EDUCATION
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 , Geoffrey Uy , MD , discusses treatment options for a transplantineligible patient with Philadelphia chromosome-positive ( Ph +) acute lymphocytic leukemia ( ALL ).
CLINICAL DILEMMA :
I am treating a 61-year-old female diagnosed with Ph + ALL who has multiple comorbidities , including severe diabetes and obesity ( body mass index of 43 ), who is not a candidate for allogeneic hematopoietic cell transplantation . She was initially treated with a single cycle of rituximab , hyper-CVAD ( hyperfractionated cyclophosphamide , vincristine sulfate , doxorubicin hydrochloride , and dexamethasone ), and dasatinib . She achieved a complete remission , but had a difficult induction course and was then switched to dasatinib , prednisone , and vincristine . A bone marrow biopsy continues to show morphologic and immunologic remission , but is still positive for BCR-ABL transcripts at a low level . Should I continue maintenance as before , switch to a different tyrosine kinase inhibitor , or try other immune treatments such as blinatumomab ?
Expert Opinion
It is fair to say that the optimal consolidation for patients with Ph + ALL who are induced with a tyrosine kinase inhibitor ( TKI ) plus steroid regimens is not known , but that relapse rates are quite high with TKIs alone ( with T315I kinase domain mutations frequently detected at the time of relapse ). While ponatinib is a consideration given its activity against T315I mutations , the patient is at high-risk for vascular complications with obesity and diabetes . Most studies with a TKI plus steroid induction include a low-dose chemotherapy regimen with central nervous system ( CNS ) prophylaxis following induction therapy .
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Geoffrey Uy , MD Professor Department of Medicine , Oncology Division Washington University School of Medicine in St . Louis
The European Working Group on Adult ALL ( EWALL ) study of dasatinib plus dexamethasone showed a relapsefree survival rate of roughly 50 % at 18 months , but also included low-intensity chemotherapy with methotrexate , asparaginase , and cytarabine . 1 The CALGB 10701 study used a dasatinib and dexamethasone combination as initial induction and also included a chemotherapy consolidation arm with methotrexate , followed by etoposide and cytarabine for those not proceeding to transplant with a disease-free survival ( DFS ) rate of approximately 40 to 50 % at 18 months . 2
More recently , the Gruppo Italiano
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Malattie Ematologiche dell ’ Adulto ( GI- MEMA ) published their results with dasatinib dexamethasone induction followed by blinatumomab plus dasatinib . 3 Although the median follow-up is quite short ( 18 months ), the 18-month DFS was 88 %, suggesting that immunotherapy may be an effective consolidation approach for Ph + ALL . However , if there is a potential for chimeric antigen receptor ( CAR ) T-cell therapy down the road , there is emerging data from the pediatric side that the use of the anti-CD19 bispecific antibody blinatumomab prior to CAR T-cell therapy may be associated with worse post- CD19 CAR T-cell therapy outcomes . 4 That being said , I would favor consolidating with blinatumomab and dasatinib at this point .
An additional consideration is the type and duration of CNS prophylaxis during treatment given that this
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patient has had minimal chemotherapy . There is no clear consensus in this area , but with the hyper-CVAD plus ponatinib regimen , intrathecal chemotherapy with methotrexate and cytarabine is given alternately for a total of 12 doses .
References
1 . Rousselot P , Coudé MM , Gokbuget N , et al . Dasatinib and low-intensity chemotherapy in elderly patients with Philadelphia chromosome – positive ALL . Blood . 2016 ; 128 ( 6 ): 774-782 .
2 . Wieduwilt MJ , Yin J , Wetzler M , et al . Dasatinib and dexamethasone followed by hematopoietic cell transplantation for adults with Ph-positive ALL [ published online ahead of print 7 Sept 2021 ]. Blood Adv . doi : 10.1182 / bloodadvances . 2021004813 .
3 . Foà R , Bassan R , Vitale A , et al . Dasatinib – blinatumomab for Ph-positive acute lymphoblastic leukemia in adults . N Engl J Med . 2020 ; 383:1613-1623 .
4 . Locatelli F , Zugmaier G , Carelo Rizzari C , et al . Superior eventfree survival with blinatumomab versus chemotherapy in children with high-risk first relapse of B-cell precursor acute lymphoblastic leukemia : A randomized , controlled phase 3 trial . Abstract # 268 . Presented at the 2020 American Society of Hematology Annual Meeting , December 5 , 2020 .
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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 :
• Anemias
• Hematopoietic cell transplantation
• Hemoglobinopathies
• Hemostasis / thrombosis
• Lymphomas
• Lymphoproliferative disorders
• Leukemias
• Multiple myeloma & Waldenström macroglobulinemia
• Myeloproliferative neoplasms
• 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 / education / clinicians / consult-a-colleague .
* 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 .
Next Month ’ s Clinical Dilemma :
A 73-year-old man with past medical history of HIV ( on treatment ), benign prostatic hypertrophy ( BPH ), hyperlipidemia , and type 2 diabetes was referred for history of bilateral iliofemoral deep vein thrombosis ( DVT ) status post vena cava ( IVC ) filter placement . The patient was admitted to our hospital after presenting with hematuria due to BPH . This required continuous bladder irrigation with urgent cystoscopy and hematoma evacuation . He then underwent a transurethral resection of the prostate and prostate artery embolization . These procedures were complicated by epididymitis requiring antibiotics . He was found to have bilateral iliofemoral DVT during this admission and , due to concurrent bleeding , underwent IVC filter placement . He was not placed on anticoagulation . An ultrasound performed a month later revealed occlusive DVT in bilateral common iliac veins , bilateral common femoral veins , the right superficial femoral vein , and the right popliteal vein that was significantly worse when compared to the ultrasound a month prior . The patient did not start anticoagulation .
A third ultrasound three months after his initial presentation was performed in the context of an evaluation for IVC filter removal . The only abnormality seen was within the left femoral vein where there was echogenic material noticed compatible with DVT . This extended from the proximal femoral vein through the distal femoral vein with a small recanalized segment . With the improvement in the clot burden and chronic appearance of the remaining clot , it was unclear to the interventional team whether the filter should be removed . He was thus referred to hematology .
How do you manage the finding of residual vein thrombosis in patients who have had a DVT ( provoked or unprovoked )?
How would you respond ? Email us at ashclinicalnews @ hematology . org .
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