to higher incidence of toxicities, esp OIs. Fludarabine also can lead to prolonged myelosuppression
If a patient has renal impairment with CLL
Bendamustine + Rituximab
What sort of infections are CLL patients prone to developing?
Strep Pneumoniae Staph Aueus H. Influenzae Herpes viruses
Between Chlorambucil and Fludarabine monotherapy for CLL, which is better?
Fludarabine N=500 Prev untreated CLL Trial comparing: 1) Fludarabine 2) Chlorambucil 3) F+C F>C: Higher 6y OS 43% vs 38% Higher 8y OS 30% vs 20%
Name me the side-effects of Cyclophosphamide
Hemorrhagic cystitis Bladder carcinogensis Impairment of fertility Leukemogenesis Interstitial pulmonary fibrosis
Fludarabine + Rituximab > Fludarabine What is the evidence?
CALGB 9011 + CALGB 9712 Retrospective analysis Better PFS Better OS Same risk of infectious complications. In favor of double therapy
Bendamustine > Chlorambucil - better tolerated - less effective than Fludarabine-based regimens Superior RR Survival benefit not shown yet
What caution will you take when Bendamustine is being administered?
Benda is not compatible with close-system transfer devices, adapters, syringes containing polycarbonate or acrylonitrile-butadiene-styrene (ABS) - these plastics can dissolve upon contact
Bendamustine > Chlorambucil. What is the evidence
N=300 Previously untreated, symptomatic CLL 2arms: 1) Chlorambucil x6# 2) Bendamustine x6# - 100 g/m2 over 30min D1-2 Q28 days Superior RR
What is CLL10
Ongoing RCT comparing FCR vs BR as initial therapy for previously untreated CLL N=560 CLL, without del17p Without significant co-morbidities 2 groups: A) 6#FCR B) 6# BR RESULTS: FCR > PFS for 2y PFS (85% vs 80%)
What is pentostatin
A purine analog. Used for CLL treatment. Combination Tx preferred to single agent therapy because: - Higher CR rates - Higher Treatment-free survival rates Most common regimen: PCR - Pentostatin 2-4mg/m2 - Cyclophosphamide 600 mg/m2 - Rituximab 375 m/2 Q21 days
FCR ~ PCR Evidence ?
Phase III N=200 Previously untreated CLL 2 arms: 1) PCR 8# 2) FCR 6 RESULTS: - similar median time to response 4m - NOT significant increase in ORR 50% vs 60% - lower ORR with 50% vs 60% - lower CRR 8% vs 16%
What are the treatment options for older CLL patients?
1) Ibrutinib 2) Chlorambucil + Obinutuzumab 3) Chlorambucil + Ofatumumab 4) Chlorambucil + Rituximab 5) Bendamustine + Rituximab 6) Pulsed intermittent single agent Chlorambucil - eg 0.8mg/kg Q4w 7) Lower dose Fludarabine (25mg/m2 X d1-3 Q28days) 8) FLudarabine, cyclophosphamide, Rituximab dose-reduced
Ibrutinib > Chlorambucil
No direct comparison between Chlorambucil+anti-CD20 Ab Ibrutinib has at least equivalent survival when compared with Chlorambucil+Obinutuzumab/Ofatumumab Higher RR Superior PFS Superior OS =============== RESONATE-2 N=270 older adults, previously untreated CLL 2 arms: A) Ibrutinib 420mg OD Q28days B) Chlorambucil 0.5-0.8mg/kg D1, 15 Q28days Up to 12 cycles RESULTS (in favor of Ibrutinib): Higher RR 90% vs 35% CRR 4% vs 2% Higher sustained improvements in Hb 80% vs 45% and platelet count 80% s 40% Superior PFS 90% vs 50% Superior OS 98% vs 85% at 2 y Fewer discontinuation due to adverse events 10% vs 20%
What are some of the S/e of Ibrutinib:
Diarrhea Peripheral edema Dry eye Arthralgia Nausea Vomiting Hypertension (14%, 4% severe) AFIb 6% Increased risk of bleeding (Severe in 6%) Liver dysfunction
What is the evidence for Obinutuzumab ?
Phase III trial, 800 older adults, prev untreated CLL 3 arms: 1) Chlorambucil 2) Chlorambucil + Rituximab 3) Chlorambucil + Obinutuzumab RESULTS: 1) CR>C - ORR 70% vs 30% - CR 8% vs 0% - higher rate of G3/4 neutropenia 25% vs 15% - similar rates of infection 10% - Improved PFS 16m vs 11m - * NO OS BENEFIT 2) OC>C - even higher CR rates - improved PFS 27m vs 11m - improved OS HR 0.41 3) RC
What is the evidence for Ofatumumab?
COMPLEMENT 1 trial Phase III 450 adults previously untreated CLL not eligible for Fludarabine-based therapy. 2 arms: 1) Ofatumumab+Chlorambucil 2) Chlorambucil Up to 12 cycles Results: - higher ORR 80% vs 70% (C) - CR 14% vs 1% - median duration of response 22m vs 13m - PFS 22 vs 13m - 2y survival ~ 90%; 3y survival ~85%
What are the side-effects of Ofatumumab?
Infusion reaction - 10% severe Neutropenia Weakness Headache Leukopenia Herpes simplex LRTI Arthralgia Upper abdominal pain Progressive Multifocal leukoencephalopathy Pre-medication required: - acetaminophen - glucocorticoid - antihistamine
How do you give Ofatumumab?
Premedications required. #1 consist of 2 doses - 300mg D1, - 1/52 later 1000mg D8 Subsequent cycles: - single dose 1000mg D1 Q28days until best response for a minimum of 3# and maximum of 12#
What is the evidence for monotherapy with Chlorambucil?
Generally used for older adults who are not candidates for: - Ibrutinib - Combination of Chlorambucil + anti-CD20 monoclonal Ab 1) Phases 3 trial - 200 adults, ECOG 2 or better - symptomatic, treatment naive CLL - 2arms: Chlorambucil vs Fludarabine RESULTS: - ORR 50% (C) vs 70% - CR 0% (C) vs 7% - ~rates of PFS 18m (C) vs 19m - non significant trend towards improved OS 60m vs 50m - lower rats of G3/4myelotoxicity 20% vs 40% - similar rates of infections 30%
How can Chlorambucil be given?
1) Pulsed intermittent dose schedule - eg. Single oral dose 0.8mg/kg Q4w 2) Chlorambucil 0.5mg/kg D1 D15 q28days for six cycles
What are the side-effects of Chlorambucil
Anemia Neutropenia Thrombocytopenia Infertility Seizures Hepatotoxic it Hypersensitivity Drug fever Pulmonary fibrosis Interstitial pneumonia
How would you manage high-risk CLL disease? Eg. Del(17p) or TP53 mutations
1) Clinical trial 2) Ibtrutinib 3) Fludarabine combinations --> Ibrutinib 4) non-myeloablative allogenic HCT for younger patients with a matched related or matched unrelated donor.
What is the evidence for FCR > FC?
An open-label, phase III randomized trial compared six courses of FCR with six courses of FC in 817 previously untreated patients with CLL. FCR resulted in the following significant findings:
●Higher rates of overall (95 versus 88 percent) and complete (44 versus 22 percent) response
●Longer median progression-free survival (52 versus 33 months)
●Better overall survival at three years (87 versus 83 percent)
●Higher rates of severe (grade 3/4) neutropenia (34 versus 21 percent), leukocytopenia (24 versus 12 percent)
●Similar rates of severe (grade 3/4) infections (25 versus 21 percent)
●Similar rates of treatment-related deaths (2 versus 3 percent)
What is the preferred treatment options for younger patients with CLL?
For most younger patients, we suggest the use of fludarabine-based therapies rather than more recently approved agents, such as bendamustine (Grade 2C). Specifically, we use combination therapy with either fludarabine plus rituximab (FR) or fludarabine, cyclophosphamide, and rituximab (FCR)
•FR results in overall response and CR rates of approximately 90 and 47 percent, respectively. The administration of FR to patients with CLL can be complicated by infusion-related reactions and tumor lysis syndrome. Several variations on dose and schedule have been used.
•FCR results in overall response and CR rates of approximately 90 to 95 and 40 to 70 percent, respectively. CR achieved with FCR appears to be "deeper" with frequent cases demonstrating no detectable disease on flow cytometry. The FCR regimen has been administered in different variations.
•Bendamustine has demonstrated superior response rates when compared with chlorambucil in prospective, randomized trials. No survival benefits have been noted and bendamustine has not been compared directly with fludarabine-based therapy.
What is the criteria to define active disease in CLL
The iwCLL defines "active disease" by the presence of one or more of the following criteria:
Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia.
Massive (ie, at least 6 cm below the left costal margin) or progressive or symptomatic splenomegaly.
Massive nodes (ie, at least 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy.
Progressive lymphocytosis with an increase of more than 50 percent over a two-month period or LDT of less than six months. LDT can be obtained by linear regression extrapolation of absolute lymphocyte counts obtained at intervals of two weeks over an observation period of two to three months. In patients with initial blood lymphocyte counts of less than 30 x 109/L (30,000/L), LDT should not be used as a single parameter to define a treatment indication. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (eg, infection) should be excluded.
Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy.
Constitutional symptoms, defined as any one or more of the following disease-related symptoms or signs:
a. Unintentional weight loss of 10 percent or more within the previous six months
b. Significant fatigue (ie, ECOG PS 2 or worse; inability to work or perform usual activities)
c. Fevers higher than 100.5°F or 38.0°C for two or more weeks without other evidence of infection
d. Night sweats for more than one month without evidence of infection