Novel Agents Change the Treatment of Acute Lymphoblastic Leukemia

Mark R. Litzow, MD

Significant advances continue to improve the outcome for patients aged 40 years and older with acute lymphoblastic leukemia (ALL). During an OncLive Peer Exchange^® moderated by Mark R. Litzow, MD, a panel of experts discussed the latest data on several novel agents for ALL and provided insights on how to align these treatments in challenging settings.

Tyrosine Kinase Inhibitors in Frontline Ph+ ALL

ALL (also called acute lymphocytic leukemia) is a rare cancer, with an estimated 5960 new cases anticipated in 2018.¹ It is most common in children, adolescents, and young adults (aged 15-39 years), with a median age of onset of 15 years.¹ Cure rates are high for children, with 98% of pediatric patients achieving remission; approximately 85% of those aged 1 to 18 years with newly diagnosed ALL can expect to become long-term event-free survivors.² However, patients aged 60 years or older with ALL continue to have poor survival rates, and there is a gray area for how to treat patients aged 40 to 60 years.From 20% to 30% of adult patients have Philadelphia chromosome—positive (Ph+) ALL, which has been associated with a poorer prognosis than Philadelphia chromosome–negative (Ph-) ALL.³ “The game changers in the treatment of this subtype of ALL have been the tyrosine kinase inhibitors [TKIs],” Litzow said. “Certainly, imatinib [Gleevec] has been the first agent that was tested in this subset of patients, but most of the tyrosine kinase inhibitors have now been tested in 1 form or another.” The panelists noted that more potent TKIs, such as dasatinib (Sprycel) and ponatinib (Iclusig), are now preferred over imatinib because of their superior response rates.

Allogeneic stem cell transplantation (ASCT) and chemotherapy are other cornerstones of Ph+ ALL therapy, but not all patients are candidates, such as the elderly or otherwise frail or unfit patients, who are at greater risk of treatment- related complications and toxicities. Recent evidence suggests that ASCT or chemotherapy could be avoided under certain circumstances without significantly worse outcomes.

“Our pediatric colleagues have relied primarily on the use of imatinib, and some of their studies have suggested that if pediatric patients with Ph+ ALL achieve MRD [minimal residual disease] negativity, becoming BCR-ABL—negative, they don’t appear to need a transplant, and their outcomes are similar to what’s seen with either a matched related or unrelated donor,” Litzow said. He noted that similar findings have yet to be definitively demonstrated in adults.

Chemotherapy for Ph+ ALL often uses a hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) regimen, with a TKI added, but Italian researchers have shown that using a TKI with corticosteroids and central nervous system prophylaxis can achieve a high rate of complete hematologic response, although complete molecular response (CMR) is lower without chemotherapy. In an initial study that used dasatinib, there was a CMR of about 20%, Litzow said.

More recently, the same investigators reported the results of their multicenter phase II study that assessed the safety and efficacy of steroids plus ponatinib alone for elderly or unfit patients with Ph+ ALL.⁴ The primary endpoint of complete hematologic response (CHR) was prematurely reached, with 40 of 42 patients (95.2%) achieving CHR after 1 treatment course. After 8 courses, 38 patients (90.5%) were in CHR. The remaining 4 patients dropped out of the study because of disease relapse (n = 1), excessive toxicity (n = 1), or medical reasons (n = 2). A CMR was observed in 11 of 24 patients at 24 weeks (45.8%), with the remaining 14 of 38 patients being unevaluable.

“Ponatinib seems to have particularly robust activity in ALL,” Aaron C. Logan, MD, PhD, said. He discussed an MD Anderson Cancer Center study that added ponatinib to hyper-CVAD.⁵ The 3-year continued remission and overall survival (OS) rates with this regimen were 79% and 76%, respectively. Furthermore, analysis at 4 months showed that cytogenetic response duration and OS did not differ significantly in patients with or without ASCT. “If we can add [ponatinib] to backbones like hyper-CVAD and other regimens and get outcomes that rival those that we see in children, then perhaps we don’t need to transplant the Ph+ population anymore,” Logan said.

The panelists concluded that using TKI inhibitors with steroids alone is most appropriate for frail, elderly patients and others who may not be fit for transplant, because they are better able to tolerate such treatments, which could help them achieve hematological remission. For more robust patients, hyper-CVAD or transplantation remain important options, with a goal to achieve a CMR.

Moving Ponatinib to the Frontline

The panelists did not agree on whether they would use ponatinib in the frontline setting, despite current promising data. “The practical implication about trying to use ponatinib in the frontline setting is the fact that it’s only approved for relapsed/refractory ALL,” Ryan D. Cassaday, MD, said. “[Although] the studies that are ongoing may be able to change how we’re able to prescribe it, right now there may be some challenges outside the context of a clinical trial, unless a patient wants to pay for it out-of-pocket.”

“My big concern is what to do after ponatinib,” Bijal D. Shah, MD, said. “I’m one of those stalwarts—I’m still using dasatinib and hyper- CVAD induction. I try to get as much mileage as I can out of a second-generation TKI. If I fail to achieve a good molecular endpoint with my TKI in preparation for allotransplant, that’s when I’ll consider moving to ponatinib, almost as a bridge to try [to] get them there.” Cassaday said he follows a similar approach.

In contrast, Logan said he is comfortable using ponatinib in the frontline, provided that payers allow it. “I would say that although I used to agree with saving ponatinib in case patients fail a second-generation TKI, I’m now reluctant to pull that punch because I think we have options for relapsed/refractory, even Ph+, disease with some of the newer agents,” he said. “You may not necessarily need to rely on ponatinib to get them back into remission.”

Using Novel Agents for Relapsed/Refractory ALL

Anthony S. Stein, MD, was also on board with a potential switch from dasatinib to ponatinib in the frontline. “My only concern is, as we treat more patients with ponatinib, are we going to get more vascular complications?” he asked. He suggested a possible way to overcome these toxicities: “Start with 45 mg and then, after 1 cycle, bring the dose down to 30 mg and 15 mg, not keeping patients at 45 mg continuously.” Blinatumomab

A key agent that has emerged in the relapsed/ refractory ALL setting is blinatumomab (Blincyto), a bispecific monoclonal antibody construct that enables CD3-positive T cells to recognize and eliminate CD19-positive acute ALL blasts.⁶ A blinatumomab treatment course includes up to 2 cycles of induction, 3 of consolidation, and up to 4 of continued therapy, with dosing based on patient weight. In December 2014, blinatumomab received accelerated approval for the treatment of Ph- relapsed or refractory B-cell precursor ALL, and it was granted regular approval for this indication in July 2017.⁷ At that time, its indication was also expanded to include Ph+ B-cell precursor ALL.7 Most recently, in March 2018, the FDA granted accelerated approval to blinatumomab for the treatment of adult and pediatric patients with B-cell precursor ALL who are in remission but have MRD.⁸

“Similar to the story in Ph- ALL, in general, blinatumomab works really well for people with low-burden disease,” Cassaday said. “It doesn’t work particularly well in people with highburden disease.”

Litzow elaborated: “If you have <50% [blasts], there’s a greater likelihood that you’re going to respond to blinatumomab.”

The panelists noted that blinatumomab also has shown a suboptimal response in extramedullary disease. “I’ve had very limited success with blinatumomab in that setting,” Shah said.

Logan reported having a similar experience. “I’ve definitely had patients who had responses in their peripheral blood and their marrow, but the tumor mass in the retroperitoneum, or wherever it was, is still hot on the PET [positron emission tomography] scan when you look again. That’s particularly problematic,” he said.

The panelists discussed several approaches for dealing with such challenges. “[In patients with high disease burden], I might try a TKI plus or minus chemotherapy to get a little bit of disease control, then maybe come in on the back end with blinatumomab,” Cassaday said. “If they’re a transplant candidate, I’d use it as a bridge. If they’re not, I’d maybe just try to string things along for as long as I can.”

Shah has used a similar approach in the extramedullary disease setting. “That may be a situation where during the 2-week break [between cycles], I’ll integrate something like Marqibo [vincristine] or—in the case of Ph+ ALL, if they weren’t getting it concurrently with a TKI— integrate a TKI,” he said. Logan suggested that use of inotuzumab ozogamicin (Besponsa) might be favorable in patients with extramedullary disease but noted the sparsity of supportive data.

Inotuzumab Ozogamicin

Inotuzumab ozogamicin is an antibody—drug conjugate composed of a monoclonal antibody that targets CD22, which is expressed on leukemic blasts in >90% of ALL patients.^9,10 It was approved by the FDA in August 2017 for the treatment of adults with relapsed or refractory B-cell precursor ALL.¹¹ Approval was based on the results of the phase III INO-VATE ALL study, which compared inotuzumab ozogamicin with standard intensive chemotherapy according to investigator’s choice.¹² Of the initial 218 randomized patients, 35.8% in the inotuzumab ozogamicin group had a complete remission for a median of 8.0 months, with 89.7% of those patients achieving MRD-negativity. In contrast, 17.4% of patients in the chemotherapy group had a complete remission for a median 4.9 months, 31.6% of whom achieved MRD-negativity.

Although inotuzumab ozogamicin appears to be more effective than the standard-of-care chemotherapy options that were assessed, significant room for improvement remains, Cassaday said. “Where it starts to get a little bit less optimistic is when you start to actually look at the survival outcomes for the patients who were treated on that study,” he said. In the study, the median OS was improved by just 1 month with inotuzumab ozogamicin (7.7 vs 6.7 months for chemotherapy).

To improve these results, various studies are assessing inotuzumab ozogamicin as part of a combination therapy strategy in the first- and subsequent-line settings. In an MD Anderson study that combined inotuzumab ozogamicin with mini hyper-CVD as a salvage therapy for relapsed/refractory ALL, 77% of patients responded to this regimen, with 59% achieving a complete response.¹³ “The challenge is that there’s still a nontrivial amount of toxicity,” he said, noting that veno-occlusive disease has been observed even outside the context of ASCT.

“One of my concerns is that many providers may reach for inotuzumab because it has some favorable features, such as its ease of administration,” Logan said. “I think we just need to urge our colleagues to really think about whether that drug is the right therapy for their patient and to really think about their prior liver toxicities and whether they have ongoing liver abnormalities, especially if they’re en route to a transplant. You don’t want to ruin that 1 opportunity they have for a cure, which right now is going to be that transplant,” he said.

CAR T-cell Therapy

Although it is not yet approved in older patients with ALL, chimeric antigen receptor (CAR) T-cell therapy is generating excitement for its efficacy in pediatric and young adult patients. Tisagenlecleucel (Kymriah) was approved by the FDA in August 2017 for treating patients up to age 25 years with B-cell precursor ALL that is refractory or in its second or later relapse. However, there are limited data on how this treatment could be beneficial in older adults.

“What we lack in the adult space is information to guide us on the durability of that response,” Shah said. “We need that before we can really understand how we integrate this not just for relapsed/refractory disease, but as a consolidation perhaps following an induction for those MRD-positive patients and perhaps even MRD-negative patients.”

The toxicity profile for this treatment is also problematic for patients 60 years or older. The adverse events associated with tisagenlecleucel can include cytokine release syndrome, hypotension, edema, thrombocytopenia, and neutropenia, according to the phase II ELIANA clinical trial.¹⁴

Concluding Thoughts

Logan noted that although the development of CAR T-cell therapy is exciting, it currently requires “extreme expertise” to administer the therapy to patients. “I don’t think that 10 years from now that this is the format that CAR T cells will have. I think there’s going to be innovation in our ability to control the activity of those cells, so that if we start to recognize higher grade neurotoxicity, we’ll be able to augment the activity of those cells so that we put them in a quiescent state, deal with the toxicity in real time, and then turn them back on,” he said.To conclude the OncLive Peer Exchange^®, the panelists expressed overall optimism about the future development of ALL treatment. “I’m excited about all of the new agents, not only because we can capture some of our relapsed/refractory patients for whom chemotherapy didn’t work, but also because of this prospect that maybe we can achieve that goal of chemotherapy-free induction, maintenance, and consolidation—and maybe eliminate transplant for even some of the high-risk patients,” Logan said. Shah expressed similar sentiments: “I think what we’re all saying is that we’re excited that we get to personalize therapy for our patients with nonchemotherapeutic options that have a potential to very meaningfully [affect] their survival.”

References

1. Cancer stat facts: leukemia — acute lymphocytic leukemia (ALL). National Cancer Institute website. seer.cancer.gov/statfacts/html/alyl.html. Accessed May 4, 2018.
2. Childhood acute lymphoblastic leukemia treatment (PDQ®)—health professional version. National Cancer Institute website. cancer.gov/types/leukemia/hp/child-all-treatment-pdq. Updated April 5, 2018. Accessed May 4, 2018.
3. Liu-Dumlao T, Kantarjian H, Thomas DA, O’Brien S, Ravandi F. Philadelphia-positive acute lymphoblastic leukemia: current treatment options. Curr Oncol Rep. 2012;14(5):387-394. doi: 10.1007/s11912-012-0247-7.
4. Martinelli G, Piciocchi A, Papayannidis C, et al. First report of the Gimema LAL1811 phase II prospective study of the combination of steroids with ponatinib as frontline therapy of elderly or unfit patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2017;130(suppl 1):99.
5. Short NJ, Kantarjian HM, Ravandi F, et al. Frontline hyper-CVAD plus ponatinib for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: updated results of a phase II study. J Clin Oncol. 2017;35(suppl 15):7013. http://ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.7013.
6. Kantarjian H, Stein A, Gökbuget N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376(9):836-847. doi: 10.1056/NEJMoa1609783.
7. FDA grants regular approval to blinatumomab and expands indication to include Philadelphia chromosome-positive B cell. FDA website. fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm566708.htm. Updated July 12, 2107. Accessed May 4, 2018.
8. FDA approves inotuzumab ozogamicin for relapsed or refractory B-cell precursor ALL. FDA website. fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm572133.htm. Updated August 17, 2017. Accessed May 4, 2018.
9. BESPONSA (inotuzumab ozogamicin): fact sheet. Pfizer website. pfizer.com/files/news/asco/BESPONSA_Fact_Sheet_08_17_17.pdf. Published August 2017. Accessed May 4, 2018.
10. Uy N, Nadeau M, Stahl M, Zeidan AM. Inotuzumab ozogamicin in the treatment of relapsed/refractory acute B cell lymphoblastic leukemia. J Blood Med. 2018;9:67-74. doi: 10.2147/JBM.S136575.
11. FDA expands approval of Blincyto for treatment of a type of leukemia in patients who have a certain risk factor for relapse [press release]. Silver Spring, MD: FDA; March 29, 2018. fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm603151.htm. Accessed May 4, 2018.
12. Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016;375(8):740-753. doi: 10.1056/NEJMoa1509277. 13. Assi R, Kantarjian HM, Khouri R, et al. Updated results of the phase II trial of inotuzumab ozogamicin (INO) combined with mini-hyper-CVD as salvage therapy for relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). Blood. 2017;130(suppl 1): 2597.
13. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439-448. doi: 10.1056/NEJMoa1709866.