ASH Clinical News ACN_4.4_FULL_ISSUE_DIGITAL | Page 66

REFERENCE

Mayo Clinic

• Anemias

ASH Clinical News 45

You Make the Call

Each month in “ You Make the Call ,” we pick a challenging clinical question submitted through the Consult a Colleague program and post the expert ’ s response , but we also want to know what you would do . Send in your response to next month ’ s clinical dilemma and see how your answer matches up to the expert ’ s in the next print issue .

This month , Ayalew Tefferi , MD , discusses managing a pregnant patient with chronic-phase ( CP ) chronic myeloid leukemia ( CML ).

Clinical Dilemma :

I am treating a 20-year-old pregnant woman at seven weeks gestation who was found to have CP-CML . Her white blood cell count is 300,000 /µ L with less than 5 percent blasts . The patient would like to keep the pregnancy and understands the risks . Leukapheresis did not provide much reduction in her counts . She remains asymptomatic with a relatively stable peripheral blood picture . Options that I have been considering include interferon now and hydroxyurea or imatinib starting in the second trimester .

Expert Opinion

Ayalew Tefferi , MD Professor of Hematology / Oncology

Rochester , MN

Thanks to tyrosine kinase inhibitors ( TKIs ), most patients with CP-CML can now look forward to a near-normal life span . Obviously , no one wants to undercut this by unnecessarily deferring or discontinuing treatment with TKI . And yet , such is the challenge for this young woman who is pregnant and may also expect to breastfeed .

None of the approved TKIs for use in CML are considered safe for pregnant patients or for those intending to have children . A limited number of studies have shown relatively little effect on fertility from TKI use in prospective parents , men or women . On the other hand , Additional points : their use during pregnancy is not advised because these drugs harbor off-target kinase inhibitory properties that • Incidental discovery of pregnancy while on TKI treatment does not necessarily mandate therapeutic abortion . could be harmful to fetal development and usually cross the placental barrier . Although CML itself can lead to complications during pregnancy , delaying TKI treatment in CP-CML , for a few weeks or months , has not pregnancy and lactation , might not be required in

• Interferon therapy , while safe for use during been shown to compromise ultimate disease outcome . asymptomatic patients who can be monitored without

Therefore , it is reasonable to either simply monitor drug intervention . asymptomatic patients without treatment or use alternative , pregnancy-safe drugs , such as interferon , to control • There is no hard evidence to support specific TKI disease symptoms until a TKI can safely be instituted . If recommendations for partners . the situation mandates cytoreductive intervention other than interferon , I suggest therapeutic leukapheresis during • Although not recommended , the use of TKIs during the first trimester and hydroxyurea during the second the second or third trimester of pregnancy is not or third trimester , considering the latter ’ s track record of absolutely contraindicated and might be necessary in safety , compared with TKIs . certain circumstances .

Apperley J . Issues of imatinib and pregnancy outcome . J Natl Compr Canc Netw . 2009 ; 7:1050-8 .

Next Month ’ s Clinical Dilemma :

A 19-year-old woman had iron studies performed by function ; however , her iron studies showed a serum iron her primary care physician . The results showed ferritin of 208 mg / dL , total iron-binding capacity of 268 mcg / dL , in the 250 ng / mL range , transferrin saturation of 38 transferrin saturation of 78 percent , and ferritin 301 ng / mL . percent , and normal liver function . Family history is Would you start phlebotomy ? And what would you use remarkable for a maternal aunt with hemochromatosis , to decide on frequency of therapy ? One hematologist and genetic testing shows that she is homozygous for told me to use transferrin saturation below 50 percent the C282Y mutation . She is gravida 0 . She has no menses because of her oral contraceptive method and eats How would you respond ? Email us at

as a goal in premenopausal women .

no red meat . Her most recent labs showed normal liver ashclinicalnews @ hematology . org . ●

ASHClinicalNews . org

TRAINING and EDUCATION

Consult a Colleague Through ASH

Consult a Colleague is a service for ASH members that helps facilitate the exchange of information between hematologists and their peers . ASH members can seek consultation on clinical cases from qualified experts in 11 categories :

• Hematopoietic cell transplantation

• Hemoglobinopathies

• Hemostasis / thrombosis

• Lymphomas

• Lymphoproliferative disorders

• Leukemias

• Multiple myeloma & Waldenström macroglobulinemia

• Myeloproliferative disorders

• Myelodysplastic syndromes

• Thrombocytopenias

Assigned volunteers (“ colleagues ”) will respond to inquiries within two business days ( either by email or phone ).

Have a puzzling clinical dilemma ? Submit a question , and read more about Consult a Colleague volunteers at hematology . org / Clinicians / Consult . aspx or scan the QR code .

* If you have a request related to a hematologic disorder not listed here , please email your recommendation to ashconsult @ hematology . org so it can be considered for addition in the future .

DISCLAIMER : ASH does not recommend or endorse any specific tests , physicians , products , procedures , or opinions , and disclaims any representation , warranty , or guaranty as to the same . Reliance on any information provided in this article is solely at your own risk .

Clinical Dilemma :

We asked , and you answered ! Here are a few responses from this month ’ s “ You Make the Call .”

For the full description of the clinical dilemma , and to see how the expert responded , turn to page 45 .

I had nearly this exact situation several years ago . The patient was on dasatinib at the time she became pregnant . We stopped dasatinib ( nothing was known at the time about its safety in pregnancy , and we stopped it based on extrapolation from the data with imatinib suggesting possible fetal harm ).

We used hydroxyurea to control her counts until late in the second trimester . Then , on three different occasions in the late second trimester and twice early in the third trimester , we gave cytosine arabinoside in a single dose at 1,000 mg / m 2 . This worked very nicely to control her WBC count . A high-risk obstetrician followed her closely with weekly ultrasounds . A healthy baby girl was delivered a few weeks early , and then the patient resumed dasatinib . Seven years later she remains on dasatinib , and the baby is now a healthy 7-year-old girl .

Tim Fenske , MD Medical College of Wisconsin

Milwaukee , WI

I am treating a 20-year-old pregnant woman at seven weeks gestation who was found to have chronic-phase ( CP ) chronic myeloid leukemia ( CML ). Her white blood cell count is 300,000 /µ L with less than 5 percent blasts . Leukapheresis did not provide much reduction in her counts . She remains asymptomatic with a relatively stable peripheral blood picture . I have been considering interferon now and hydroxyurea or imatinib starting in the second trimester .

Despite her white blood cell ( WBC ) count , she still seems to be in CP-CML . The longest experience with CML in pregnancy has been with interferon alpha . It has a high molecular weight and does not cross the placental barrier and therefore is safe for the fetus . It does not increase the risk of major malformations , miscarriage , stillbirth , or preterm delivery . It is associated with significant side effects , mostly constitutional , hematologic , hepatic , and neuropsychiatric , that may interfere with the patient ’ s quality of life .

Hydroxyurea is better tolerated and is effective in dropping the WBC count . It is generally safe in pregnancy , but preeclampsia has been reported in association with hydroxyurea use in the second and third trimesters . Additionally , hydroxyurea rarely results in cytogenetic response .

There are not enough data to suggest that imatinib , or any tyrosine kinase inhibitor ) is safe during pregnancy , and the general consensus is not to start with that in a pregnant person . For those on it who become pregnant , it is advisable to hold or switch to interferon or hydroxyurea .

I would recommend using interferon while closely monitoring her complete blood count and leukocytes .

64 ASH Clinical News

Zeina Al-Mansour , MD University of Massachusetts

Boston , MA

I suggest interferon through the entire pregnancy and then imatinib . I would switch to imatinib in the third trimester if interferon is intolerable .

Dan Zuckerman , MD St . Luke ’ s Mountain States

Tumor Institute Boise , ID

CALQUENCE ® ( acalabrutinib ) capsules , for oral use Initial U . S . Approval : 2017

Brief Summary of Prescribing Information . For complete prescribing information consult official package insert .

INDICATIONS AND USAGE CALQUENCE is indicated for the treatment of adult patients with mantle cell lymphoma ( MCL ) who have received at least one prior therapy .

This indication is approved under accelerated approval based on overall response rate [ see Clinical Studies ( 14 ) in the full Prescribing Information ]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials .

DOSAGE AND ADMINISTRATION

Recommended Dosage The recommended dose of CALQUENCE is 100 mg taken orally approximately every twelve hours until disease progression or unacceptable toxicity .

Advise patients to swallow capsule whole with water . Advise patients not to open , break or chew the capsules . CALQUENCE may be taken with or without food . If a dose of CALQUENCE is missed by more than 3 hours , it should be skipped and the next dose should be taken at its regularly scheduled time . Extra capsules of CALQUENCE should not be taken to make up for a missed dose .

Dose Modifications

Adverse Reactions Recommended dose modifications of CALQUENCE for Grade 3 or greater adverse reactions are provided in Table 1 .

Table 1 : Recommended Dose Modifications for Adverse Reactions

Event

Grade 3 or greater non-hematologic toxicities ,

Grade 3 thrombocytopenia with bleeding ,

Grade 4 thrombocytopenia or

Grade 4 neutropenia lasting longer than 7 days

Adverse Reaction Occurrence

First and Second

Third

Dose Modification ( Starting dose = 100 mg twice daily )

Interrupt CALQUENCE . Once toxicity has resolved to Grade 1 or baseline level , CALQUENCE therapy may be resumed at 100 mg twice daily .

Interrupt CALQUENCE . Once toxicity has resolved to Grade 1 or baseline level , CALQUENCE therapy may be resumed at 100 mg daily .

Fourth Discontinue CALQUENCE .

Concomitant Use with Gastric Acid Reducing Agents Proton Pump Inhibitors : Avoid concomitant use [ see Drug Interactions ( 7 ) in the full Prescribing Information ].

H2-Receptor Antagonists : Take CALQUENCE 2 hours before taking a H2-receptor antagonist [ see Drug Interactions ( 7 ) in the full Prescribing Information ].

Antacids : Separate dosing by at least 2 hours [ see Drug Interactions ( 7 ) in the full Prescribing Information ].

CONTRAINDICATIONS None .

WARNINGS AND PRECAUTIONS

Hemorrhage Serious hemorrhagic events , including fatal events , have occurred in the combined safety database of 612 patients with hematologic malignancies treated with CALQUENCE monotherapy . Grade 3 or higher bleeding events , including gastrointestinal , intracranial , and epistaxis have been reported in 2 % of patients . Overall , bleeding events including bruising and petechiae of any grade occurred in approximately 50 % of patients with hematological malignancies .

The mechanism for the bleeding events is not well understood . CALQUENCE may further increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs of bleeding . Consider the benefit-risk of withholding CALQUENCE for 3-7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding .

Infection Serious infections ( bacterial , viral or fungal ), including fatal events and opportunistic infections have occurred in the combined safety database of 612 patients with hematologic malignancies treated with CALQUENCE monotherapy . Consider prophylaxis in patients who are at increased risk for opportunistic infections .

Grade 3 or higher infections occurred in 18 % of these patients . The most frequently reported Grade 3 or 4 infection was pneumonia . Infections due to hepatitis B virus ( HBV ) reactivation and progressive multifocal leukoencephalopathy ( PML ) have occurred . Monitor patients for signs and symptoms of infection and treat as medically appropriate .

Cytopenias In the combined safety database of 612 patients with hematologic malignancies , patients treated with CALQUENCE monotherapy experienced Grade 3 or 4 cytopenias , including neutropenia ( 23 %), anemia ( 11 %) and thrombocytopenia ( 8 %) based on laboratory measurements . In the CALQUENCE clinical Trial LY-004 , patients ’ complete blood counts were assessed monthly during treatment .

Second Primary Malignancies Second primary malignancies , including non-skin carcinomas , have occurred in 11 % of patients with hematologic malignancies treated with CALQUENCE monotherapy in the combined safety database of 612 patients . The most frequent second primary malignancy was skin cancer , reported in 7 % of patients . Advise protection from sun exposure .

Atrial Fibrillation and Flutter In the combined safety database of 612 patients with hematologic malignancies treated with CALQUENCE monotherapy , atrial fibrillation and atrial flutter of any grade occurred in 3 % of patients , and Grade 3 in 1 % of patients . Monitor for atrial fibrillation and atrial flutter and manage as appropriate .

ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling :

• Hemorrhage [ see Warnings and Precautions ( 5.1 ) in the full Prescribing Information ]

• Infection [ see Warnings and Precautions ( 5.2 ) in the full Prescribing Information ]

• Cytopenias [ see Warnings and Precautions ( 5.3 ) in the full Prescribing Information ]

• Second Primary Malignancies [ see Warnings and Precautions ( 5.4 ) in the full Prescribing Information ]

• Atrial Fibrillation and Flutter [ see Warnings and Precautions ( 5.5 ) in the full Prescribing Information ]

Clinical Trials Experience As clinical trials are conducted under widely varying conditions , adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice .

The safety data described in this section reflect exposure to CALQUENCE ( 100 mg twice daily ) in 124 patients with previously treated MCL in Trial LY-004 [ see Clinical Studies ( 14 ) in the full Prescribing Information ]. The median duration of treatment with CALQUENCE was 16.6 ( range 0.1 to 26.6 ) months . A total of 91 ( 73.4 %) patients were treated with CALQUENCE for ≥ 6 months and 74 ( 59.7 %) patients were treated for ≥ 1 year .

The most common adverse reactions ( ≥ 20 %) of any grade were anemia , thrombocytopenia , headache , neutropenia , diarrhea , fatigue , myalgia , and bruising . Grade 1 severity for the non-hematologic , most common events were as follows : headache ( 25 %), diarrhea ( 16 %), fatigue ( 20 %), myalgia ( 15 %), and bruising ( 19 %). The most common Grade ≥ 3 non-hematological adverse reaction ( reported in at least 2 % of patients ) was diarrhea .

Dose reductions or discontinuation due to any adverse reaction were reported in 1.6 % and 6.5 % of patients , respectively .

Tables 2 and 3 present the frequency category of adverse reactions observed in patients with MCL treated with CALQUENCE .

Table 2 : Non-Hematologic Adverse Reactions * in ≥ 5 % ( All Grades ) of Patients with MCL in Trial LY-004

Body System Adverse Reactions

CALQUENCE 100 mg twice daily N = 124

All Grades (%) Grade ≥ 3 (%)