Shira N. Dinner, MD
Associate Professor of Medicine
Northwestern University Feinberg School of Medicine
Executive Officer, Alliance for Clinical Trials in Oncology
CLINICAL DILEMMA
A 46-year-old female patient was diagnosed with Philadelphia chromosome (Ph)-positive B-cell acute lymphoblastic leukemia (B-ALL) after presenting with leukocytosis, lymphadenopathy, and hepato-splenomegaly. A bone marrow biopsy showed hypercellularity (>90%), and flow cytometry analysis showed 36% B-cell lymphoblasts. Cytogenetics were abnormal with hyperdiploidy karyotype; gain of 2, 5, and 8; t(9;22); del 11q; and +der(22). Fluorescence in situ hybridization showed t(9;22) and detected KMT2A.
In total, she received seven cycles of Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) plus ponatinib (four odd — or “A” — cycles and three even — or “B” — cycles); the last cycle was omitted because of excessive toxicity. She was in complete remission (CR) and negative for measurable residual disease after her first two cycles. She also received intrathecal (IT) prophylaxis with 15 alternating cycles of methotrexate (MTX) and cytarabine.
She was not a candidate for an allogeneic hematopoietic cell transplant (alloHCT) because of social issues. Therefore, over the next two years she received POMP (prednisone, oncovin, melphalan, and cyclophosphamide) and ponatinib as maintenance, but treatment was often interrupted and then discontinued because of intolerability and frequent infections. Her ponatinib was also switched to dasatinib because of increased liver enzymes and abdominal pain. During the two years of maintenance treatment after CR, her polymerase chain reaction (PCR) test results remained negative.
The patient has a history of Arnold Chiari malformation, which had been under observation. She was admitted with headaches and noted to have hydrocephalus, likely from Arnold Chiari malformation; however, cerebrospinal fluid (CSF) cytology was also positive for B-ALL. Her bone marrow showed no morphologic evidence of leukemia, and flow cytometry was negative, but PCR for BCR-ABL was 0.8% positive. She was treated for hydrocephalus with a ventriculoperitoneal (VP) shunt. She also received IT chemotherapy plus one cycle of high-dose MTX with clearing of CSF. Later, she was readmitted with headaches. At that time, she had a VP shunt, malposition, and an infected ommaya reservoir. The ommaya reservoir was removed, and the VP shunt was replaced. CSF cytology remains negative, and peripheral blood PCR remains negative for any transcript.
What do you recommend as future treatment for this patient? Some have advised chimeric antigen receptor (CAR) T-cell therapy, but the current plan is one more cycle of high-dose MTX followed by blinotumumab.
EXPERT OPINION
The patient is status post-first relapse with measurable residual disease (MRD) recurrence in the bone marrow and CSF. She achieved a second deep molecular response and cleared the CSF with high-dose MTX and IT chemotherapy. Additional high-dose MTX will be given to consolidate the effects of this remission in the marrow and central nervous system (CNS). The key question at this point is how to further consolidate and maintain this response in the long term. Ideally, the patient should proceed to an alloHCT because she did not have one previously. A total body irradiation containing preparative regimen is more commonly used in pediatric, adolescent, and young adult patients, but might be considered in her case if she is fit in order to provide adequate CNS treatment.1
If she is still not a candidate for alloHCT because of social issues, we must consider other therapies versus close observation and MRD surveillance for relapse. If she does not currently have evidence of MRD in the marrow, it is not clear that blinatumomab would benefit her. One could consider the ECOG-ACRIN E1910 trial data for newly diagnosed Ph-negative ALL, which demonstrated a survival benefit with blinatumomab added to consolidation chemotherapy for patients who were MRD negative, but we have no data that a similar survival benefit would be seen in the relapsed setting, particularly for Ph-positive disease.2 The advantage of blinatumomab is that it is a readily available, off-the-shelf option and is generally well tolerated with minimal side effects for patients with disease that is in CR. However, if the patient lacks social support, it may be difficult to receive a continuous intravenous infusion for 28 days straight and coordinate weekly drug bag changes.
In the ZUMA-3 trial of the CD19 targeted CAR T-cell therapy brexucabtagene autoleucel (brexu-cel), 9% of patients were in CR after bridging therapy and before CAR-T infusion. After more than two years of follow-up of the ZUMA-3 study, responses remained durable with a median duration of response (DOR) of 20 months for those in CR, translating into a median overall survival of more than two years in all patients and not reached in those in CR who were generally more heavily pretreated than the patient described in this case. Because only five patients were in CR prior to brexu-cel infusion, numbers are too small to say if using the CAR-T therapy as a consolidation treatment could have as meaningful an impact as alloHCT to prevent relapse and improve long-term survival.3 This will need to be studied further in future prospective, randomized clinical trials as we gain more experience with CAR T-cell products. Newer CAR T-cell products in development are also focused on prolonging duration of CAR-T persistence in the body, which may improve DOR and survival.4
The other potential benefit of CAR T cells for this patient is CNS penetrance. Data from tisagenlecleucel studies in children and young adults demonstrated that CAR T cells could effectively clear CNS involvement by ALL and prevent relapse.5 Of note, there are social challenges with administering CAR T cells. Because of the high cost, one must ensure insurance will authorize CAR T-cell manufacturing and administration. For some patients’ insurance plans, the review process can take a month or longer to complete, which creates significant treatment delays. Treatment centers also may require long hospital stays, identification of a designated outpatient caregiver, and close follow-up to monitor for cytokine release syndrome and neurotoxicity, which have been reported up to eight weeks out from treatment in some trials.
Finally, depending on the patient’s social circumstances or preference, one could consider rechallenging the patient with ponatinib as a maintenance therapy or even observing the patient in second remission off additional treatment with MRD surveillance testing several times per year. Should an MRD or morphologic relapse occur, the patient could then proceed with blinatumomab, inotuzumab ozogamicin, CAR T cells, or a clinical trial.
References
- Gupta T, Kannan S, Dantkale V, et al. Cyclophosphamide plus total body irradiation compared with busulfan plus cyclophosphamide as a conditioning regimen prior to hematopoietic stem cell transplantation in patients with leukemia: a systematic review and meta-analysis. Hematol Oncol Stem Cell Ther. 2011;4(1):17-29.
- Litzow M, Zhouxin S, Mattison R, et al. Consolidation therapy with blinatumomab improves overall survival in newly diagnosed adult patients with B-lineage acute lymphoblastic leukemia in measurable residual disease negative remission: results from the ECOG-ACRIN E1910 randomized phase III National Cooperative Clinical Trials Network Trial. Blood. 2022;140(Suppl 2):LBA-1.
- Shah B, Ghobadi A, Oluwole O, et al. Two-year follow-up of KTE-X19 in patients with relapsed or refractory adult B-cell acute lymphoblastic leukemia in ZUMA-3 and its contextualization with SCHOLAR-3, an external historical control study. J Hematol Oncol. 2022;15(170).
- Roddie C, Sandhu K, Tholouli E, et al. Obecabtagene autoleucel (obe-cel, AUTO1) for relapsed/refractory adult B-cell acute lymphoblastic leukemia (R/R B-ALL): pooled analysis of the ongoing FELIX phase Ib/II study. Blood. 2023;142(Suppl 2):222.
- Newman H, Barz Leahy AE, Li Y, et al. CD19-targeted chimeric antigen receptor (CAR) T cells in CNS relapsed acute lymphoblastic leukemia (ALL). J Clinic Oncol. 2020;38(15):10511.
NEXT MONTH'S CLINICAL DILEMMA
I have a 20-year-old male patient with strong family history of recessive hereditary methemoglobinemia. He has had cyanosis since birth but has experienced no medical complications or issues playing sports. None of his family members ever had globin sequence testing. He did well with bilateral inguinal hernia surgery and is now being seen pre-op for a tonsillectomy. His complete blood count hemoglobin (Hb) was 177 g/L, and alpha globin sequencing showed Hb M-Iwate mutation.
My questions are as follows: Do we still need to avoid medications that can cause acquired methemoglobinemia? Assuming the pulse oximeter is inaccurate for perioperative monitoring, would an arterial blood gas test be needed in the event of respiratory problems? Is it correct to assume there is never a role for methylene blue? Is there anything else I need to tell this patient?
How would you respond? Email us at [email protected].
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.
