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Taking a BiTE Out of ALL
Taking a BiTE Out of ALL

Released: October 16, 2015

Expiration: October 14, 2016

Elias Jabbour
Elias Jabbour, MD
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I recently saw a patient with relapsed ALL who illustrates the challenges of this disease, along with the new immunotherapeutic approaches available to these patients. Currently, even though 80% of adult patients with ALL achieve a CR to first-line therapy, less than 50% will achieve long-term remission and most will eventually relapse.

Managing a Patient With Relapsed ALL
A 30-year-old man came into my clinic with fever and fatigue. He had no previous medical history and stated that he did not smoke or drink alcohol and that he had no allergies. A complete blood count showed pancytopenia, with hemoglobin of 9 g/dL, white blood cell count of 1800 cells/mm3, and platelet count of 40,000 cells/mm3. His bone marrow biopsy showed 90% blasts and was MPO negative, CD10 positive, CD20 positive, and CD19 positive. His karyotype was found to be diploid. He was diagnosed as having ALL and was started on R-hyperCVAD induction chemotherapy. After his initial therapy, he achieved CR and was found to be MRD negative. Then he received 7 subsequent courses of hyperCVAD, alternating with methotrexate and cytarabine. In addition, he had 8 doses of intrathecal chemotherapy for CNS prophylactic therapy. At the end of the consolidation, he was placed on maintenance with POMP (mercaptopurine, vincristine, methotrexate, and prednisone). He received the consolidation and maintenance therapy for 2.5 years and did extremely well, remaining in remission for 4 years.

At the time of relapse, he presented with fatigue and pancytopenia again. So, augmented hyperCVAD (an asparaginase-based regimen) was initiated. He achieved a second CR and was deemed MRD negative by flow cytometry after cycle 2. However, he did have somewhat increased LFTs due to the asparaginase component of his treatment but recovered nicely. The patient then received a transplantation from an unrelated donor with a conditioning regimen of clofarabine and busulfan after induction treatment. He had some complications; most notably grade 2 acute GVHD, but overall did well after transplantation.

He recovered and maintained his second remission for 22 months before presenting with cytopenias again. A repeat bone marrow biopsy showed relapse of his disease: His karyotype remained diploid and his phenotype was the same, CD19 positive. Therefore, we gave him blinatumomab as a second salvage.

Blinatumomab
Blinatumomab is a bispecific antibody (BiTE), meaning that it has 2 binding targets: CD3 on T cells and CD19 on the tumor cells. This first-in-class treatment brings the T cells in close proximity to kill CD19-positive B cells. Blinatumomab was approved by the FDA based on a multicenter phase II trial showing efficacy in patients with ALL who have progressive disease after multiple agents. In the phase II trial, 43% of patients achieved CR or CR with incomplete hematologic recovery, with 40% going on to allogeneic SCT. Unfortunately, these responses do not seem to be durable so far, with a median OS of 6.1 months.

There are a few issues to consider with blinatumomab—first, the administration and, to a lesser extent, the cost. The administration of blinatumomab requires some logistical considerations. Each cycle of blinatumomab treatment is 6 weeks in duration, with 4 weeks of continuous blinatumomab infusion followed by a 2-week treatment-free interval. Due to safety concerns, including potential cytokine release syndrome and CNS events, the initial dose of blinatumomab is 9 μg/day for the first 7 days of treatment and then can be dose escalated up to 28 μg/day starting on Day 8 (Week 2) through Day 28 (Week 4). For all subsequent cycles, 28 μg/day is used. The cost of blinatumomab may also be a consideration for many patients. In general, I use blinatumomab with an intent to cure my patients—like in this case where I gave a transplantation after treatment to secure a favorable long-term outcome—which makes the cost of this agent worth every penny.

Patient Case Resolution
At the beginning of blinatumomab treatment, our patient experienced some fever, which resolved with dexamethasone. At the end of his first cycle at Week 4, he achieved a bone marrow CR. At Week 6, he recovered his count, showed a CR, and was MRD negative. He received a subsequent cycle of blinatumomab and maintained his remission along with MRD negativity. This patient then received a second allogeneic transplantation from a different donor, and he remains in remission as of today.

Current Role of Blinatumomab in the Clinic
Although I used this patient case as an example, based on available data, blinatumomab should be considered earlier in the course of relapsed disease. At the time I saw this patient in first relapse, we did not have blinatumomab available in the clinic, but now we know that the efficacy of blinatumomab can be greater when used earlier. Additional data in patients with a CR to their previous therapy, but with persistent MRD showed that 78% converted to MRD-negative status after 1 cycle of blinatumomab treatment (Capsule Summary).

Of importance, blinatumomab is the only nonchemotherapeutic agent available to us that is FDA approved in this setting. Compared with other available agents—like clofarabine, nelarabine for T cells, and liposomal vincristine—blinatumomab is the best option as a single agent. It also allows for the potential to achieve MRD negativity and option of transplantation, which is not typically the case for the other drugs available. Currently, blinatumomab is the best option for eligible patients.

Looking to the Future
There are also other new generation bispecific antibodies that may be interesting in the future, but these agents are still in their infancy. Other therapeutics such as the anti-CD22 antibody–drug conjugate inotuzumab ozogamicin and CD19-targeted CAR-T cells may also soon be available for patients with ALL.

Your thoughts?
Have you used blinatumomab in your clinical practice? What has been your experience with this agent? I have received some questions from physicians using blinatumomab in clinical practice, including questions on when to use it in combination or as a single agent, and how to manage adverse events that can occur.

ALL is not a common disease, and blinatumomab is a new, first-in-class agent, so there is a definite learning curve involved. However, I always advocate for my colleagues to call if I can be of any help because we do have experience using this agent.

Please see my next post on managing potential adverse events with immunotherapy in ALL.

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If you have not used blinatumomab, what is the most important reason for not doing so?
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