Dr. Kantarjian Shares His Thoughts on Optimizing the Treatment of Adults With ALL

In the treatment of adults with acute lymphoblastic leukemia (ALL), use of newer antibodies and de-intensification of chemotherapy have greatly improved outcomes, according to Hagop ­Kantarjian, MD, who has been very involved in much of the research in ALL treatment. Dr. Kantarjian, Professor and Chair of the Department of Leukemia at The University of Texas MD Anderson Cancer Center and the Samsung Distinguished Leukemia Chair in Cancer Medicine, described what he considers the optimal approach to adult ALL at the 2020 Debates and Didactics in Hematology and Oncology Virtual Conference, sponsored by Emory University Winship Cancer Institute.¹

Hagop ­Kantarjian, MD

With current chemotherapy regimens, cure is possible for nearly 80% of children but only about 50% of adults with ALL, he noted. “This figure cannot be improved upon with further intensification of chemotherapy; therefore, we need to find other approaches that will increase cure rates to those of childhood ALL,” Dr. Kantarjian said.

One reason for the discrepancy is that adults are more likely to have Philadelphia chromosome–positive (Ph+) ALL and Philadelphia-like (Ph-like) ALL—subtypes with generally poor prognoses. Recent successes are being observed, however, by adding newer agents to chemotherapy:

• Tyrosine kinase inhibitors in Ph-positive ALL
• Rituximab in Burkitt lymphoma and precursor B-cell ALL
• The anti-CD19–directed CD3-bispecific T-cell engager antibody blinatumomab and the CD22 monoclonal antibody drug conjugate inotuzumab ozogamicin in salvage and front-line treatments
• Chimeric antigen receptor T-cell therapy (though not given with chemotherapy and still largely confined to the salvage setting).

Approximately 25% to 30% of adults with ALL have the Ph-like subtype. In these patients, treatment is tailored according to certain molecular findings. In general, Dr. Kantarjian treats patients with Ph-like ALL the same as those with Ph+ ALL if they have ABL translocations and thus are candidates for BCR-ABL inhibitors and by using the combination of chemotherapy and blinatumomab/inotuzumab in patients who do not have the ABL translocations.

Hyper-CVAD: Mainstay Treatment in ALL

the Hyper-CVAD regimen (cyclophosphamide, vincristine, doxorubicin, dexamethasone with methotrexate and cytarabine) remains a mainstay of ALL treatment, but it can be difficult to complete. Dr. Kantarjian and his team recently published their approach to hyper-CVAD,² which may prevent some of the more common complications:

• Give even-numbered courses of methotrexate at 750 mg/m² and cytarabine at 2 g/m² and dose-adjust for older patients.
• Check creatinine level after methotrexate; if it is increased (> 1.4 mg/dL), hold the cytarabine to avoid renal failure and cerebellar toxicity.
• Prescribe vincristine as a 2-mg flat dose (not 2 mg/m²); if severe constipation or neuropathy occurs, omit vincristine.
• Administer infection prophylaxis with levofloxacin or cefpodoxime; posaconazole or voriconazole; and valacyclovir. Hold azoles on days –1, 0, and +1 of vincristine to avoid excess neurotoxicity.
• Switch intrathecal methotrexate on day 2 to cytarabine in even-numbered courses to avoid neurotoxicity.

Tyrosine Kinase Inhibitors in Ph+ ALL

Historically, Ph+ ALL was almost incurable without allogeneic stem cell transplantation; and even then, only 30% to 40% of patients were cured. The introduction of BCR-ABL tyrosine kinase inhibitors changed these outcomes.

Hyper-CVAD plus ponatinib is the recommended treatment, with ponatinib given at 30 mg/d (after 45 mg/d for the first cycle) to avoid cardiovascular problems; the dose is further reduced to 15 mg/d after complete molecular response is achieved. After eight cycles of hyper-CVAD plus methotrexate/cytarabine and ponatinib, maintenance includes ponatinib plus vincristine and prednisone. Intrathecal prophylaxis (two doses per course for six courses) is recommended to protect against relapse in the central nervous system.

With this approach, achievement of complete response and minimal residual disease (MRD) negativity is virtually “universal” in patients treated at MD Anderson, stated Dr. Kantarjian. The incidence of complete molecular response (which allows patients to avoid transplantation) is approximately 85%,

“Ponatinib plus blinatumomab may constitute a nonchemotherapy regimen that could be curative in Ph+ ALL.”

— Hagop Kantarjian, MD

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and the 5-year survival rate is “extremely positive” at 76%,³ he added. Of note, because the mortality risk associated with transplant is avoided, nontransplant patients have better overall survival at 5 years (83%) than those who undergo transplantation (66%).

Among the BRC-ABL inhibitors, ponatinib is considered to be superior, according to Dr. Kantarjian, based on higher rates of complete remission and survival. “No doubt, from sequential studies at our institution, ponatinib is a major contributor to improving outcomes in Ph+ ALL,” he commented.

Blinatumomab and Inotuzumab

“However, the story doesn’t stop there,” Dr. Kantarjian continued. “Now we know that both blinatumomab and inotuzumab as single agents in relapsed or refractory Ph+ ALL are superior to chemotherapy, producing marrow complete response rates of around 35% (blinatumomab) to 66% (inotuzumab). The next step is to combine these drugs with ponatinib…hoping we can cure Ph+ ALL without chemotherapy and without allogeneic transplantation.”

In a study of 63 patients, dasatinib combined with blinatumomab yielded a complete molecular response rate of around 41% but an overall survival rate of more than 90% at 1.5 years.⁴ This can no doubt be improved upon by using ponatinib, which is not impeded by resistance driven by the T315I mutation, Dr. Kantarjian noted. Ponatinib plus blinatumomab may constitute a nonchemotherapy regimen that could be curative in Ph+ ALL, he predicted.

Precursor B-Cell ALL: The Other 75%

In precursor B-cell ALL, the combination of hyper-CVAD and rituximab improves survival. More robust anti-CD20 antibodies will likely bring the cure rate into the 80% range, suggested Dr. Kantarjian.

Recently, pediatric-inspired regimens became a new standard of care in the treatment of young adults. Using this approach, Stock et al reported in 2019 a complete remission rate of 89%, a 3-year survival rate of 73%, and an estimated 5-year survival of 60%.⁵

Dr. Kantarjian maintained, however, that hyper-CVAD is at least as effective. “We’ve used the pediatric-inspired regimens at our institution. Compared with hyper-CVAD, we don’t see a difference in survival. In fact, the complete remission rate is almost the same, if not slightly better, with hyper-CVAD, so we recently returned to using hyper-CVAD, which you can use in patients up to age 60, not just age 40,” he added.

His group has also replaced rituximab with ofatumumab (plus hyper-CVAD), as described in their study of 69 ­patients with Ph-negative CD20-positive B-cell ALL.⁶ The remission rate was 98%, the MRD negativity rate was 93%, and the 4-year overall survival rate was 68%, rising to 74% among patients younger than age 40. “We are pretty happy with the hyper-CVAD–based regimen,” he said, adding that ofatumumab appears superior to rituximab, based on historical data.

More recently, his team has incorporated blinatumomab into the hyper-CVAD regimen. Instead of eight courses of intensive chemotherapy, the patient receives four cycles, and blinatumomab is added after the fourth cycle for four courses. Maintenance is given for 1 year, and blinatumomab is intermittently re-introduced. This approach has yielded “universal” complete remissions, an MRD negativity rate of 97%, and a 3-year estimated survival close to 86%.⁷

Do All Patients Still Need Transplant?

Despite these advances, some patients will still need allogeneic transplants: those with mixed-lineage leukemia or the KMT2A rearrangement, early T-cell precursor ALL (ETP-ALL), and uncommon entities of complex karyotypes and low hypodiploidy/tetraploidy. “At MD Anderson, we generally reserve transplant in Ph+ ALL to patients whose disease remains positive by polymerase chain reaction and in Ph-like ALL to patients who remain MRD-positive,” Dr. Kantarjian noted. “We often add blinatumo­mab or inotuzumab before considering transplantation.”

Blinatumomab/Inotuzumab
Plus Chemotherapy

In an effort to gain as much benefit as possible from blinatumomab and inotuzumab, one idea is to combine them with chemotherapy. Dr. Kantarjian and his team are using “mini–hyper-CVD” plus both drugs in a regimen with lower-intensity chemotherapy, which seems to be better tolerated by older patients:

• Dose-reduced hyper-CVD for four courses
• Cyclophosphamide (150 mg/m² × 6), 50% dose reduction
• Dexamethasone (20 mg), 50% dose reduction
• No anthracycline
• Methotrexate (250 mg/m²), 75% dose reduction
• Cytarabine (0.5 g/m²), 83% dose reduction
• Inotuzumab dose modified to 0.9 mg/m² first course (0.6 on day 1 and 0.3 on day 8) and 0.6 mg/m² for courses 2, 3, and 4 (0.3 on day 1, 0.3 on day 8)
• Rituximab on days 2 and 8 (first four courses) for patients who have CD20-positive disease
• Intrathecal chemotherapy on days 2 and 8 (first four courses)
• Blinatumomab for four courses during consolidation and four courses during maintenance
• One year of maintenance (not 3 years) with 6-mercaptopurine, vincristine, methotrexate, prednisone).

Using a slightly modified mini–hyper-CVD regimen, the MD Anderson group achieved excellent outcomes incorporating inotuzumab and blinatumomab in a study of 70 elderly patients (median age = 78 years).⁸ Responses were achieved by 98%; complete responses, by 88%; and MRD negativity, by 96%, with an “amazing” 5-year survival rate exceeding 50%, similar to outcomes in younger patients, Dr. Kantarjian noted.

Further refinements to these combination approaches are underway. They include more modifications of schedules and incorporation of new agents such as BCL2 inhibitors. ν

DISCLOSURE: Dr. Kantarjian has received honoraria from AbbVie, Actinium, Agios, Amgen, Ariad, Bristol Myers Squibb, Immunogen, Orsenix, Pfizer, and Takeda; and has received institutional research funding from AbbVie, Agios, Amgen, Ariad, Astex Pharmaceuticals, Bristol Myers Squibb, Cyclacel, Immunogen, Jazz Pharmaceuticals, Novartis, and Pfizer.

REFERENCES

1. Kantarjian H: Progress in frontline ALL therapy: Adding targeted agents to chemotherapy. 2020 Debates and Didactics in Hematology and Oncology Virtual Conference. Presented July 16, 2020.

2. Rausch CR, Jabbour EJ, Kantarjian HM, et al: Optimizing the use of the hyperCVAD regimen. Cancer 126:1152-1160, 2020.

3. Short NJ, Kantarjian HM, Ravandi F, et al: Long-term safety and efficacy of hyper-CVAD plus ponatinib as frontline therapy for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 134:283, 2019.

4. Chiaretti S, Bassan R, Vitale A, et al: A dasatinib-blinatumomab combination for the front-line treatment of adult Ph+ ALL patients: Preliminary results of the GIMEMA LAL2116 D-ALBA trial, on behalf of the GIMEMA Acute Leukemia Working Party. 2019 European Hematology Association Annual Congress. Abstract S1617. Presented June 16, 2019.

5. Stock W, Luger SM, Advani A, et al: A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: Results of CALGB 10403. Blood 133:1548-1559, 2019.

6. Jabbour E, Richard-Carpentier G, Sasaki Y, et al: Hyper-CVAD regimen in combination with ofatumumab as frontline therapy for adults with Philadelphia chromosome-negative B-cell acute lymphoblastic leukaemia: A single-arm, phase II trial. Lancet Haematol 7:e523-e533, 2020.

7. Richard-Carpentier G, Kantarjian HM, Short NJ, et al: Updated results from the phase II study of hyper-CVAD in sequential combination with blinatumomab in newly diagnosed adults with B-cell acute lymphoblastic leukemia. Blood 134:3807, 2019.

8. Sasaki K, Kantarjian HM, Ravandi F, et al: Sequential combination of inotuzumab ozaogamicin with low-intensity chemotherapy (mini-hyper-CVD) with or without blinatumomab is highly effective in patients with Philadelphia chromosome-negative acute lymphoblastic leukemia in first relapse. Blood 134:3806, 2019.