Hematologic Malignancies

CLL & CML

Dr. Sherif Kamal

Patient Case #1:

• MM is a retired 68-year-old male with a history of chronic kidney

disease, hypertension and hypercholesterolemia.
• He was in his usual state of health until approximately 6 months ago,
when he noted significant and painful lymph node swelling in his neck
and groin.
• His family medical doctor prescribed an antibiotic, but his symptoms
did not resolve.
• He returned to his family doctor, where his CBC revealed marked
lymphocytosis (lymphocytes = 27,000 B cells/mm3).
• Flow cytometry confirmed the diagnosis of CLL.
• After further workup, MM is diagnosed with Binet stage B disease.
• His cytogenetic analysis reveals that he has a del(13q) mutation and
unmutated IGHV.
• He is considered medically fit to receive treatment.
• Which of the following treatment regimens is the most appropriate first-
line therapy for FB?
• A. Acalabrutinib +/- obinutuzumab
• B. Chlorambucil + ofatumumab
• C. Fludarabine, cyclophosphamide and rituximab (FCR)
• D. Alemtuzumab + rituximab
Patient evaluation / goals of therapy
• CLL is primarily a disease of the elderly. The median age at diagnosis is 72 years,
with 40% of patients being > 75 years and ~30% being > 80 years old.
• Up to 90% of patients with CLL have one or more comorbidities.
• A decline in organ function and/or co-existing disease(s) may impact the choice of
therapy.
Patient evaluation / goals of therapy
• It is critical to assess each individual patient’s comorbidities, age and
performance status to evaluate the patient’s “fitness” for therapy.
• a. Younger or physiologically fit patients are called “go-go” patients.
• In these patients, achieving a durable response is the goal of treatment.
• b. Older patients who cannot tolerate aggressive regimens, but may still
benefit from active therapy, are called “slow-go” patients.
• c. Frail patients with significant comorbidities, called “no-go” patients, should
be treated with palliative therapy.
• In these patients, controlling symptoms is the essential treatment goal.
• A regimen with a more favorable toxicity profile should be applied in this
setting.
Fitness for therapy
• At this time, there is no standard tool to assess a patient’s fitness for therapy.
• a. Patients were traditionally classified based on age alone, but it is now recognized that chronological age is
not a reliable surrogate marker of fitness.
• b. Creatinine clearance (CrCl), rather than age, has been noted as the primary predictor of higher toxicity
with fludarabine-based regimens. References suggest reducing the dose of fludarabine when CrCL < 80
mL/min.
• Suggested tools to assess comorbidity that have been validated include the :
• Charlson Comorbidity Index (CCI)
• Cumulative Illness Rating Scale (CIRS)
• National Cancer Institute (NCI) comorbidity index
• Comprehensive Geriatric Assessment (CGA)
“minimal residual disease”,
• MRD describe the inability to detect measurable disease at a specified reporting
threshold.
• Undetecable MRD (U-MRD) at the end of treatment has demonstrated
independent prognostic significance in CLL, correlating with favorable
progression-free survival and overall survival with chemoimmunotherapy in both
the first and second-line settings.
• MRD may not be the treatment goal for every patient.
• This may be particularly relevant for elderly patients with multiple
comorbidities or patients in the relapsed/refractory setting, in which
achieving durable disease control while minimizing adverse effects may be a
more desirable goal.
 The Rai staging system classifies CLL

https://www.lls.org/leukemia/chronic-lymphocytic-leukemia/diagnosis/cll-staging
CLL International Prognostic Index (CLL-IPI)

• The CLL-IPI combines genetic, biochemical and clinical parameters to

categorize patients into four prognostic risk groups. Five independent
prognostic factors were identified:
• TP53 deleted or mutated = 4 points
• Unmutated IGHV = 2 points
• Serum beta-2 microglobulin concentration > 3.5 mg/L = 2 points
• Rai Stage I - V or Binet Stage B - C = 1 point
• Patient age > 65 years = 1 point
International Prognostic Index for CLL
(CLL-IPI)
• Using data from 3472 previously untreated patients with CLL who participated in prospective, randomized controlled clinical trials,
five independent prognostic factors were identified:
• a. TP53 deletion or mutation, or both
• b. IGHV mutational status
• c. Serum β2-microglobulin concentration
• d. Clinical stage of disease
• e. Age
• Patients were classified into one of four risk groups based on a weighted grading
of the independent factors:
• Low 5 y OS was low risk = 93%
• Intermediate 79%,
• High 63%
• very high risk. 23%
Natural history of disease

• CLL is considered an indolent disease.

• transformation to an aggressive non-Hodgkin lymphoma.
• Survival following diagnosis ranges from 1-20 years.
• Some CLL patients survive for many years without therapy
• others have a rapidly fatal disease despite aggressive therapy.
Prognostic factors and genomics

• β-2 microglobulin
• elevated levels of β-2 microglobulin are a strong independent prognostic indicator for treatment-free
intervals, response to treatment and overall survival.
• Comorbidity has been identified as an independent adverse prognostic factor in CLL.
• Disease control was less likely in patients with increased comorbidities
• This was likely due to more dose reductions and treatment discontinuations as compared to healthier
patients.
• In this study, toxicity rates in patients with increased comorbidity were equivalent to healthier patients, likely
due to pre-emptive dosage reductions of chemoimmunotherapy.17 However, some studies suggest that
patients with increased comorbid conditions have higher rates of discontinuation of novel agents due to
adverse effects.
Genetic markers

• Cytogenetic mutations can be detected by fluorescence in situ hybridization (FISH) and provide prognostic
information.
• 80% of previously untreated CLL have at least one cytogenetic mutation.
Specific deletions and prognosis

• 1) Del(13q) as the sole abnormality is associated with a favorable prognosis and the longest median survival.
• 2) Del(11q) is associated with bulky lymphadenopathy, rapid disease progression, and shorter median
survival.
• a) Patients with this mutation may have an impaired response to radiation or cytotoxic drugs, resulting in a poor outcome.
• b) Previously untreated patients with del(11q) respond well to the combination of fludarabine and an alkylating agent.
• c) When patients with del(11q) were treated with ibrutinib in the first-line setting, progression-free survival was comparable
to patients who did not have del(11q).
• 3) Del(17p) is the single most important prognostic factor in CLL.
• a) This mutation reflects the loss of the key tumor suppressor TP53 gene and is frequently associated with mutations in the
remaining TP53 allele (80% of cases).
• b) Patients with this mutation progress more often and more rapidly to symptomatic disease.
• c) The mutation may be acquired during the disease course. Reassessing mutational status by DNA sequencing at the time of
disease progression is warranted.
• d) The presence of TP53 mutations is associated with the worst outcomes, including short treatment-free intervals, poor
response to chemotherapy, and short median survival (median < 3 years) with standard chemoimmunotherapy and/or
rituximab.
• e) Patients with this mutation are considered to have “ultra-high risk” CLL and may be selectively treated with emerging
therapies. 4) Complex karyotype (≥3 unrelated chromosomal abnormalities) is associated with an unfavorable prognosis.
• Favorable prognosis refers to deletion 13q as the sole abnormality,
while neutral prognosis includes normal cytogenetics and trisomy
• Unfavorable prognosis includes del(11q) and del(17p).
• When multiple abnormalities exist, the impact on prognosis is
ordered as del(17p) > del(11q) > trisomy 12 > del(13q).
Frequency of occurrence of the most commonly observed cytogenetic abnormalities in CLL
Immunoglobulin heavy-chain variable
• Immunoglobulin heavy-chain variable (IGHV) region gene mutation
status is an important predictor of survival outcomes.
• All cases of CLL contain clonal rearrangements of the immunoglobulin
heavy and light chain genes, consistent with their malignant nature.
• Recent data show there are two types of CLL, as determined by the
presence or absence of somatic hypermutations in the
immunoglobulin gene.
Genetic markers

• Unmutated IGHV is associated with a poor prognosis and significantly

decreased survival compared to cases of mutated IGHV.
• This difference is independent of the stage of disease.

• (≤ 2% mutated, also reported as ≥ 98% homology with germline

sequence)
• CD38 expression in ≥ 30% of B lymphocytes is associated with shorter progression-free survival and overall
survival.
• ZAP-70 is an intracellular protein that transmits activation signals to T lymphocytes. It is rarely present in
normal B cells, but has been found in patients with CLL. a. Expression of ZAP-70 in ≥ 20% of B lymphocytes is
associated with shorter progression-free survival (PFS) and overall survival (OS).
• b. Standardization and reproducibility of ZAP-70 flow cytometry methods remains a challenge. In clinical
practice, evaluation of ZAP-70 expression is not recommended outside the context of a clinical trial.
• Expression of CD49d in ≥ 30% of B lymphocytes is associated with lymphadenopathy, progressive disease
and aggressive disease biology. a. Among the prognostic factors that are based on flow cytometry (CD38,
CD49d and ZAP-70), CD49d appears to be the strongest predictor of OS and treatment-free survival.
• Both CD38 and ZAP-70 positivity correlate with unmutated IGHV, and have been suggested as surrogate
markers for IGHV mutational status. However, results are inconclusive, and the evaluation of CD38, CD49d
and ZAP-70 are not currently recommended outside of clinical trials.
Outcomes associated with IGHV gene mutations and surrogate markers in CLL
Prognosis associated with cytogenetics in CLL

In the general clinical practice setting, prognostic factors should not determine
treatment choices, with the exception of del(17p).
Treatment
• The clinical course of CLL varies greatly.
• significant portion of CLL patients never require treatment, or can be effectively managed with supportive
care.
• In contrast, other patients have a very aggressive clinical course and suffer early disease progression and
death.
• For all patients with CLL, the goal of frontline therapy is to palliate symptoms and extend survival.
Initiating treatment

• Early-stage, low-risk disease (Rai stage 0 or Binet stage A).

• An “active surveillance” approach may be appropriate for asymptomatic
patients with
• Two phase III studies and a meta-analysis revealed that there is no
statistically significant difference in survival between patients who
were treated early versus those who were deferred until there was a
clinical indication for treatment.
• The potential benefit of early-intervention therapy with the currently
available treatment agents remains to be proven.
Initiating treatment
• Intermediate-risk disease (Rai stage I or II or Binet stage B)
• may benefit from therapy if they show evidence of progressive disease or
become symptomatic.
• Absolute lymphocyte count (ALC) or symptoms related to leukostasis
should not be the sole indicator to begin treatment.
• The symptoms of leukostasis that develop in patients with acute
leukemia rarely occur in patients with CLL.
Initiating treatment
• advanced stage or high-risk CLL (Rai stage III or IV or Binet stage C) typically present with symptomatic
disease and require immediate treatment.
Initiating treatment
• Indications for initiating treatment include:
• 1) Disease-related constitutional symptoms:
• severe fatigue
• unintended weight loss
• drenching night sweats
• and/or fever without infection
• Threatened end-organ function
• Progressive bulky disease:
• massive or symptomatic
• splenomegaly or lymphadenopathy
• Progressive bone marrow failure:
• worsening anemia and/or thrombocytopenia
Choice of first-line therapy

• 1. The current standard of care has evolved from single-agent alkylating agents, through the introduction of
purine analogs, to chemoimmunotherapy combinations and small molecule inhibitors.
• 2. Choice of therapy can be subdivided based on age and genetic mutation:
• a. Age < 65 years without significant comorbidities vs age ≥ 65 years or younger patients with significant
comorbidities
• b. Presence of del (17p)/TP53 mutation
Age < 65 years without significant comorbidities
without del (17p)/TP53 mutation
• Ibrutinib is an NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Category 1
recommendation in this setting.
• The “ECOG-E1912” study was a randomized phase III trial that compared ibrutinib + rituximab (IR) to
fludarabine, cyclophosphamide and rituximab (FCR) in 529 treatment-naïve patients with CLL who were ≤ 70
years of age and required therapy. The primary endpoint was PFS, with a secondary endpoint of OS.
• Patients with del(17p)/TP53 mutation were excluded from trial participation.
• The hazard ratio for PFS at 45 months favored IR over FCR (HR = 0.39, 95% CI = 0.26 – 0.57; p < 0.0001).
• The improvement in PFS was seen across subgroups, including in patients with IGHV-unmutated disease.
However, the difference was not significant in patients with IGHV mutated disease.
• The results of this trial and others call the benefit of adding an anti-CD20 monoclonal antibody to ibrutinib
into question.
• Therefore, the NCCN Guidelines® recommend ibrutinib alone in this setting.
bAcalabrutinib +/-obinutuzumab is an NCCN
Guidelines® Category 1 regimen
• The “ELEVATE-TN” study was a phase III trial of 535 patients with previously untreated CLL who were 65
years of age or older, or under 65 years of age with comorbidities (considered as a Cumulative Illness Ratings
Scale score > 6 or CrCl < 70 mL/min).
• The results of this trial have been extrapolated to young, medically fit patients with CLL
• Patients were randomized to acalabrutinib alone, acalabrutinib + obinutuzumab or chlorambucil +
obinutuzumab.
• Note that patients who received chlorambucil + obinutuzumab received treatment for 6 cycles, whereas
acalabrutinib was continued until disease progression in both of the acalabrutinib-containing arms.
• The primary endpoint was PFS of acalabrutinib + obinutuzumab compared to chlorambucil + obinutuzumab
as assessed by an independent review committee.
• At a median follow-up of 28 months, both acalabrutinib monotherapy and acalabrutinib + obinutuzumab
had significantly longer PFS compared to chlorambucil + obinutuzumab, reducing the risk of progression or
death by 80% with acalabrutinib monotherapy and by 90% with acalabrutinib + obinutuzumab .
• Improvement in PFS with acalabrutinib monotherapy or acalabrutinib + obinutuzumab was consistent
across subgroups, including del(17p).
Venetoclax + obinutuzumab is an NCCN
Guidelines® preferred regimen in this setting.
• The “CLL14” study was a phase III trial of 432 patients with previously untreated CLL who had co-existing
conditions (considered as a CIRS score > 6 or CrCl < 70 mL/min).
• The median age of trial participants was 72 years of age.
• The results of this trial have been extrapolated to young, medically fit patients with CLL.
• Patients were randomized to venetoclax + obinutuzumab or chlorambucil + obinutuzumab. The total
duration of therapy with venetoclax + obinutuzumab was 1 year, while the total duration of therapy with
chlorambucil + obinutuzumab was 6 months. The primary endpoint was investigator-assessed PFS.
• After a median follow-up of 39.6 months, PFS was superior for venetoclax + obinutuzumab compared to
chlorambucil + obinutuzumab (median not reached vs 35.6 months; HR 0.31, p < 0.001).
• At 3 years, the estimated PFS was 81.9% with venetoclax + obinutuzumab compared to 49.5% with
chlorambucil + obinutuzumab.
• The benefit in PFS was observed in patients with TP53 mutation, patients with unmutated IGHV, and other
prespecified subgroups.
• A notable portion of both treatment groups required growth factor support.
Bendamustine and rituximab
• Bendamustine and rituximab (BR) combinations have been evaluated, and the final results of a phase III trial
(the “CLL10 study”) have been reported.
• This trial randomized 564 previously untreated, medically fit CLL patients without del(17p) to FCR or BR.
• The primary endpoint was non-inferiority of PFS.
• The FCR arm had significantly improved PFS, but OS was not different between the groups.
• The benefit of improved PFS with FCR was not seen in patients > 65 years of age.
• Patients who received FCR experienced more grade 3-4 neutropenia and grade 3-4 infections. The use of
prophylactic growth factor support was not permitted in this trial.
• The updated results of the study confirmed that the rates of secondary AML or MDS were greater in the FCR
arm (7% vs 1% in patients > 65 years and < 3% vs 1% in patients ≤ 65 years).
FCR
• FCR is still a recommended regimen and preferred for first-line therapy in young,
fit patients with mutated IGHV based on the E1912 study and others
Subcutaneous rituximab in CLL92

• A combination of rituximab and the endoglycosidase hyaluronidase human.

• The prescribing information explicitly states that the product should only be initiated after patients have
received at least one full dose of a rituximab product by intravenous infusion. Current NCCN Guidelines®
reiterate this concept.
• For CLL, the dose is 1600 mg/26,800 units (13.4 mL of product) subcutaneously according to the
recommended schedule. The product is supplied in single dose vials. Note that the doses and vial sizes differ
between CLL and lymphoma.
• The product should be injected into the subcutaneous tissue of the abdomen over approximately 7 minutes.
Note that this administration time is different than that which is recommended for lymphoma.
Age ≥ 65 years and younger patients with
significant comorbidities without del (17p)/TP53
mutation
• Ibrutinib is an NCCN Guidelines® Category 1 recommendation in this setting
RESONATE-2” study
• The “RESONATE-2” study was an open-label, randomized phase III trial that compared ibrutinib and
chlorambucil in 269 previously untreated older patients with CLL or small lymphocytic leukemia (SLL).
• The primary endpoint was PFS as assessed by an independent review committee.
• Patients who received ibrutinib had a statistically significantly longer PFS. This benefit was consistent in
higher-risk subgroups (TP53 mutation, 11q deletion, and/or unmutated IGHV).
• OS and ORR were also statistically significantly improved with ibrutinib.
• Rates of sustained increases in both hemoglobin and platelet levels were higher with ibrutinib. In addition,
greater improvements in quality of life occurred in the ibrutinib arm.
• Patients who progressed during the study were allowed to cross over to the alternate therapy; ultimately,
more than half of the chlorambucil patients crossed over to ibrutinib, which may have influenced OS.
• The prolongation of OS with ibrutinib seems to suggest that better results might be obtained when ibrutinib
is used as first-line treatment rather than in the relapsed or refractory settings.
The phase III Alliance North American
Intergroup Study
• The phase III Alliance North American Intergroup Study (“A041202”) compared ibrutinib monotherapy,
ibrutinib + rituximab and bendamustine + rituximab in 547 patients with untreated CLL who were ≥ 65 years
old.
• The primary endpoint was PFS.
• The results of the trial were released on the results of protocol-defined interim analyses.
• Median PFS was reached only with bendamustine + rituximab.
• The estimated percentage of patients with PFS at two years was statistically significantly higher with ibrutinib
alone and with ibrutinib + rituximab than with bendamustine + rituximab. There was no significant
difference between ibrutinib and ibrutinib + rituximab with regard to PFS.
• In the subgroup analyses, PFS was longer with ibrutinib-containing regimens in all risk factor-related
subgroups. There was no significant difference in OS between the groups.
• The rate of grades 3-5 hematologic adverse events was greater in the bendamustine + rituximab arm, while
the rates of grades 3-5 non-hematologic adverse events was greater in the ibrutinib-containing regimens.
• Acalabrutinib +/-obinutuzumab is a NCCN Guidelines® Category 1
regimen in this setting based on the “ELEVATE TN” trial
• Venetoclax + obinutuzumab is a NCCN Guidelines® Category 1
regimen in this setting based on the “CLL14” trial
Chlorambucil + obinutuzumab is a recommended
regimen in the NCCN Guidelines®
• The “CLL11 study” randomized nearly 800 previously untreated CLL patients with co-existing conditions (CIRS
>6 and/or CrCl 30-69 mL/min) to single-agent chlorambucil, rituximab + chlorambucil, or obinutuzumab +
chlorambucil.
• The direct comparison of obinutuzumab + chlorambucil to chlorambucil revealed statistically superior PFS
and OS, as well as improved ORR, with the combination.
• PFS, ORR and OS were statistically superior with obinutuzumab + chlorambucil compared to rituximab +
chlorambucil.
• Infusion reactions were common, and severe in some cases. They can be managed in a manner similar to
rituximab-related reactions – see separate section on Infusion-Related Reactions from Monoclonal
Antibodies Used in Hematologic Malignancies.
• Bendamustine and anti-CD20 monoclonal antibody combinations have been evaluated in phase II trials, and
phase III trials are ongoing in this patient population.
• NCCN Guidelines® recommend initiating bendamustine 70 mg/m2 in cycle 1, with dose escalation to 90
mg/m2 in subsequent cycles if tolerated, in patients age 65 or older and in younger patients with significant
comorbidities.
• The phase II CLL2M trial evaluated bendamustine + rituximab in previously untreated patients, with a
subgroup of patients >70 years.
• Response rates and survival outcomes were similar in the subgroup of elderly patients.
Patients with del (17p)/TP53 mutations
• Preferred regimens for first-line therapy in this setting include ibrutinib, venetoclax + obinutuzumab and
acalabrutinib +/-obinutuzumab.2
• Other current options in this setting include high-dose methylprednisolone + rituximab, obinutuzumab and
alemtuzumab +/-rituximab.2
• Zanubrutinib (BGB-3111)2,24,106-108 1) A next-generation irreversible BTK inhibitor with high specificity for BTK.
• Its off-target activity with structurally related kinases such as EGFR, ITK and SRC is comparatively lower than
ibrutinib.
• Currently recommended as an option for first-line treatment of patients with CLL with del(17p) who have
intolerance or contraindications to other BTKis.
• This recommendation is based on the phase 3 trial “SEQUOIA” trial.
• Arm C of the trial only enrolled patients with newly diagnosed CLL with del(17p); these patients were not
randomized, but were assigned to single-agent zanubrutinib at 160 mg PO BID.
• After a median of 18.2 months, the overall response rate in the 109 patients enrolled was 94.5%.
• The estimated 18-month PFS was 88.6%, and the estimated 18-month OS was 95.1%.
• The most frequently reported serious adverse effects were myelosuppression and pneumonia. Transient
lymphocytosis was also observed.
First-line therapy options historically included
alemtuzumab.
• Alemtuzumab is a humanized monoclonal antibody that targets CD52.
• Although it was initially approved as first-line treatment for CLL, adverse effects such as infusion-related
events, cytomegalovirus infections, and neutropenia limited its use.
• With the introduction of other novel agents, it currently has a very limited role in the management of CLL.
• It is no longer commercially available for the treatment of CLL, although it may be available from the
manufacturer if necessary via the Campath® Distribution Program.
Patient Case #1:

• MM is a retired 68-year-old male with a history of chronic kidney

disease, hypertension and hypercholesterolemia.
• He was in his usual state of health until approximately 6 months ago,
when he noted significant and painful lymph node swelling in his neck
and groin.
• His family medical doctor prescribed an antibiotic, but his symptoms
did not resolve.
• He returned to his family doctor, where his CBC revealed marked
lymphocytosis (lymphocytes = 27,000 B cells/mm3).
• Flow cytometry confirmed the diagnosis of CLL.
• After further workup, MM is diagnosed with Binet stage B disease.
• His cytogenetic analysis reveals that he has a del(13q) mutation and
unmutated IGHV.
• He is considered medically fit to receive treatment.
• Which of the following treatment regimens is the most appropriate first-
line therapy for FB?
• A. Acalabrutinib +/- obinutuzumab
• B. Chlorambucil + ofatumumab
• C. Fludarabine, cyclophosphamide and rituximab (FCR)
• D. Alemtuzumab + rituximab
Patient Case #1, continued:
• Correct answer = A (Acalabrutinib +/- obinutuzumab).
• This patient is over 65 years of age and has chronic kidney disease,
making him ineligible for fludarabine-based chemoimmunotherapy
regimens in the first-line setting.
• Acalabrutinib +/-obinutuzumab has a NCCN Guidelines® Category 1
recommendation in this setting based on the results of the ELEVATE-
TN trial.
• Treatment with ofatumumab is only recommended in the relapsed
and refractory setting. Alemtuzumab is not recommended in the first-
line setting in patients without del(17p).
Response criteria2,29,109 1
• The National Cancer Institute-sponsored Working Group (NCI-WG) revised its guidelines in 2018 to provide
the most recent recommendations for general clinical practice.
• In clinical practice, response assessment requires both a physical examination and evaluation of blood
parameters.
• Response should be evaluated at least 2 months after the completion of therapy.
• Response definitions
Definitions of response to therapy in CLL.
Patient Case #2:
• LK is a 63-year old male with CLL with del(11q). His past medical history is significant for hypothyroidism,
well-controlled atrial fibrillation and gastroesophageal reflux disease. He received treatment with FCR three
years ago and achieved a complete response. After experiencing a recurrence of painful cervical
lymphadenopathy, he has recently been diagnosed with relapsed CLL.
• Which of the following regimens is most appropriate for DG at this point in his course?
• A. Repeat FCR
• B. Zanubrutinib
• C. Venetoclax + rituximab
• D. Bendamustine, rituximab + idelalisib
Treatment of relapsed / refractory disease

• Although newer agents have improved the results of first-line therapy, CLL remains incurable. Patients will
universally relapse after primary treatment
• The management of relapsed disease depends on age, performance status, previous therapy, response and
duration of response to therapy, time from last therapy, adverse effect profile and cost.127
• Early relapse (within 24-36 months) or a poor response to chemoimmunotherapy suggests aggressive
disease and is associated with a short
Treatment regimens in the relapsed /
refractory setting
• Ibrutinib (NCCN Guidelines® Category 1 recommendation)
• A phase III randomized trial comparing ibrutinib to ofatumumab in relapsed /
refractory CLL patients (“RESONATE”) was stopped at the interim analysis due to
statistically significant improvements in PFS and OS
• 391 patients with CLL or SLL who had received at least one prior therapy were
included.
• The primary endpoint was investigator-assessed PFS.
• The endpoint was significantly improved in patients receiving ibrutinib.
• OS was significantly better in patients who received ibrutinib, despite a large
number of patients who were assigned to ofatumumab and crossed over to
ibrutinib at disease progression.
• Patient-reported outcomes were significantly greater in patients receiving
ibrutinib.
Outcomes after ibrutinib discontinuation

• Patients with disease progression on ibrutinib typically develop Richter’s transformation or progressive CLL.
Richter’s transformation tends to occur earlier than progressive CLL, with RT typically occurring in the first 1-
2 years of treatment and progressive CLL occurring later.
• Patients with RT or progressive CLL tend to have rapid disease progression following discontinuation of
ibrutinib, with some sources estimating survival at 3 months or less. Patients require rapid initiation of
additional therapy (within 2 weeks of discontinuing ibrutinib) to achieve disease control. It is recommended
to transition to the next therapy as soon as possible after stopping ibrutinib.
• In single institution studies, the median survival after ibrutinib discontinuation was 3-12 months.
Venetoclax + rituximab (NCCN Guidelines®
Category 1 recommendation)
• The phase III “MURANO” trial was the basis for FDA approval of venetoclax in combination with rituximab in
relapsed or refractory CLL.144-148 a) 389 patients with relapsed or refractory CLL were randomized to
receive venetoclax for up to 2 years plus rituximab for the first 6 months or bendamustine + rituximab for 6
months.
• The primary endpoint was investigator-assessed PFS.
• Note that ibrutinib was not widely available at the time of study design and patient recruitment. Therefore,
bendamustine + rituximab was considered an appropriate control arm.
• Median PFS and OS were both statistically significantly higher in the venetoclax + rituximab group. This
benefit was maintained across all clinical and biologic subgroups, including patients with del(17p).
Acalabrutinib (NCCN Guidelines® Category 1
recommendation)
• The phase III “ASCEND” trial evaluated the efficacy and safety of acalabrutinib monotherapy vs investigators’
choice of therapy (either idelalisib + rituximab or bendamustine + rituximab) in 310 patients with relapsed or
refractory CLL. The primary endpoint was PFS as assessed by an independent review committee.
• At a median follow-up of 16.1 months, acalabrutinib significantly prolonged independently-assessed PFS
compared to both other therapies (median not reached vs 16.5 months; HR 0.31, 95% CI 0.20-0.49, p <
0.0001). This represented a 69% reduction in risk of progression or death in patients who received
acalabrutinib.
• PFS improvement with acalabrutinib were seen across subgroups including del(17p), TP53 mutation and
higher Rai stage.
• Overall survival rates at 12 months were not different between the treatment groups; however, 23% of
patients randomized to either idelalisib + rituximab or bendamustine + rituximab crossed over to receive
subsequent acalabrutinib monotherapy.
Idelalisib (per NCCN Guidelines®, an “other
recommended regimen” both as a single agent
and in combination with rituximab
• An oral inhibitor of phosphoinositide 3-kinase (PI3K) delta.
• FDA approval for the treatment of relapsed CLL was based on a phase III randomized clinical trial (“Study
116”) comparing idelalisib + rituximab to placebo + rituximab.
• The trial was stopped after the first interim analysis revealed a significant improvement in RR, PFS and OS in
favor of idelalisib and rituximab.
• 220 patients with relapsed CLL and who were unable to receive cytotoxic chemotherapy due to co-existing
illnesses were included.
• Patients in the placebo group could cross over to receive idelalisib at the time of disease progression, and
patients receiving idelalisib could receive a dosage increase at the time of disease progression.
• The primary endpoint was investigator-assessed PFS.
• The treatment effect of idelalisib and rituximab was favorable in all treatment subgroups, including those
with del(17p) and other poor prognostic markers.
Study 116
• Patients in either arm of Study 116 could receive idelalisib monotherapy after study termination as part of
an extension study.
• Final results of this study showed a median PFS of 20.3 months in patients who received idelalisib +
rituximab followed by idelalisib.
• Median OS was 40.6 months and 34.6 months for patients assigned to the idelalisib + rituximab and placebo
+ rituximab groups, respectively.
Duvelisib
• An inhibitor of PI3K, with predominant activity against PI3K-δ and PI3K-γ isoforms that are
expressed in normal and malignant B cells.
• Approved for the treatment of adult patients with relapsed or refractory CLL or SLL after at least
two prior therapies.
• Approval was based on a randomized, open-label trial comparing duvelisib (“DUO”) to
ofatumumab in 319 patients with relapsed or refractory CLL or SLL.
• The estimated median PFS, as assessed by an independent review committee, was 13.3 months in
the duvelisib arm and 9.1 months in the ofatumumab arm.
• Benefit was also seen in patients with del(17p) and/or TP53 mutations.
• Fatal and/or serious reactions occurred in 31% of patients.
• Black Box Warnings for infection, diarrhea or colitis, cutaneous reactions and pneumonitis are
included in the prescribing information.
Zanubrutinib (BGB-3111)

• Currently recommended as second-line line or subsequent treatment of CLL in patients who are intolerant to
or have contraindications to other BKTis.
• This recommendation is based on a single-arm phase II study of 91 Chinese patients with relapsed/refractory
CLL/SLL. The primary endpoint of overall response rate, as assessed by an independent review committee,
was 84.6% after a median follow-up of 15.1 months.
• The phase III “ALPINE” trial compared zanubrutinib to ibrutinib in patients with relapsed/refractory CLL.
• Interim results at a median follow-up of 15 months reported a statistically higher overall response rate with
zanubrutinib versus ibrutinib (78.3% vs. 62.5%).
• The 12 month PFS and OS were also higher with zanubrutinib.
• Patients who achieve a CR or PR to treatment of relapsed or refractory disease may be considered for
allogeneic hematopoietic stem cell transplantation, if eligible.
• Note that the majority of patients will not be considered candidates due to advanced age and/or
comorbidities.
Sequence of therapy in relapsed / refractory
disease
• At this time, there are no formal recommendations for the sequencing of agents in the relapsed / refractory
setting.
• A multicenter study of 683 patients with relapsed or refractory CLL to determine the optimal sequence of these
agents.
• The authors reported that ibrutinib had superior PFS when compared to other kinase inhibitors and venetoclax as a
first choice, and that venetoclax may be preferred over idelalisib or chemoimmunotherapy combinations in cases
of ibrutinib failure.
• Other reports also suggest that the clinical benefit of ibrutinib is highest when used in the first-line setting versus a
later line of therapy.
• In the setting of ibrutinib failure, venetoclax may be preferred over idelalisib.
• Selections are often made based on the unique toxicities of each agent, as well as patient and physician
preference.
• Ibrutinib may be preferred in patients with underlying hepatic dysfunction, gastrointestinal or pulmonary
comorbidities, or if monotherapy is desired
• idelalisib may be preferred in patients on anticoagulation or with other bleeding risks, or if rituximab therapy is
necessary or desired.
Patient Case #1, continued:
• JF is a 68 year old male with newly diagnosed CLL who will be initiating therapy with acalabrutinib.
• Which of the following adverse effects are frequently seen with acalabrutinib and should be discussed
during your counseling session with JF?
• A. Hypotension
• B. Tumor lysis syndrome
• C. Headache
• D. Periorbital edema
Patient Case #1, continued:

• MM is a 68 year old male with newly diagnosed CLL who will be initiating therapy with acalabrutinib.
• Which of the following adverse effects are frequently seen with acalabrutinib and should be discussed
during your counseling session with JF?
• A. Hypotension
• B. Tumor lysis syndrome
• C. Headache
• D. Periorbital edema
•
Patient Case #1, continued:

• Correct answer = C (Headache).

• Headache is the most commonly reported adverse effect of acalabrutinib treatment, occurring in up to 40%
of patients. This effect is usually transient and can be mitigated with fluids, caffeine, and treatment with
NSAIDs or other agents. Acalabrutinib is associated with hypertension, but hypotension has not been
reported. Tumor lysis syndrome is associated with venetoclax, not acalabrutinib. Periorbital edema is
commonly seen with imatinib therapy, but not acalabrutinib.
Patient Case #2, continued:

• Correct answer = C (Venetoclax + rituximab).

• Of the proposed choices, venetoclax + rituximab is the most appropriate. This regimen has an NCCN
Guidelines® Category 1 recommendation for use in the second-line setting based on the results of the
MURANO study. Zanubrutinib is currently only recommended as second-line line or subsequent treatment of
CLL in patients who are intolerant to or have contraindications to other BKTis, and DG may be a candidate
for ibrutinib and/or acalabrutinib since his atrial fibrillation is well-controlled (see below). Repeating FCR
would not be the most appropriate as there are more effective choices for second-line treatment. The
combination of bendamustine, rituximab and idelalisib is a Category 2B recommendation at this time and
therefore is not the most appropriate choice of the proposed options.
Patient Case #2, continued:

• DG is a 63-year old male with relapsed CLL. He is not a candidate for ibrutinib, and thus he was planning to
start venetoclax + rituximab. However, he cannot afford venetoclax + rituximab, so he will initiate idelalisib +
rituximab instead.
• Which of the following statements about idelalisib is correct?
• A. Pancreatitis is common.
• B. Diarrhea may be severe.
• C. Lower extremity edema often occurs.
• D. Visual changes are frequent.
•
Toxicities of small molecule inhibitors and
management
• Ibrutinib
• Diarrhea frequently occurs early in the treatment course, but can be
managed with standard supportive care and is self-limiting.
• Minor bleeding has been reported in up to 66% of patients.
• Serious bleeding events are observed in up to 9% of patients on ibrutinib
• It is postulated that ibrutinib selectively inhibits platelet signaling and strongly affects platelet adhesion on von
Willebrand factor.
• The risk of ibrutinib-related bleeding is highest during the first 3-6 months of treatment, and then decreases with
continued therapy.
• Consider the benefit-risk of ibrutinib in patients requiring anti-platelet or anticoagulant therapies
• Patients should be advised to discontinue vitamin E, fish oils and NSAIDs while on ibrutinib, as these agents were
prohibited in the ibrutinib trials.
• For planned surgical procedures considered as high risk for bleeding, ibrutinib should be held for 3 days prior to
and after minor surgical procedures, and for 7 days prior to and after major surgical procedures.
Atrial fibrillation is observed in up to 16% of
patients.
• Ibrutinib may exacerbate atrial fibrillation by inhibiting cardiac BTK proteins, thus silencing a critical
regulator of cardiac protection against stressors. However, other unidentified off-target effects may also play
a role, and the exact mechanism remains unknown.
• The risk of atrial fibrillation is intrinsically higher in this patient population, given the advanced age and
comorbid conditions of most patients with CLL.166 Conditions that have been associated with increased risk
of atrial fibrillation on ibrutinib therapy include older age, male sex, history of hypertension, history of
coronary artery disease, and history of valvular heart disease.
• Some references suggest that atrial fibrillation typically occurs early after ibrutinib initiation and remains
constant or decreases over time.
• Modifiable risk factors for atrial fibrillation should be identified and treated, if possible. Such factors include
obesity, hypertension, heart failure, diabetes, and thyroid function.
• Atrial fibrillation that develops during BTKi treatment should be
treated according to standard practice. However, drug-drug
interactions with the non-dihydropyridine calcium channel blockers
and amiodarone must be considered; rate control may be preferred
over rhythym control in this scenario. Consulation with cardiology
services is encouraged.
CHA2DS2-VASc risk stratification
• A validated tool to estimate the patient’s risk of stroke, such as the
CHA2DS2-VASc risk stratification, should be used to determine the
patient’s need for concomitant anticoagulation.
• Clinical trials of ibrutinib excluded patients on concurrent warfarin.
Non-warfarin alternatives should be considered, if possible, in
patients who have pre-existing atrial fibrillation requiring
anticoagulation.
• Low molecular weight heparins may be preferred in this setting.
• If treatment with a direct oral anticoagulant is appropriate, some
references suggest apixaban or rivaroxaban due to minimal drug
interactions with ibrutinib.
• Pre-existing atrial fibrillation is not an absolute contraindication to the use of ibrutinib.
• However, patients with recurrent atrial fibrillation that is not medically controllable should be changed to
other CLL therapy
• If atrial fibrillation occurs during ibrutinib therapy, it is not recommended to hold or reduce the dose of
ibrutinib while treatment is initiated. Withholding ibrutinib does not result in higher resolution rates of atrial
fibrillation, but may compromise PFS and OS.
Hypertension

• Hypertension is emerging as an important adverse effect of ibrutinib.

• Early trials reported that approximately 25% of patients taking ibrutinib developed new or worsened hypertension.
Follow-up data suggests a potential continual rise in the incidence of hypertension over time.
• In a retrospective study of 562 patients who received ibrutinib, more than 75% of patients developed new or
worsened hypertension over a median of 30 months.
• The increase in hypertension remained after adjustment for ibrutinib dose.
• No single anti-hypertensive agent or class was associated with prevention or control of ibrutinib-related
hypertension.
• The risk of major adverse cardiovascular events, such as atrial fibrillation and ventricular arrhythmias,
disproportionally elevated in patients who developed hypertension during ibrutinib therapy.
• However, the initiation of an anti-hypertensive agent was associated with a lower risk of a subsequent major
adverse cardiovascular event.
• Hypertension that occurs during ibrutinib therapy should be managed according to local/national hypertension
management guidelines.
• However, caution should be used when prescribing non-dihydropyridine calcium channel blockers due to drug-drug
interactions.
• There are several reports of invasive fungal infections and other
atypical infections in patients who received ibrutinib.
• However, it is unclear to what extent these infections are attributable
solely to ibrutinib, and therefore routine prophylaxis is not
recommended at this time.
• Consideration may be given to patient at high risk of fungal infections,
including concomitant corticosteroid therapy or patients with
diabetes.
Acalabrutinib

• Headache is commonly reported, occurring in up to 40% of patients early in the treatment course and
usually resolving in 4-8 weeks. Management includes hydration, analgesics and caffeine supplementation.
• Grade 3 or 4 bleeding events are rare. The risks and benefits of withholding acalabrutinib before and after
surgery depends on the type of surgery and risk of bleeding.
• Grade 3 or 4 hypertension is reported in ~3% of patients, and atrial fibrillation is reported in ~4% of patients.
• Co-administration with proton pump inhibitors must be avoided. If histamine 2 receptor antagonists or
antacids are necessary, the doses should be staggered to allow for maximum absorption of acalabrutinib.
Zanubrutinib

• Myelosuppression, upper respiratory infection and pneumonia are the most frequently reported adverse
effects.
• Grade 3 or 4 bleeding events are reported in ~ 5% of patients. The risks and benefits of withholding
zanubrutinib before and after surgery depends on the type of surgery and risk of bleeding.
• Atrial fibrillation and hypertension have been reported, but follow-up has been short compared to other
studies of BTKis.
• Prophylaxis for herpes simplex virus, Pneumocystis jiroveci and other opportunistic infections may be
considered.
Comparison of BTKi toxicities
“ELEVATE-RR” trial
• The “ELEVATE-RR” trial was the first head-to-head trial comparing ibrutinib to acalabrutinib in patients with
previously treated CLL and del(17p) or del(11q).
• Key secondary endpoints included the incidence of any grade atrial fibrillation / flutter and grade ≥ 3
infections.
• Patients who received acalabrutinib had statistically significantly less atrial fibrillation / flutter of any grade
(9.4% vs 16.0%, p = 0.02).
• The incidence of grade ≥ 3 atrial fibrillation / flutter and incidence among patients without a prior history of
atrial fibrillation / flutter were both less in the acalabrutinib arm.
• The incidence of grade ≥ 3 infections was not different between the two treatment arms.
• Bleeding events were not a key secondary endpoint, but there were significantly more events of all grades of
bleeding as well as numerically more grade ≥ 3 bleeding events in the ibrutinib arm.
• The incidence of grade ≥ 3 adverse events, serious adverse events, and treatment discontiuations due to
adverse events all tended to be lower in the acalabrutinib arm.
Venetoclax
• Neutropenia is the most commonly reported adverse effect of venetoclax, occurring in approximately 60% of
patients (53% grade 3 or higher).
• Neutropenia can be managed with neutrophil growth factor or dose reduction.
• Dosing of venetoclax requires a stepwise “ramp-up” schedule over 5 weeks to minimize the risk of tumor
lysis syndrome (TLS).
• The suggested “ramp-up” dosing schedule as per the prescribing information is listed below.
• However, alterations of this dosing schedule have been proposed.
• If treatment is interrupted for longer than one week during dose escalation, consider re-initiating therapy at
a lower dose and continuing dose escalation as appropriate.
• All patient comorbidities should be considered before the final determination of prophylaxis and monitoring
schedule.
• Suggested “ramp-up” dosing schedule of venetoclax to minimize risk of tumor lysis syndrome
Recommended tumor lysis prophylaxis for patients receiving
venetoclax
Idelalisib
• Idelalisib is associated with immune-mediated adverse effects, including elevated liver function tests, rash, pneumonitis and
severe diarrhea / colitis. Recent reports have also noted a potential increase in infections.
• Diarrhea is common and has 2 peaks of occurrence.
• A lower-grade diarrhea occurs in 30% of patients in the first weeks of therapy. The median time to onset of severe diarrhea /
colitis is 9.5 months and occurs in ~10% of patients. Colitis should be managed promptly with steroids (either budesonide or
intravenous products).
• Grade 3 or higher transaminitis occurs in ~14% of patients receiving idelalisib in the second-line setting.
• In a small phase II study using idelalisib in patients with previously untreated CLL, the incidence of hepatoxicity was much higher
(54%) and occurred rapidly after treatment initiation.
• This hepatotoxicity was felt to be autoimmune mediated, and occurred more often in younger patients.
• Due to these findings and a potential increased risk of infections (see below), many trials of idelalisib in the first-line setting have
closed.
• The FDA alerted healthcare professionals of reports of an increased rate of adverse events, including deaths, in clinical trials with
idelalisib in combination chemotherapy, generally due to an increased risk of infections.
• The majority of these infections occurred within the first 6 months of treatment. Some sources advise that Pneumocystis jiroveci
prophylaxis be administered with this agent.
• Anti-infective prophylaxis for herpes virus and cytomegalovirus should be considered. See Supportive Care section below.
• Monitoring for hepatitis B reactivation is recommended
Duvelisib
• Duvelisib has Black Box Warnings for infection, diarrhea or colitis, cutaneous reactions and pneumonitis
Redistribution lymphocytosis
• A transient increase in ALC occurs in many patients due to the inhibition of the CXCR4/5 chemokine
receptors, which results in trafficking of CLL cells from the lymph nodes and other sites into the peripheral
blood.
• This “redistribution lymphocytosis” does not signify disease progression. A new category of disease response
(partial response with lymphocytosis) is used in these cases.
• The onset of isolated lymphocytosis occurs during the first few weeks and persists for several weeks on
treatment.
• This phenomenon is not associated with tumor lysis syndrome or leukostasis. Clinical consequences are
extremely rare and therapy should be continued.
• Lymphocytosis is more pronounced in patients with mutated IGHV and those with del(13q).
• This phenomenon can occur with all of the kinase inhibitors used to treat CLL.
• Slow or incomplete resolution of lymphocytosis does not appear to impact outcomes.
• In “Study 116,” the addition of rituximab to idelalisib blunted and shortened the duration of lymphocytosis.
The onset of isolated lymphocytosis peaked at week 2 and resolved by week 12 in the idelalisib group
Summary of treatment recommendations

• Suggested treatment regimens for treatment of CLL in patients age < 65 years without significant
comorbidities without del(17p)/TP53 mutation per the NCCN Guidelines
Suggested treatment regimens for treatment of CLL in patients age ≥ 65 years or younger patients with
significant comorbidities without del(17p)/TP53 mutation per the NCCN Guidelines
Suggested treatment regimens for treatment of CLL in patients with del(17p)/TP53 mutation per the NCCN
Guidelines.
Patient Case #1, continued:

• MM is now a 71-year old male with CLL who has been receiving ibrutinib for the past 18 months. Over the
past two weeks, he has noted rapidly enlarging cervical, axillary and inguinal lymphadenopathy. He also
reports new fevers, splenomegaly and unintentional weight loss.
• Which of the following is the most likely the cause of FB’s new complaints?
• A. Richter’s transformation
• B. Ibrutinib resistance
• C. Redistribution lymphocytosis
• D. Tuberculosis infection
Patient Case #1, continued:
• Correct answer = A (Richter’s transformation).
• The rapid onset, nature and severity of FB’s symptoms suggests a transformation to a more aggressive
malignancy, commonly known as histologic transformation or Richter’s transformation (RT). While ibrutinib
resistance does occur, the onset is often insidious. Redistribution lymphocytosis occurs early in a patient’s
treatment course and would not occur after 18 months of therapy. Tuberculosis infection is not associated
with ibrutinib.
Richter’s transformation / histologic
transformation
• 1. Approximately 2-16% of CLL patients will develop Richter’s transformation (RT), a transformation into
diffuse large B-cell non-Hodgkin lymphoma (DLBCL) (90% of these patients) or Hodgkin lymphoma (10% of
these patients).
• 2. The incidence of transformation increases with the presence of complex cytogenetics, del(17p),
inactivation of TP53, unmutated IGHV status, NOTCH1 mutation, increased age and with number of prior
regimens received.
• 3. RT is typically suspected in a patient with known CLL who develops inappropriate weight loss, rapidly
growing and/or asymmetrical lymphadenopathy, new constitutional symptoms, a rapidly rising lactate
dehydrogenase level and/or new hypercalcemia
• 4. The clinical outcome of RT is generally poor. The disease is typically resistant to chemotherapy, has an
aggressive course and a median survival of only 8-12 months from transformation.
• 5. There are no randomized trials comparing treatment approaches for RT. Treatment should be directed at
aggressive non-Hodgkin lymphoma or Hodgkin lymphoma (see Hodgkin Lymphoma and Non-Hodgkin
Lymphoma).
• 6. Allogeneic hematopoietic stem cell transplantation has shown promising results in this patient population
(see Hematopoietic Stem Cell Transplantation).
Patient Case #2, continued:

• DG is a 63-year old male who is receiving idelalisib + rituximab for the treatment of relapsed CLL. He has no
known drug allergies.
• What supportive care measure should DG receive to prevent complications from his underlying disease
and/or treatment regimens?
• A. Sulfamethoxazole - trimethoprim
• B. Zostavax®
• C. Ganciclovir
• D. IVIG
Patient Case #2, continued:

• Correct answer = A (Sulfamethoxazole - trimethoprim).

• Sulfamethoxazole -trimethoprim (or an equivalent) is recommended as Pneumocystis jiroveci pneumonia
(PJP) prophylaxis with sulfamethoxazole-trimethoprim or an equivalent is recommended for patients
receiving purine analogs, bendamustine, idelalisib, corticosteroids or alemtuzumab. DG has received
fludarabine and idelalisib as treatment for his CLL so this would be an appropriate supportive care
medication to initiate. The use of prophylactic ganciclovir would not be warranted unless DG had CMV
viremia present at the initiation of therapy. Live vaccines such as Zostavax® should be avoided in patients
with CLL. Finally, IVIG would only be appropriate if DG had suffered recurrent infections and had an IgG level
<500 mg/dL.
Supportive Care of Patients with CLL

• Infections
• Infections are a major cause of morbidity and mortality in patients with CLL.
• Patients with CLL are more susceptible to infections than the general population due to their underlying
disease, as well as the immunosuppressive properties of chemotherapy and monoclonal antibody
treatments.
• The development of infections is influenced by the reduction of immunoglobulin levels.
Hypogammaglobinemia increases with the duration of disease.
• Intravenous immunoglobulin (IVIG)
• Use of IVIG is associated with a significant decrease in the occurrence of
sinopulmonary infections, but does not improve survival outcomes.
• IVIG may be considered in patients with serum IgG < 500 mg/dL and who
have recurrent sinopulmonary infections (≥2 in 6 months) requiring
intravenous antibiotics or hospitalization.
• In appropriate candidates, IVIG or subcutaneous immunoglobulin (SCIG)
0.3-0.5 mg/kg should be given monthly to maintain IgG nadir levels of
approximately 500 mg/dL.
• In patients who do not qualify or cannot tolerate IVIG, antibacterial
prophylaxis may be useful.
Anti-infective prophylaxis a. Antiviral prophylaxis

• For the prevention of herpes virus infections in patients receiving

purine analogs, idelalisib, duvelisib, corticosteroids, bendamustine
and/or alemtuzumab, acyclovir or an equivalent is recommended
during treatment and thereafter.
Cytomegalovirus (CMV)
• Cytomegalovirus (CMV) reactivation may occur in patients receiving
PI3K inhibitors or alemtuzumab.
• The optimal approach to CMV monitoring and management has not
yet been defined.
• Regular monitoring for the presence of CMV antigens with
quantitative polymerase chain reactions (PCR) every 4 weeks and for
2 months after the completion of treatment has been suggested
• If CMV viremia is present prior to therapy, prophylactic ganciclovir or
valganciclovir may be considered.
• Consultation with an infectious diseases expert may be necessary.
Pneumocystis jiroveci pneumonia (PJP)
• Pneumocystis jiroveci pneumonia (PJP) prophylaxis with sulfamethoxazole-trimethoprim or an equivalent is
recommended for patients receiving purine analogs, bendamustine, idelalisib, duvelisib, or alemtuzumab.
• The risk of developing PJP is directly proportional to prior treatment status and corticosteroid exposure.
• The majority of patients with CLL diagnosed with PJP are older than 65 years of age.
• For patients receiving alemtuzumab, prophylaxis should continue for a minimum of 2 months after the
completion of therapy and until the CD4 count is > 200 cells/mcL.
• For patients receiving purine analogs, consider continuing prophylaxis until the CD4 count is >200 cells/mcL.
Hepatitis B virus (HBV)
• Hepatitis B virus (HBV) reaction may occur in patients treated with
anti-CD20 antibodies, alemtuzumab, purine analogs and idelalisib.
• Patients should be screened for hepatitis B and C; screening is
necessary prior to starting anti-CD20 antibody therapy and
prophylaxis may be required
Vaccinations

• Vaccination efficacy is suboptimal in patients with CLL.

• Annual influenza vaccination is recommended for all patients with CLL.
• Patients with CLL tend to have poor response to this vaccination, and
should be counseled to use caution during influenza season even if they
have been vaccinated.
• In patients who have received rituximab, B-cell recovery occurs by
approximately 9 months after completion of therapy.
• Prior to B-cell recovery, patients generally do not respond to influenza
vaccine. If administered during this timeframe, patients should not be
considered as vaccinated.
• COVID-19 vaccination is recommended in all CLL patients.
• There is some evidence that the protective response rate to COVID-19
vaccination may be lower in patients with CLL, regardless of
treatment status.
• Appropriate precautions should be taken.
• The utility of antibody testing in this population is unknown at this
time.
• Pneumococcal polysaccharide (PPSV23) vaccination is recommended
every 5 years.
• All live vaccines should be avoided, including the live herpes zoster
vaccine.
• Zoster vaccine recombinant, adjvanted is recommended in treatment-
naïve patients or those treated with a BTK inhibitor.
Autoimmune cytopenias
• Autoimmune cytopenias are associated with CLL and may precede the diagnosis of CLL in up to 10% of
patients.
• Patients with CLL have a 10-25% lifetime risk of hematologic autoimmune complications.
• Treatment of CLL may trigger autoimmune cytopenias, and these complications may occur at any time
during the course of the disease.
• Loss of immune self-tolerance causes non-malignant B cells to produce high-affinity polyclonal IgG
antibodies directed against blood cell antigens.
Autoimmune hemolytic anemia (AIHA)
• Autoimmune hemolytic anemia (AIHA) is the most common form of
autoimmune cytopenia.
• Patients with advanced disease, unmutated IGHV, increased serum β-2
microglobulin, and high expression of ZAP-70 are at a higher risk of
developing AIHA.
• Purine analog-based therapy has been associated with AIHA.
• If AIHA develops in the setting of treatment with fludarabine, fludarabine
should be stopped and avoided in subsequent therapies.
• Management is directed against the autoimmune phenomenon and
typically begins with corticosteroids.
• Cyclosporine, IVIG, splenectomy and/or anti-CD20 antibodies such as
rituximab may be considered in refractory cases.
Immune thrombocytopenic purpura (ITP)
• Immune thrombocytopenic purpura (ITP) occurs in 2-5% of patients with CLL.
• The presence of ITP is associated with poorer survival, independent of other common clinical prognostic
factors.
• Management typically begins with corticosteroids. Synthetic thrombopoietin-like agents such as romiplostim
and eltrombopag are now viable options.
• IVIG, cyclosporine, splenectomy and/or rituximab may be considered in refractory cases.
• In the absence of specific guidelines, the therapeutic approach is generally based on physician or treatment
center experience.
Pure red cell aplasia (PRCA)
• Pure red cell aplasia (PRCA) occurs in approximately 1% of patients with CLL.
• Management includes corticosteroids, cyclophosphamide, cyclosporine or anti-thymocyte globulin.
• Corticosteroids tend to be less effective in PRCA than in ITP or AIHA.
Tumor lysis syndrome
• Tumor lysis syndrome (TLS)
• Patients with CLL that have a high white blood cell counts may experience TLS.
• This is especially true in cases of high circulating lymphocyte count, the use of bendamustine-based therapy,
and venetoclax
Non-melanomatous skin cancer
• Patients with CLL have a markedly increased risk of non-melatomatous skin malignancies.
• Squamous cell and basal cell carcinoma rates are increased by 5-14 fold.
• These malignancies are more likely to be locally aggressive or metastatic and are more likely to be fatal than
in patients without CLL
• Risk factors include Caucasian ethnicity and history of invasive sun exposure at a young age.
• Patients should be educated on avoidance of ultraviolet radiation, and should be evaluated by a
dermatologist annually.
Ibrutinib
rituximab
fludarabine
cyclophosphamide
chlorambucil
obinutuzumab
Bendamustine
rituximab
Venetoclax
Acalabrutinib
Zanubrutinib
 LEARNING OBJECTIVES:
• At the end of the presentation and after reviewing the accompanying reading
materials, the participant should be able to:
• 1.Design an appropriate patient-specific treatment, supportive care, and
monitoring plan taking into consideration relevant molecular biology testing,
genomic information, efficacy and safety outcomes from clinical trials, and
current treatment guidelines for patients with chronic leukemia.
• 2.Develop an appropriate plan for preventing, monitoring, and treating
infusion-related reactions from monoclonal antibodies used in the treatment of
hematologic malignancies.
• 3.Develop an appropriate plan for preventing, monitoring, and treating adverse
reactions associated with pharmacotherapy for the treatment of cancers,
including toxicities from tyrosine kinase inhibitors used to treat hematologic
cancers.
Chronic lymphocytic leukemia
• significant advances in care over the last 5 years with the approval of
oral agents such as ibrutinib and venetoclax for the treatment of this
disease.
• As such, there has been a substantial shift away from the traditional
chemotherapy infusions which have allowed patients greater
autonomy with oral cancer therapies.
• This paradigm shift poses new challenges for the medical team,
including drug–drug interactions, adherence counseling, and financial
toxicity.
• Ibrutinib a small-molecule Bruton tyrosine kinase (BTK) inhibitor, was
the first orally-administered, targeted agent approved for CLL in 2014.
• Since then, another BTK inhibitor, acalabrutinib,
• two phosphatidylinositol-3-kinase (PI3K) inhibitors, idelalisib and
duvelisib,
• a B-cell lymphoma 2 (BCL-2) inhibitor, venetoclax, have also been
approved
• Choosing the optimal treatment for a patient with CLL has become a
complex task that requires in-depth knowledge of drug therapy while
taking into account patient characteristics such as age, cytogenetics,
and comorbidities.
• The advent of these therapies has also brought with it a new set of
practical considerations, including patient adherence, drug–drug
interactions (DDIs), toxicity management, supportive care
requirements, and medication access.
 Role of Pharmacists in the Management of CLL
• Pharmacists are uniquely trained and equipped to help to manage the
changing landscape of CLL care.
• From identifying common medications which may impair ibrutinib clearance
• to ensuring patients are on the appropriate anti-infective prophylaxis while
receiving obinutuzumab,
• ensuring the highest quality of patient care.
• greater involvement, particularly for initiation of venetoclax and management
of ibrutinib-induced toxicities.
• Pharmacists are essential to both expanding and enhancing the care of
patients with CLL and should be leveraged to improve patient outcomes
whenever possible.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355755/
https://www.pharmacytimes.com/view/role-of-pharmacists-in-the-management-of-cll
https://www.clinicaloptions.com/oncology/programs/2021/optimal-cll-care/interactive-decision-support-tool/idst-2022/page-1?origin=2
http://www.htct.com.br/en-detection-somatic-tp53-
mutations-17p-articulo-S2531137920300778
https://www.haematologica.org/article/view/8691
 the immunoglobulin
heavy chain (IGHV) gene
As the therapeutic landscape for chronic lymphocytic leukemia
(CLL) continues to expand, biological predictors of response to
therapy are becoming increasingly important. One such
predictive biomarker is the mutational status of the variable
region of the immunoglobulin heavy chain (IGHV) gene, which
is a powerful predictor of duration of response and overall
survival with chemoimmunotherapy (CIT).
• https://www.clinicaloptions.com/oncology/programs/2021/optimal-
cll-care/interactive-decision-support-tool/idst-2022/page-1?origin=2
Thank You