You Make the Call: How would you treat this transplant-ineligible patient with Ph+ ALL?

This month, Geoffrey Uy, MD, discusses treatment options for a transplant-ineligible patient with Philadelphia chromosome-positive (Ph+) acute lymphocytic leukemia (ALL).

And don’t forget to check out next month’s clinical dilemma – send in your responses for a chance to win an ASH Clinical News-themed prize!

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?

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.

The European Working Group on Adult ALL (EWALL) study of dasatinib plus dexamethasone showed a relapse-free 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 Malattie Ematologiche dell'Adulto (GIMEMA) 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 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 event-free 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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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)?

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