REFERENCES
2009 ; 113:1875-91 .
You Make the Call : Readers ’ Response
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 , Olatoyosi Odenike , MD , discusses a patient with a morphologic presentation suggestive of acute promyelocytic leukemia ( APL ), but with a negative PML / RARA fusion transcript result .
Clinical Dilemma :
I have a 40-year-old patient who presented with complaints of fever lasting three months . He had a few atypical cells in his peripheral smear and his bone marrow ( BM ) aspiration was morphologically suggestive of APL . PML / RAR alpha was not detected from peripheral blood . He was started on all-trans retinoic acid plus arsenic trioxide ( ATRA ). He developed cytopenia after starting hydroxyurea . How should I manage this patient ? I repeated a BM aspiration and sent the aspirate for PML / RAR alpha testing . Fluorescence in situ hybridization ( FISH ) results are pending . Does low promyelocyte count in the BM sample influence the PML / RAR alpha transcript detection ?
Expert Opinion
Olatoyosi Odenike , MD and ZBTB16 / RARA fusions , are resistant to therapy with
Associate Professor of Medicine
ATRA . The ZBTB16 / RARA variant is the most common Section of Hematology / Oncology and best studied and is also associated with resistance to The University of Chicago Medicine arsenic trioxide . Specific management recommendations are lacking for these ATRA-resistant variants given their rarity and the consequent paucity of available evidence , but
APL is a medical emergency . Prompt diagnosis and treatment with ATRA , coupled with supportive care , is essential By contrast , variant cases involving NPM1 / RARA , NUMA /
AML-like chemotherapy approaches have been proposed .
to maximize the odds of a successful outcome and reduce RARA , and FIP1L1 / RARA fusions have been reported to the risk of early mortality from complications related to retain sensitivity to ATRA . disseminated intravascular coagulopathy . The hallmark of Metaphase cytogenetics performed on the BM aspirate diagnosis is the demonstration of the t ( 15 ; 17 )( q24.1 ; q21.2 ) sample is instrumental in detecting variant translocations . chromosomal translocation or the PML / RARA chimeric fusion gene . The PML / RARA fusion can be detected by reverse also be useful in this regard . Ultimately , for cases of APL
FISH analysis using a probe that spans the RARA gene can transcriptase PCR ( RT-PCR ) or by FISH . RT-PCR is generally regarded as the gold standard for diagnosis , given the phase cytogenetics and FISH analysis can provide comple-
lacking a PML / RARA fusion , the combination of meta-
heightened sensitivity and specificity and the ability to define mentary information that establishes the presence of a the specific breakpoint in PML , allowing subsequent reliable variant translocation involving RARA , allowing therapy to monitoring of minimal residual disease . The turnaround time be tailored accordingly . is variable , but in many centers these assays may take up to 48 hours or longer . Hematologists should commence ATRA as soon as a diagnosis of APL is suspected , even while genetic confirmation is pending , since the risk of early mortality from hemorrhagic complications has been correlated with delay in treatment initiation . In most cases where the morphology is consistent with APL , the diagnosis will subsequently be confirmed by the detection of the PML / RARA fusion . But what about cases where there is no evidence of a PML / RARA fusion transcript ?
Variant translocations involving the RARA gene have been described in some patients whose disease has morphologic features resembling APL , but in which there is no evidence of a PML / RARA fusion . The fusion partners involved in these variant translocations include ZBTB16 I am evaluating a 60-year-old man for cervical spine ( previously known as PLZF ) located at 11q23.2 , NUMA1 at surgery ( disc disease with neurologic symptoms ) who has 11q13.4 , NPM1 at 5q35.1 , and STAT5B at 17q21.2 . Other a prolonged prothrombin time ( PT ). He appears to have more recently described variants include PRKAR1A / RARA mild factor VII ( FVII ) deficiency . His bleeding history is as and FIP1L1-RARA fusions . Collectively , these variant follows : catheter ablation for atrial fibrillation ( followed translocations account for approximately 1 to 2 percent by warfarin for 10 months without bleeding ), shockwave of APL cases . Morphologic differences can sometimes lithotripsy ( no bleeding problems ), and tooth extractions be appreciated between these cases and classic APL . For about 30 years ago ( followed by bleeding for about 2 days , example , APL associated with the 11 ; 17 translocation resulting in the ZBTB16 / RARA fusion often lacks Auer rods , problems with minor lacerations ( e . g ., shaving ) and is
with no need for reevaluation or hemostasis ). He has no
and some cases involving the NPM1 / RARA fusion have physically active in taekwondo . The initial abnormality that both hypergranular and hypogranular promyelocytes and prompted referral was a baseline PT of 15.2 seconds , international normalized ratio ( INR ) of 1.3 , with normal partial an absence of Auer rods . The World Health Organization recommends that these cases be classified as APL with a thromboplastin time . Repeat PT was 13.8 seconds , INR 1.2 , variant RARA translocation . with the following factor levels : FVII 46 percent , factor II 86
ATRA and arsenic trioxide-based regimens have percent , factor V 87 percent , and factor X 87 percent . The revolutionized the treatment of classic APL , turning it into FVII deficiency literature suggests that surgical bleeding is a highly curable malignancy . The therapeutic implication of rare if FVII is above 10 percent . One discussion suggested the diagnosis of APL with a variant RARA translocation is that 30 percent should be okay , but I am concerned about that some variants , including those with the STAT5B / RARA this being a critical bleeding site . ●
1 . Larson RA , Kondo K , Vardiman JW , et al . Evidence for a 15 ; 17 translocation in every patient with acute promyelocytic leukemia . Am J Med . 1984 ; 76:827-41 .
2 . Arber DA , Brunning RD , LeBeau MM , et al . Acute myeloid leukemia with recurrent genetic abnormalities . In : WHO Classification of tumors of haematopoietic and lymphoid tissues ( Revised 4th edition ). IARC : Lyon 2017 . Swerdlow SH , Carp E , Harris NL , et al .
3 . Zelent A , Guidez F , Melnick A , et al . Translocations of the RARα gene in acute promyelocytic leukemia . Oncogene . 2001 ; 20:7186-203 .
4 . Lo-Coco F , Avvisati G , Vignetti M , et al . Retinoic acid and arsenic trioxide for acute promyelocytic leukemia . N Engl J Med . 2013 ; 369:111-21 .
5 . Sanz MA , Grimwade D , Tallman MS , et al . Management of acute promyelocytic leukemia : recommendations from an expert panel on behalf of the European LeukemiaNet . Blood .
Next Month ’ s Clinical Dilemma :
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54 ASH Clinical News May 2018 remained generally constant over the follow-up period in both cohorts . All patients who tested positive for anti-recombinant human hyaluronidase antibodies at any point during the study were negative for neutralizing antibodies .
In the SAWYER study , where previously untreated patients with CLL were treated with RITUXAN HYCELA or rituximab in combination with FC , the incidence of treatment-induced / enhanced anti-rituximab antibodies was 2.4 % in the RITUXAN HYCELA group vs . 6.7 % in rituximab group . The incidence of treatmentinduced / enhanced anti- recombinant human hyaluronidase antibodies was 10.6 % in the RITUXAN HYCELA treatment arm . None of the patients who tested positive for anti-recombinant human hyaluronidase antibodies tested positive for neutralizing antibodies .
The clinical relevance of the development of anti-rituximab or anti-recombinant human hyaluronidase antibodies after treatment with RITUXAN HYCELA is not known .
6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of rituximab-containing products . Because these reactions are reported voluntarily from a population of uncertain size , it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure .
• Hematologic : prolonged pancytopenia , marrow hypoplasia , Grade 3 – 4 prolonged or lateonset neutropenia , hyperviscosity syndrome in Waldenstrom ’ s macroglobulinemia , prolonged hypogammaglobulinemia
• Cardiac : fatal cardiac failure
• Immune / Autoimmune Events : uveitis , optic neuritis , systemic vasculitis , pleuritis , lupus-like syndrome , serum sickness , polyarticular arthritis , and vasculitis with rash .
• Infection : viral infections , including progressive multifocal leukoencephalopathy ( PML ), increase in fatal infections in HIV-associated lymphoma , and a reported increased incidence of Grade 3 and 4 infections
• Neoplasia : disease progression of Kaposi ’ s sarcoma .
• Skin : severe mucocutaneous reactions .
• Gastrointestinal : bowel obstruction and perforation .
• Pulmonary : fatal bronchiolitis obliterans and fatal interstitial lung disease .
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary Based on human data , rituximab-containing products can cause adverse developmental outcomes including B-cell lymphocytopenia in infants exposed to rituximab in-utero ( see Clinical Considerations ). There are no available data on RITUXAN HYCELA use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage . In animal reproduction studies , intravenous administration of a rituximab product to pregnant cynomolgus monkeys during the period of organogenesis caused lymphoid B cell depletion in the newborn offspring at doses resulting in 80 % of the exposure ( based on AUC ) of those achieved following a dose of 2 grams in humans . Reduced fetal weight and increased fetal lethality were observed following subcutaneous administration of hyaluronidase human in mice at a dose > 2700 times higher than the human dose . Comparable systemic exposure levels could occur in a pregnant patient following accidental intravenous administration of an entire vial of RITUXAN HYCELA ( see Data ). Advise pregnant women of the risk to a fetus .
Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications . The background risk of major birth defects and miscarriage for the indicated population is unknown . The estimated background risk in the U . S . general population of major birth defects is 2 %– 4 % and of miscarriage is 15 %– 20 % of clinically recognized pregnancies .
Clinical Considerations Fetal / Neonatal Adverse Reactions
Observe newborns and infants for signs of infection and manage accordingly .
Data Human Data
Postmarketing data indicate that B-cell lymphocytopenia generally lasting less than six months can occur in infants exposed to rituximab in-utero . Rituximab was detected postnatally in the serum of infants exposed in-utero .
Animal Data RITUXAN HYCELA for subcutaneous injection contains rituximab and hyaluronidase human [ see Description ( 11 )].
We asked , and you answered ! Here are a few responses from this month ’ s “ You Make the Call .”
To see how the expert responded , turn to page 54 .
Rituximab Product :
• An embryo-fetal developmental toxicity study was performed on pregnant cynomolgus monkeys . Pregnant animals received rituximab via the intravenous route during early gestation ( organogenesis period ; post coitum days 20 through 50 ). Rituximab was administered as loading doses on post coitum ( PC ) Days 20 , 21 and 22 , at 15 , 37.5 or 75 mg / kg / day , and then weekly on PC Days 29 , 36 , 43 and 50 , at 20 , 50 or 100 mg / kg / week . The 100 mg / kg / week dose resulted in 80 % of the exposure ( based on AUC ) of those achieved following a dose of 2 grams in humans . Rituximab crosses the monkey placenta . Exposed offspring did not exhibit any teratogenic effects but did have decreased lymphoid tissue B cells .
• A subsequent pre-and postnatal reproductive toxicity study in cynomolgus monkeys was completed to assess developmental effects including the recovery of B cells and immune function in infants exposed to rituximab in utero . Animals were treated with a loading dose of 0 , 15 , or 75 mg / kg every day for 3 days , followed by weekly dosing with 0 , 20 , or 100 mg / kg dose . Subsets of pregnant females were treated from PC Day 20 through postpartum Day 78 , PC Day 76 through PC Day 134 , and from PC Day 132 through delivery and postpartum Day 28 . Regardless of the timing of treatment , decreased B cells and immunosuppression were noted in the offspring of rituximab-treated pregnant animals . The B-cell counts returned to normal levels , and immunologic function was restored within 6 months postpartum .
Hyaluronidase Human :
• In an embryo-fetal study , mice have been dosed daily by subcutaneous injection during the period of organogenesis with hyaluronidase human at dose levels up to 2,200,000 U / kg , which is > 2700 times higher than the human dose . The study found no evidence of teratogenicity . Reduced fetal weight and increased numbers of fetal resorptions were observed , with no effects found at a daily dose of 360,000 U / kg , which is > 450 times higher than the human dose .
• In a peri-and post-natal reproduction study , mice have been dosed daily by subcutaneous injection , with hyaluronidase human from implantation through lactation and weaning at dose levels up to 1,100,000 U / kg , which is > 1,300 times higher than the human dose . The study found no adverse effects on sexual maturation , learning and memory or fertility of the offspring .
8.2 Lactation There are no data on the presence of rituximab or hyaluronidase human in human milk , the effect on the breastfed infant , or the effect on milk production . However , rituximab is detected in the milk of lactating cynomolgus monkeys , and IgG is present in human milk . Since many drugs including antibodies are present in human milk , advise a lactating woman not to breastfeed during treatment and for at least 6 months after the last dose of RITUXAN HYCELA due to the potential for serious adverse reactions in breastfed infants .
8.3 Females and Males of Reproductive Potential Rituximab-containing products can cause fetal harm [ see Use in Specific Populations ( 8.1 )].
Contraception Females
Females of childbearing potential should use effective contraception while receiving RITUXAN HYCELA and for 12 months following treatment .
8.4 Pediatric Use The safety and effectiveness of RITUXAN HYCELA in pediatric patients have not been established .
8.5 Geriatric Use Of the total number of subjects in the SABRINA , MabEase , and SAWYER studies , 37 % were 65 and over , while 10 % were 75 and over . No overall differences in safety or effectiveness were observed between these subjects and younger subjects , and other reported clinical experience has not identified differences in responses between the elderly and younger patients , but greater sensitivity of some older individuals cannot be ruled out .
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Medication Guide ).
Severe Mucocutaneous Reactions Advise patients to contact their healthcare provider immediately for symptoms of severe mucocutaneous reactions , including painful sores or ulcers on the lips or mouth , blisters , peeling skin , rash , and pustules [ see Warnings and Precautions ( 5.1 )].
Clinical Dilemma :
I have a 40-year-old patient who presented with complaints of fever lasting three months . He had a few atypical cells in his peripheral smear and his bone marrow ( BM ) aspiration was morphologically suggestive of acute promyelocytic leukemia ( APL ). PML / RAR alpha was not detected from peripheral blood . He was started on all-trans retinoic acid ( ATRA ) plus arsenic trioxide ( ATO ). He developed cytopenia after
Hepatitis B Virus Reactivation Advise patients to contact their healthcare provider immediately for symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes [ see Warnings and Precautions ( 5.2 )].
Progressive Multifocal Leukoencephalopathy ( PML ) Advise patients to contact their healthcare provider immediately for signs and symptoms of PML , including new or changes in neurological symptoms such as confusion , dizziness or loss of balance , difficulty talking or walking , decreased strength or weakness on one side of the body , or vision problems [ see Warnings and Precautions ( 5.3 )].
Hypersensitivity and Other Administration Reactions Inform patients about the signs and symptoms of hypersensitivity and administration-related reactions . Advise patients to contact their healthcare provider immediately to report symptoms of administrationrelated reactions including dizziness , nausea , chills , fever , vomiting , diarrhea , urticaria , angioedema , breathing problems , or chest pain [ see Warnings and Precautions ( 5.4 )].
Tumor Lysis Syndrome ( TLS ) Advise patients to contact their healthcare provider immediately for signs and symptoms of tumor lysis syndrome such as nausea , vomiting , diarrhea , and lethargy [ see Warnings and Precautions ( 5.5 )].
Infections Advise patients to contact their healthcare provider immediately for signs and symptoms of infections including fever , cold symptoms ( e . g ., rhinorrhea or laryngitis ), flu symptoms ( e . g ., cough , fatigue , body aches ), earache or headache , dysuria , cold sores , and painful wounds with erythema [ see Warnings and Precautions ( 5.6 )].
Cardiovascular Adverse Reactions Advise patients of the risk of cardiovascular adverse reactions , including ventricular fibrillation , myocardial infarction , and cardiogenic shock . Advise patients to contact their healthcare provider immediately to report chest pain and irregular heartbeats [ see Warnings and Precautions ( 5.7 )].
Renal Toxicity Advise patients of the risk of renal toxicity . Inform patients of the need for healthcare providers to monitor kidney function [ see Warnings and Precautions ( 5.8 )].
Bowel Obstruction and Perforation Advise patients to contact their healthcare provider immediately for sign and symptoms of bowel obstruction and perforation , including severe abdominal pain or repeated vomiting [ see Warnings and Precautions ( 5.9 )].
Embryo-Fetal Toxicity Advise a pregnant woman of the potential risk to a fetus . Advise female patients that rituximab containing products can cause fetal harm if taken during pregnancy and to use effective contraception during treatment with RITUXAN HYCELA and for at least 12 months after the last dose of RITUXAN HYCELA . Advise patients to inform their healthcare provider of a known or suspected pregnancy [ see Warnings and Precautions ( 5.11 ) and Use in Specific Populations ( 8.1 , 8.3 )].
Lactation Advise women not to breastfeed during treatment with RITUXAN HYCELA and for 6 months after the last dose [ see Use in Specific Populations ( 8.2 )].
RITUXAN HYCELA ™ [ rituximab and hyaluronidase human ]
Manufactured by : Genentech , Inc . A Member of the Roche Group 1 DNA Way South San Francisco , CA 94080-4990
U . S . License No .: 1048
RITUXAN HYCELA ™ is a trademark of Biogen .
Jointly marketed by : Biogen and Genentech USA , Inc .
© 2017 Biogen and Genentech USA , Inc .
RSC / 062017 / 0061 06 / 17 starting hydroxyurea . How should I manage this patient ? I repeated a BM aspiration and sent the aspirate for PML / RAR alpha testing . Fluorescence in situ hybridization ( FISH ) results are pending . Does low promyelocyte count in the BM sample influence the PML / RAR alpha transcript detection ?
In the described case of probable PML , I would prefer adding an anthracycline ( e . g ., daunorubicin 60 mg / m for 3 consecutive days ) to ATRA plus ATO . Low promyelocyte count in BM does not influence detection of PML / RARA transcript RNA . If no rearrangement of RARA is detected , I would add anthracycline as in regular acute myeloid leukemia .
Alexey Maschan , MD Moscow , Russia
Unlikely to be APL . Evan D . Slater , MD
Ventura , CA
The possibility of PML is present so I would recommend flowcytometry and polymerase chain reaction ( PCR ) for PML / RARA detection , as there are sporadic cases with negative FISH results and positive PCR results . Some possible variants of PML include t ( 11,17 ) and t ( 5,17 ). If the diagnosis is confirmed , I would start ATO plus ATRA with hydroxyurea and adjust dose according to white blood cell count . Supportive therapy indicating low promyelocyte count does not influence detection of the PML / RARA gene .
Bassam Francis Matti , MD Baghdad , Iraq