CLL/SLL

Question 1

How frequent are chromosomal aberrations detected in CLL?

Answer 1

80%

Question 2

What is the most frequent genetic aberrations?

Answer 2

1) 13q deletion (50%) 2) 11q deletion (20%) 3) 12q Trisomy (15%) 4) 17p deletion (7%) 5) 6q deletion (6%)

Question 3

How do chromosomal aberrations in CLL correlate with survival ?

Answer 3

17p deletion - 30m 11q deletion - 80m 12q deletion - 114m Normal karyotype - 110m (9years) 13q deletion - 120months

Question 4

What contributed to the prognosis of CLL?

Answer 4

Presence/absence of 17p deletion Presence/absence of 11q deletion Age Binet stage Serum LDH WCC

Question 5

What can Binet and Rai staging NOT do?

Answer 5

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)

Question 6

What is the immunophenotyping of CLL?

Answer 6

CD19+ CD20+ CD23+ CD5+ CD10- BCL6+

Question 7

What is the difference between CLL and SLL?

Answer 7

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.

Question 8

What are the initial treatment options available?

Answer 8

Purine analogs (Fludarabine, pentostatin) Alkylating agents (Chlorambucil, cyclophosphamide, Bendamustine) Monoclonal Ab (Rituximab, Ofatumumab, Obinutuzumab) Bruton’s tyrosine kinase inhibitor (Ibrutinib)

Question 9

What is the estimated median OS of CLL with modern regimens?

Answer 9

3-8 years

Question 10

What is the preferred treatment for those

Answer 10

Regimen that contains both Fludarabine and Rituximab 1) FCR is used (Fludarabine, Cyclophosphamide, Rituximab) 2) FR (Fludarabine, Rituximab)

Question 11

What is the preferred treatment of CLL For >70yo?

Answer 11

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

Question 12

If a patient has renal impairment with CLL

Answer 12

Bendamustine + Rituximab

Question 13

What sort of infections are CLL patients prone to developing?

Answer 13

Strep Pneumoniae Staph Aueus H. Influenzae Herpes viruses

Question 14

Between Chlorambucil and Fludarabine monotherapy for CLL, which is better?

Answer 14

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%

Question 15

Name me the side-effects of Cyclophosphamide

Answer 15

Hemorrhagic cystitis Bladder carcinogensis Impairment of fertility Leukemogenesis Interstitial pulmonary fibrosis

Question 16

Fludarabine + Rituximab > Fludarabine What is the evidence?

Answer 16

CALGB 9011 + CALGB 9712 Retrospective analysis Better PFS Better OS Same risk of infectious complications. In favor of double therapy

Question 17

Bendamustine/Rituximab Chlorambucil

Answer 17

Bendamustine > Chlorambucil - better tolerated - less effective than Fludarabine-based regimens Superior RR Survival benefit not shown yet

Question 18

What caution will you take when Bendamustine is being administered?

Answer 18

Benda is not compatible with close-system transfer devices, adapters, syringes containing polycarbonate or acrylonitrile-butadiene-styrene (ABS) - these plastics can dissolve upon contact

Question 19

Bendamustine > Chlorambucil. What is the evidence

Answer 19

N=300 Previously untreated, symptomatic CLL 2arms: 1) Chlorambucil x6# 2) Bendamustine x6# - 100 g/m2 over 30min D1-2 Q28 days Superior RR

Question 20

What is CLL10

Answer 20

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%)

Question 21

What is pentostatin

Answer 21

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

Question 22

FCR ~ PCR Evidence ?

Answer 22

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%

Question 23

What are the treatment options for older CLL patients?

Answer 23

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

Question 24

Ibrutinib > Chlorambucil

Answer 24

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%

Question 25

What are some of the S/e of Ibrutinib:

Answer 25

Diarrhea Peripheral edema Dry eye Arthralgia Nausea Vomiting Hypertension (14%, 4% severe) AFIb 6% Increased risk of bleeding (Severe in 6%) Liver dysfunction

Question 26

What is the evidence for Obinutuzumab ?

Answer 26

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

Question 27

What is the evidence for Ofatumumab?

Answer 27

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%

Question 28

What are the side-effects of Ofatumumab?

Answer 28

Infusion reaction - 10% severe Neutropenia Weakness Headache Leukopenia Herpes simplex LRTI Arthralgia Upper abdominal pain Progressive Multifocal leukoencephalopathy Pre-medication required: - acetaminophen - glucocorticoid - antihistamine

Question 29

How do you give Ofatumumab?

Answer 29

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#

Question 30

What is the evidence for monotherapy with Chlorambucil?

Answer 30

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%

Question 31

How can Chlorambucil be given?

Answer 31

1) Pulsed intermittent dose schedule - eg. Single oral dose 0.8mg/kg Q4w 2) Chlorambucil 0.5mg/kg D1 D15 q28days for six cycles

Question 32

What are the side-effects of Chlorambucil

Answer 32

Anemia Neutropenia Thrombocytopenia Infertility Seizures Hepatotoxic it Hypersensitivity Drug fever Pulmonary fibrosis Interstitial pneumonia

Question 33

How would you manage high-risk CLL disease? Eg. Del(17p) or TP53 mutations

Answer 33

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.

Question 34

What is the evidence for FCR > FC?

Answer 34

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)

Question 35

What is the preferred treatment options for younger patients with CLL?

Answer 35

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.

Question 36

What is the criteria to define active disease in CLL

Answer 36

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