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Immunotherapeutic Combos for Leukemia/Lymphoma
New Immunotherapeutic Combinations for Hematologic Malignancies

Released: February 26, 2016

Expiration: February 24, 2017

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Authors: Jonathan Webster, MD, and B. Douglas Smith, MD

Case
The patient is a 57 year-old male with Ph-negative pre-B acute lymphoblastic leukemia (ALL) with normal cytogenetics and negative CNS studies at diagnosis. He was initially treated with a dose-intensive regimen of 8 alternating courses of hyper-CVAD with high-dose methotrexate and cytarabine and intrathecal prophylaxis. He achieved CR and received maintenance with POMP (6-mercaptopurine, vincristine, methotrexate, and prednisone) but relapsed after 9 months of maintenance. He underwent reinduction with FLAG-IDA (high-dose cytarabine and fludarabine with G-CSF in combination with idarubicin) but did not achieve a remission. His performance status is ECOG 0.

Treatment Paradigms for ALL
Treatment paradigms for patients with ALL are evolving, and multiple, reasonable strategies exist to achieve a second CR. Most clinicians agree that the patient will ultimately need an allogeneic hematopoietic stem cell transplantation to have the best chance to maintain a durable response in this setting, but he must achieve a remission before proceeding to transplantation. Unfortunately, resistance is a hallmark of relapsed ALL, and salvage regimens have historically been limited in their success in early treatment failures. Recently, immunotherapies such as chimeric antigen receptor (CAR) T cells and blinatumomab have demonstrated great promise in harnessing the immune system to achieve remissions in a significant subset of patients with relapsed/refractory ALL. Although traditional chemotherapy-based salvage regimens have variable remission rates in relapsed/refractory ALL, reported remission rates with blinatumomab and CAR T cells in this setting are 43% and 84%, respectively. Liposomal vincristine is approved for second relapse and beyond based on a more modest ORR of 35%. However, the longer-term success of these novel agents is limited, not unlike chemotherapy, as the emergence of drug resistance has been seen. Many groups are now focusing on ways to prolong and increase responses to such immunotherapy approaches through combinations that may overcome resistance mechanisms. For patients with relapsed/refractory ALL, the NCCN recommends consideration of a clinical trial for eligible patients. The following is a brief summary of strategies for novel combination approaches in development for clinical trials in hematologic malignancies.

Blinatumomab Plus Immune Checkpoint Inhibitors 
Blinatumomab is a bispecific T-cell engager antibody construct with dual affinity for CD19 and CD3, which serves to bring CD19+ tumor cells in close contact with CD3+ cytotoxic T cells that can attack and eliminate the tumor cells. Blinatumomab is approved by the FDA for treatment of Ph-negative relapsed or refractory ALL based on the data mentioned above. However, relapses following blinatumomab treatment do occur and have been attributed to poor drug penetration into extramedullary sites and loss of expression of the drug target CD19 on tumor cells. The recent work of Köhnke and colleagues has suggested that another mechanism of blinatumomab resistance in patients who retain CD19 expression is the upregulation of the immune checkpoint PD-L1 on tumor cells following blinatumomab treatment leading to the inactivation of cytotoxic T cells. In addition, Feuchtinger and colleagues noted that PD-L1 was more highly expressed on tumor cells from blinatumomab-refractory pediatric ALL and relapsed leukemia patients, which led to the treatment of a single patient with blinatumomab and the PD-1 inhibitor pembrolizumab. Based on these data, combination approaches using blinatumomab and immune checkpoint inhibitors will soon be the subject of clinical trials.

CAR T Cells Plus Immune Checkpoint Inhibitors
Using CAR T cells, the patient-derived T cells engineered to express a receptor that specifically targets an antigen commonly expressed on tumor cells such as CD19 in B-cell malignancies, is a promising new approach for hematologic malignancies. Primary resistance to CAR T cells is much less common than resistance to blinatumomab in patients with relapsed/refractory ALL. However, when this does occur, the activation of immune checkpoints including PD-1 and TIM3 have been implicated in this setting as well. This suggests that combining immune checkpoint inhibition with CAR T cells may lead to even higher response rates. In lymphoma, where responses to CAR T cells are more modest, there is already a pending clinical trial investigating the addition of the immune checkpoint inhibitor ipilimumab to treatment with CAR T cells in an effort to augment the immune response.

CAR T-Cell Combinations
Similar to blinatumomab, a well-characterized mechanism of relapse following the induction of remission with CAR T cells is loss of expression of the target antigen on tumor cells or early depletion of the CAR T cells. One potential means of overcoming this resistance would be to infuse 2 separate types of CAR T cells with distinct target antigens, such as CD19 and CD123 or CD19 and CD22. Notably, the simultaneous delivery of 2 distinct CAR T cells has proven safe in non-Hodgkin lymphoma, although both CAR T cells in this study targeted CD19. Unfortunately, few data currently exist to support the efficacy of CAR T cells with targets other than CD19, and any studies of combined approaches will likely need to wait until a successful alternative target is validated. There are already a number of trials investigating CAR T cells targeting CD22 in B-cell malignancies, adult ALL, and pediatric ALL; CD22 has previously proven to be a successful target using the drug–antibody conjugate inotuzumab ozogamicin.

Final Thoughts
The evolution of immunotherapy for treating hematologic malignancies is exciting, and based on current data, clinical trials of combination approaches should be considered for eligible patients. In my practice, we expect to enroll patients with relapsed/refractory ALL on these trials as they become available. If these treatments improve efficacy, as anticipated, without significantly exacerbating toxicities, combination immunotherapy approaches may change the standard of care for relapsed/refractory ALL, as blinatumomab monotherapy has already done.

Please let me know in the comments below what you think about these potential new treatment approaches, or describe how you treat adult patients with relapsed ALL. Do you think these data have the potential to change your clinical practice in the future? Leave a note.

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Given the medical case history presented, how would you treat this patient to achieve a second CR?
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