Vignettes
71F diagnosed with CLL 6 weeks ago by flow cytometry; WBC 22,500 (82% lymphs). Hgb is 12.0 and platelets 155,000. No B symptoms. She has a palpable 1 cm lymph node in the cervical area and in left axilla. Prognostic panel shows: (+) 13q del, (+) IGHV mut, ZAP70 < 20%, no CD38 overexpression.
What treatment would you recommend?
Observation
- Indications for treatment are at least 1 of following:
1) marrow failure (hgb < 11, plt < 100)
2) massive splenomegaly (> 6cm below costal margin) or symptomatic/progressive
3) massive lymphadenopathy (> 10 cm) or symptomatic/progressive
4) lymphocyte increase > 50% in 2 months, LDT < 6 months. Very high lymphocyte counts may be reasonable to consider treatment.
5) autoimmune complications not responsive to steroids
6) symptomatic or functional extranodal involvement
7) disease related symptoms weight loss > 10% in 6mo, marked fatigue (ECOG 2 or worse), unexplained fevers > 2 weeks, night sweats > 1 month
49F diagnosed with CLL with 13q del and IGHV mutation. She requires treatment for progressive anemia and thrombocytopenia. Performance status is excellent other than a history of atrial fibrillation. She asks what treatment will offer her the best chance at a potential cure or prolonged remission.
FCR
What patient population may be considered for FCR?
Fit patient, < 65 y/o, with IGHV mutant status.
E1912 trial – age < 70, assigned in 2:1 ratio to ibrutinib + rituximab vs FCR
PFS favored ibrutinib (HR 0.35, p<0.001), OS favored ibrutinib (HR 0.17, p<0.001)
IGHV unmutated: PFS 90.7 (IR) vs 62,5 (FCR); HR 0.26
IGHV mutated: PFS 87.7 (IR) vs 88% (FCR); HR 0.44, p=0.07 (CI 0.14 - 1.36)
What is monoclonal B cell lymphocytosis?
Pre CLL condition. Monoclonal B cell lymphocytosis (MBL) refers to a monoclonal population of B lymphocytes <5000 cells/microL (<5 x 109/L) in peripheral blood for ≥3 months, without other features of a B cell lymphoproliferative disorder (eg, lymphadenopathy, organomegaly, cytopenias, or extramedullary involvement)
What is recommended management for localized SLL?
Observation
Some may offer RT.
62F recently diagnosed with CLL. FISH shows 13q del. WBC is 56,000, increased from 45,000 8 months ago. No lymphadenopathy of other clinical symptoms are noted. On exam scleral icterus is noted. Platelet count is 256,000 and hgb is 7.8 (from 13.9 eight months ago). What do you recommend?
Additional labs (e.g. LDH, haptoglobin, indirect bili, Coombs, retic ct) and steroids.
Likely patient had AIHA. This is not, in itself, an indication for treatment. CLL directed treatment is indicated, however, for autoimmune cytopenia refractory to corticosteroids.
68F with CLL presents for 6 month follow up. Exam normal. WBC=32,000 (was 22,000 at last visit), HGB=12, PLT=200,000. She reports monthly sinus infections since last visit, with persistence despite trials of various antibiotics per her PCP. What do you recommend?
Check IgG levels
If IgG < 500 mg/dL you can begin 0.3-0.5 g/kg IVIG monthly which may help in preventing recurrent infectious complications.
No clear indication for CLL directed treatments based on history provided.
Name 3 adverse prognostic markers which can inform disease trajectory and/or treatment recommendations.
17p del/TP53 mut - marker of lack of response to chemo/targeted therapy, more frequent relapse after initial therapy
IGHV unmutated - shorter survival and higher rate of relapse
CD38 - detected by flow; correlates with unmutated IGHV. Independently associated with poorer prognosis.
ZAP 70 - Increased levels by flow denotes poorer prognosis (? 20% cutoff); associated with unmutated IGHV
complex karyotype (at least 3 structural or numerical chromosomal aberrations) - marker of worse prognosis
beta 2 microglobulin - levels correlate with disease burden and increasing levels predict poorer prognosis
Describe the stages of the Rai staging system.
Stage 0 = lymphocytosis only (ALC > 5000)
Stage 1 = lymphocytosis + lymphadenopathy
Stage 2 = lymphocytosis + hepatosplenomegaly
Stage 3 = lymphocytosis + anemia
Stage 4 = lymphocytosis + thrombocytopenia
What should be considered for a patient who has had a complete response to chemotherapy after Richter's transformation to DLBCL?
Allogeneic transplant. Some data for auto transplant as well. (clinical trial also a correct answer).
Transformed DLBCL is often chemo refractory and unresponsive to immunotherapy (ORR 40-60%). Most patients will relapse shortly after initial response and OS is around 1-2 years.
Response to chemo is important in predicting outcome of allo transplant. 3-year OS of 41% and 75%, respectively, when RS patients were allografted in CR/PR compared with those transplanted with R/R disease (3-year OS, 17% to 27%)
64M with CLL and 17p del is started on ibrutinib. One month later labs are repeated and shows increased WBC to 135,000 from 75,000 with 82% lymphocytes. He reports increased fatigue. LDH is normal. Otherwise he is feeling unchanged from pre-treatment baseline and labs are stable. What do you recommend?
Continue ibrutinib
Ibrutinib causes a transient increase in lymphocyte count due to transfer of cells from nodes and marrow into circulation due to inhibition of CLL cell adhesion to stroma. Usually this resolves within 8-12 months.
72M has been undergoing observation for stage I CLL for 5 years. Baseline WBC is 52,000 (85% lymphs). He calls office in between office visits reporting new drenching night sweats and extreme fatigue. He comes to office and you palpate a large spleen as well as a 7 cm lymph node in his neck increased from 2 cm at last office visit. Hemoglobin and platelet counts are stable. WBC=65,000. What do you recommend?
PET/CT and biopsy t or/o Richter's transformation. Likely rapidly enlarging left node would be an appropriate site to biopsy.
Which of the following features would have lowest chance of responding to chemotherapy + monoclonal antibody therapy (anti-CD20)?
a. del 11q
b. del 17p
c. trisomy 12
d. IgHV unmutated
e. del 13q
b. del 17q
German CLL study group (2012) evaluated BR in 117 CLL patients. ORR 88% with 23% CR. 90% of patients with del 11q, 95% with trisomy 12, and 38% del 17p responded to therapy.
Preferred 1st line therapy: ibrutinib, acalabrutinib +/- obinutuzumab, or venetoclax + obinutuzumab
How long should ibrutinib be held prior to and after surgery?
Hold for 3 days prior to and after minor procedures (e.g. tooth extraction, bunionectomy), and 7 days prior to and after major procedures (e.g. cholecystectomy, knee surgery)
What drugs have black box warning for potentially fatal hepatotoxicity, colitis, or pneumonitis?
PI3K inhibitors idelalisib and duvelisib
76M with CLL Rai stage IV (plt 66,000). WBC 128,000 with 88% lymphs. FISH shows trisomy 12 and unmutated IGHV. He is quite frail, and has a history of peptic ulcer disease with repeated GI bleeds requiring transfusions. What would you recommend for initial therapy?
Venetoclax + obinutuzumab or maybe acalabrutinib.
Likely cannot tolerate chemo. Concern for bleeding risk with ibrutinib (likely lower with acalabrutinib).
CLL14 study: obinutuzumab + venetoclax vs obinutuzumab + chlorambucil in 432 treatment naiive patients with coexisting medical comorbidity. Median f/up 28 mo, 30 primary end-point events (disease progression or death) vs 77 events favoring venetoclax. PFS at 24 months 88% vs 64% favoring venetoclax. Similar toxicity.
64M planned to start 4th line therapy for CLL with 13q del, IGHV mutant. Initially treated with FCR and had 8 year response prior to progression. He then was treated with venetoclax and rituximab and had partial response for 2 years. He started on ibrutinib, but had significant bleeding from internal hemorrhoids and this had to be stopped. He takes aspirin and plavix for recent cardiac stents. What treatment do you recommend?
Options: acalabrutinib, duvelisib, idelalisib, rituximab. Also, could consider chemotherapy plus targeted agent as it has been many years since initial therapy.
idelalisib approved for r/r CLL in combination with rituximab after 1 prior therapy; generally given after both BTK and venetoclax due to toxicity
develisib approved as single agent after at least 2 prior lines of therapy.
BONUS: What prophylaxis should be considered when giving these PI3K inhibitors?
What is the most favorable cytogenetic abnormality seen in patients with CLL?
When starting venetoclax, what is the criteria for patients that are generally recommended for hospital admission and inpatient administration?
High risk: Lymph node > 10 cm or any node > 5 cm and ALC > 25 x 10^9. Treat with oral and IV hydration, allopurinol, inpatient administration of initial dose 20 mg and 50 mg. Consider rasburicase if uric acid is elevated at baseline.
Risk stratification for TLS is based on tumor volume and TLS labs should be drawn prior to starting therapy.
Low risk: all nodes < 5 cm and ALC < 25 x 10^9. Treat with oral hydration, allopurinol, outpatient administration.
Medium risk: any node 5-10 cm or ALC > 25 x 10^. Treat with oral hydration (can consider IV), allopurinol, outpatient administration.
Ramp up schedule: 20 mg x 1 week, 50 mg x 1 week, 100 mg x 1 week, 200 mg x 1 week, 400 mg thereafter.
CLL is commonly associated with what NON-hematologic malignancy risk?
Skin cancer
5-10 fold increase in risk for squamous cell and basal cell skin cancer, and have more aggressive biology (increased risk of invasion and metastasis). Risk of melanoma is also increased.
Patients should be counseled re: skin protection and UV exposure risk. Consider annual skin exams with dermatologist.
58M with history of CLL initially treated 8 years ago with FCR. Molecular studies at that time showed 13q del and mutated IgHV. He shows signs of relapse with anemia, splenomegaly, and 2 cm lymphadenopathy in bilateral cervical and axillary areas. LDH is 275. What do you recommend as next step in management?
Check for 17p del/p53 mut.
In 2nd line setting, patients can commonly acquire 17p deletion, which would change management, if this is the case.
PET/CT would also be reasonable to look for transformation, but this is probably less likely. Transformation classically characterized by acute decompensation - increased lymphadenopathy, splenomegaly, B symptoms, increased LDH.
What is the FDA indication for ofatumumab?
Initially approved for treatment of CLL refractory to fludarabine and alemtuzumab or if patient not a candidate for alemtuzumab. (ORR 58%) --Also used for treating MS.
Ofatumumab is a fully human anti-CD20 antibody that targets a different epitope - binds more tightly with slower dissociation rate (IgG1 antibody)
Also approved in combination with chlorambucil in treatment naive patients who are not candiated for fludarabine based therapy. Old study where comparator was chlorambucil alone.
Not commonly used
What is the significant of C481S point mutation with regard to CLL treatment?
Mechanism of resistance to 1st and 2nd generation BTK inhibitors. Mutation which occurs in BTK that disrupts the binding of BTK inhibitors ibrutinib and acalabrutinib to BTK.
LOXO-305 is a novel BTK-i currently in clinical trials that binds at different site.
66M with CLL noted to have rapidly increasing white blood count from 22,000 t o120,000 in recent labs. On peripheral smear many medium sized cells are seen with some prominent appearing nucleoli and condensed chromatin. Flow shows bright surface IgM, bright Ig kappa light chain restriction, bright CD20, CD19, CD22, CD79a, & FMC7. FISH shows 17p deletion. Patient is noted to have splenomegaly and anemia. What is most likely diagnosis and what treatment do you recommend?
B-cell prolymphocytic leukemia (B-PLL); treat with ibrutinib
B-PLL is a rare B-cell neoplasm comprised of prolymphocytes involving blood, BM, and spleen. By definition, prolymphocytes compose > 55% of blood or marrow. (CLL is between 15 - 55%). Mainly affects older adults (mean age 55-60). Present with rapid WBC elevation and marked splenomegaly. Usually no prominent adenopathy. >50% have TP53 mut.
Young/fit patients are candidates for transplant; trials (e.g. CAR T).
FCR can be considered if no 17pdel/TP53 mutation
Patient with CLL presents with anemia and very low reticulocyte count. No evidence of hemolysis or bleeding is found. Bone marrow biopsy is performed and shows erythroid-cell lineage maturation arrest. What is the likely diagnosis and treatment? What additional test should be ordered?
Likely autoimmune pure red cell aplasia.
Need to evaluate for parvovirus and other viral infection. Order PCR rather than viral serology due to low yeild of latter related to depressed humoral response.
Treatment is prednisone (10 mg/kg daily) and cyclosporine (300 mg daily); usually long course of therapy.