Doctors Debate: Is Intensive or Low-Intensity Chemotherapy Plus BCR-ABL TKI Therapy Best for Treatment of Ph+ ALL?

Nicholas J. Short, MD

Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) can be treated using either intensive chemotherapy with a BCR-ABL tyrosine kinase inhibitor (TKI) or nonintensive chemotherapy. Which strategy to employ is an ongoing clinical question that affects patients from the front-line to third-line settings.

Sabina Chiaretti, MD, PhD

During the Society of Hematologic Oncology Virtual Annual Meeting, Nicholas J. Short, MD, an assistant professor in the Department of Leukemia at the University of Texas MD Anderson Cancer Center in Houston, argued that intensive chemotherapy combined with a BCR-ABL TKI still holds the place of standard-of-care treatment for Ph+ ALL. Sabina Chiaretti, MD, PhD, a researcher in the Department of Translational and Precision Medicine at Sapienza University in Rome, Italy, made the case that “less is more,” arguing for a targeted approach to managing Ph+ ALL.^1,2

The Standard of Care Remains Relevant

Perhaps the best reason to use the standard-of-care strategy for treating patients with Ph+ ALL is that it is known to improve survival in the front-line setting and has demonstrated increased molecular responses and survival in the second- and third-line settings, Short explained in his presentation. When complete molecular responses (CMRs) are observed with a therapy, Short says, it increases the chance of cure in patients.¹

“The best opportunity to cure someone with newly diagnosed acute leukemia of any type, and in particular, Philadelphia chromosome–positive ALL, is in the frontline setting. It is therefore very important that you choose the frontline regimen appropriately. This an important debate because of the emerging data with lower-intensity regimens that have brought on some desire to treat patients with less chemotherapy,” Short told Targeted Therapies in Oncology (TTO) in an interview.

Understanding How Patients Benefit

Prior to 2016, the impact of CMRs on patients with Ph+ ALL had not yet been defined. Findings from a study conducted by Short and colleagues showed that achieving a CMR at 3 months can potentially identify which patients will have long-term overall survival (OS) and relapse-free survival (RFS) on intensive chemotherapy without stem cell transplant (SCT) compared with those who have lower CMRs at 3 months.³

The study enrolled 202 patients with Ph+ ALL to receive the frontline intensive chemotherapy combination of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD). At 3 months, the OS was 127 months for patients who had higher CMRs compared with 38 months among those with lower CMRs (HR, 0.42; 95% CI, 0.21-0.82; P =.0). Also, at 3 months, the RFS among the higher-CMR population was 26 months versus 18 months for the lower-CMR population (HR, 0.43; 95% CI, 0.21-0.78; P =.01).

Overall, the findings showed that higher CMRs resulted in superior survival, whereas lower CMRs left patients with poor outcomes.

This research laid the groundwork for an understanding of how patients benefit from and which patients have the best responses to intensive chemotherapy.

Patient Outcomes With Intensive Chemotherapy Plus a BCR-ABL TKI

Short previously presented long-term safety and efficacy results from the combination of hyper-CVAD and the third-generation BCR-ABL inhibitor ponatinib (Iclusig) at the 2019 American Society of Hematology (ASH) Annual Meeting. Patients with newly diagnosed Ph+ ALL had sustained responses on this treatment without hematopoietic SCT (HSCT), demonstrating its potential for cure, Short noted.

“The best outcomes that have been reported so far in the literature have been with the combination of intensive chemotherapy with hyper-CVAD plus ponatinib. For the study, we have long-term outcomes data available. There’s a 5-year overall survival rate of 74%, which is better than we see with other tyrosine kinase inhibitors and also better than what we we’ve seen to date with lower-intensity regimens,” Short said.

“This is likely driven by the higher rate of complete molecular response that we see with the combination of intensive chemotherapy plus ponatinib,” he added.

Of the 68 patients evaluated, at a median follow-up of 43 months (range, 2-92), 71% were alive and still in remission at the time of data cutoff. After 3 years, the complete remission (CR) rate observed with the combination was 84%. Patients also achieved an event-free survival (EFS) rate of 70% and OS of 78% with hyper-CVAD plus ponatinib. It was estimated that the 5-year rates for CR, EFS, and OS would be 84%, 68%, and 73%, respectively.⁴

Notably, during this analysis, 11 patients relapsed after a median of 20 months in remission (range, 5-64 months). Three of the patients who relapsed were still receiving ponatinib, but 6 were being treated with another TKI, and 2 were not receiving any TKI. Among those who relapsed while receiving ponatinib, an ABL1 E255K kinase domain mutation was detected in 2 patients, which may have affected outcomes. The remaining patients who were treated with ponatinib but relapsed within 20 months did not have a tumor mutation.

It was also notable that a trend toward improved OS was observed in patients who did not undergo HSCT compared with those who did, according to a landmark analysis. Specifically, the OS rate for patients who did not undergo HSCT was 90% versus 66% for those who did (P=.07).

The safety profile of hyper-CVAD combined with ponatinib was tolerable in the newly diagnosed Ph+ ALL study population. The majority of adverse events (AEs) observed with the combination were grade 1 and 2 in severity. Still, dose reductions were necessary in 37% of patients as a results of AEs. The most common events that occurred were rash (n=7), liver function test abnormalities (n=5), pancreatitis (n=3), deep vein thrombosis (n = 2), and thrombocytopenia (n=2). There were 9 deaths in the study of patients who were in CR. Also, 2 ponatinib-related deaths occurred, leading to a protocol amendment regarding the dose level of the drug. After the amendment, no additional patients died.

Similar efficacy and safety were observed in earlier studies of hyper-CVAD plus a BCR-ABL TKI. First, results of the 2015 study of hyper-CVAD in combination with imatinib (Gleevac; NCT00038610) showed a 93% CR rate in the 45 patients with active disease at the time of enrollment. Additionally, at 5 years, the OS rate with hyper-CVAD plus imatinib was 43%.⁵

Satisfactory outcomes were reported with the intensive chemotherapy and BCR-ABL TKI combination of frontline hyper-CVAD and dasatinib (Sprycel) in patients with Ph+ ALL. Long-term follow-up results from the phase 2 study were published in the journal Cancer. The investigators concluded that the combination is able to achieve long-term remission in patients. In the 72 patients evaluated, the CR rate was 96% and the 5-year OS rate was 46%.⁶

Based on these 2015 data from 2 combinations, the 2019 data presented at ASH confirm the benefit of intensive chemotherapy combined with BCR-ABL TKI therapy, noted Short; however, the study conclusion mentioned that other BCR-ABL TKIs, such as blinatumomab (Blincyto), still must be evaluated in the frontline setting of Ph+ ALL.^1,4

Is There a Role for Low-Intensity Chemotherapy?

To further support his argument around intensive chemotherapy plus TKI therapy, Short reviewed the emerging data of lower-intensity chemotherapy regimens. His overarching point was that the trials are too preliminary to change the current standard of care.

“While I agree that lower-intensity therapies need to be evaluated, my argument is that those are not yet standard of care. There are not enough long-term data for those studies that show promise for treating patients with low-intensity chemotherapy outside of clinical trials,” Short stated during the interview.

Short examined data from the 2007 study of imatinib plus chemotherapy in elderly patients with Ph+ ALL, which showed a superior CR rate compared with induction chemotherapy but did not show a survival benefit. The 1-year OS rate was 74%.⁷ In addition, the 2016 study of dasatinib with low-intensity chemotherapy in elderly patients, as well as the 2019 study of nilotinib (Tasigna) in patients with newly diagnosed Ph+ALL, demonstrated improved cure rates compared with induction therapy, but the OS was not satisfactory.^8,9 Specifically, dasatinib plus low-intensity chemotherapy resulted in a 36% OS at 5 years, and nilotinib plus low-intensity chemotherapy led to a 2-year OS rate of 47%.

The most impressive survival results were observed with low-intensity chemotherapy plus ponatinib in elderly or unfit patients with Ph+ ALL treated in the phase 2 Gimema LAL1811 trial (NCT01641107). The combination led to a 2-year OS rate of 64%, which Short attributed to the higher CMR rate of 46%.¹⁰

After reviewing these data, Short maintained his argument that intensive chemotherapy combined with a BCR-ABL inhibitor is a proven frontline standard of care for Ph+ ALL. The only question that remains, Short told TTO, is whether the ability to skip transplant is an important accomplishment with the regimens.

Low-Intensity Chemotherapy as Ph+ ALL Treatment

Ph+ ALL is of the highest concern in patients 60 years and above. Perhaps due to the age of these patients, the satisfactory outcomes observed with intensive chemotherapy are often cancelled out by the overwhelming toxicity, Chiaretti explained during her presentation. Because of the toxicity of intensive chemotherapy, Chiaretti argues that long-term outcomes for this strategy are unsatisfactory, with ponatinib being the only exception.²

“Today, we are lucky enough to be able to manage our patients with targeted therapies instead of chemotherapy. We should aim to use the best drugs that we have, which are TKIs and targeted therapies. The outstanding question is which are those patients who are at higher risk of relapse, so that we can use the best treatment for those patients,” Chiaretti told TTO in an interview.

Success With Low-Intensity Chemotherapy and TKIs

In terms of low-intensity chemotherapy with a BCR-ABL TKI, the research around the GIMEMA strategy has shown high complete hematological response (CHR) rates, Chiaretti said, beginning with the study of imatinib in combination with steroids and without additional chemotherapy in elderly patients with Ph+ ALL (LAL0201-B; NCT00376467). Of the 30 participants aged 60 to 89 years, 29 were evaluable for response. The CHR rate achieved was 100%.¹¹ Later, in the GIMEMA LAL1205 protocol study (NTC02744768), patients aged 18 to 84 with Ph+ ALL were treated with frontline dasatinib in combination with intrathecal chemotherapy and also achieved a 100% CHR rate.¹²

Chiaretti made note that all the GIMEMA protocols resulted in satisfactory CHR without additional chemotherapy, demonstrating that intensive chemotherapy may no longer be necessary for this patient population.

In the LAL0904 study (NCT00458848), a 96% CHR rate was observed in 49 evaluable patients. The regimen consisted of imatinib plus induction and consolidation chemotherapy in patients aged 16 to 60 years with Ph+ ALL. The treatment was deemed feasible for adult patients with Ph+ ALL based on this protocol.¹³ Similarly, 39 patients with Ph+ ALL 60 years and older in the LAL1408 study (NCT01025505) achieved a CHR rate of 94% on treatment with nilotinib in combination with imatinib. Investigators led by Giovanni Martinelli, MD, concluded that the results of this combination were not different from those observed with single-agent imatinib.¹⁴

For patients 60 years and older in the LAL1811 study, the CHR was 95% with ponatinib. This study confirmed the activity of ponatinib in this patient population.¹⁵

Finally, Chiaretti noted unpublished results from the LAL1509 trial (NCT01361438), which evaluated dasatinib total therapy in patients aged 18 to 60 . The CHR rate was reported as 97%.2 Notably, the safety profile of the drugs evaluated in all these GIMEMA studies were well tolerated.

Homing in on the difference in survival in patients treated with intensive chemotherapy versus de-intensified chemotherapy, intensive chemotherapy appeared to have better rates. Results of a 2012 study showed a 2-year event-free survival of 63% (95% CI, 39%-87%) with de-intensified chemotherapy in 29 patients with Ph+ ALL.¹⁶ In another study of 30 patients, low-intensity chemotherapy with imatinib led to a 5-year EFS rate of 32.1% compared with 42.2% with intensive chemotherapy. The 5-year OS rate in this study was 43% with low-intensity chemotherapy compared with 48.3% with intensive chemotherapy.¹⁷ Chiaretti noted, however, that the CT rate was not significantly different between these studies. Moreover, both responses and survival would be improved upon with a more target treatment approach, Chiaretti said.

Targeted Treatment of Ph+ ALL

Highlighting the results of the Gimema LAL2116 D-ALBA trial of front-line dasatinib in combination with blinatumomab as treatment of adults patients with Ph-ALL (NCT02744768), Chiaretti made the case of targeted therapy without addition of chemotherapy in this patient population.

The study of 63 evaluable patients at a median age of 54.50 years (range, 24.1-81.7 years) achieved a CMR rate of 60.4% (95% CI, 46%-73.5%), meeting the study’s primary end point. Median follow-up was 14.3 months (range, 0.9-25), and the OS rate observed with the amount of follow-up was 95.2% (95% CI; 90.1%-100%). The disease-free survival rate was 89.7% (95% CI, 82.2%-97.9%).¹⁸

In terms of safety, 148 AEs were observed, and 41 serious AEs were observed. The most common AEs included infections and infestations, general disorders, and gastrointestinal disorders.

The key takeaway from Chiaretti’s presentation was that although low-intensity chemotherapy with a TKI is less toxic than intensive chemotherapy, ultimately, patients would have better overall outcomes with chemotherapy removed from the course of treatment: “We don’t want patients to succumb to their disease. If we use chemotherapy, the risk of treatment-related morality is very high.”

Chiaretti concluded that a chemotherapy therapy-free induction and consolidation approach may be best for patients with Ph+ ALL.

_References:

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_{8. Ottmann OG, Pfeifer H, Cayuela JM, et al. Nilotinib (Tasigna) and low intensity chemotherapy for first-line treatment of elderly patients with BCR-ABL1-positive acute lymphoblastic leukemia: final results of a prospective multicenter trial (EWALL-PH02). Blood. 2018;132(suppl 1):31. doi:10.1182/blood-2018-99-114552}

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_{10. Martnelli G, Piciocchi A, Papayanndis 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.}

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_{14. Martinelli G, Papyannidis C, Piciocchi A, et al. Extremely high rate of complete hematological response of elderly Ph+ acute lymphoblastic leukemia (ALL) patients by innovative sequential use of nilotinib and imatinib. a GIMEMA protocol LAL 1408. Presented at: American Association for Cancer Research Annual Meeting 2014; April 5-9, 2014; San Diego, CA. Abstract 5552.}

_{15. Papayannidis C, De Benedittis C, Soverini S, et al. Ponatinib is well tolerated and active in patients with relapsed/refractory Philadelphia positive acute lymphoblastic leukemia (PH+ ALL) and advanced phase of chronic myelogenous leukemia (DML) harbouring T315i mutation: the Bologna experience. Blood. 2013;122(21):3911. doi:10.1182/blood.V122.21.3911.3911}

_{16. Ribera JM, García J, Fernández-Abellán P, et al; PEHEMA Group. Lack of negative impact of Philadelphia chromosome in older patients with acute lymphoblastic leukaemia in the thyrosine kinase inhibitor era: comparison of two prospective parallel protocols. Br J Haematol. 2012;159(4):485-488. doi:10.1111/bjh.12043}

_{17. Chalandon Y, Thomas X, Hayette S, et al; Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL). Randomized study of reduced-intensity chemotherapy combined with imatinib in adults with Ph-positive acute lymphoblastic leukemia. Blood. 2015;125(24);3711-3719. doi:10.1182/blood-2015-02-627935}

_{18. 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 GIMEMA Acute Leukemia Working Party. Presented at: European Hematology Association 2019 Annual Meeting; June 13-16, 2019; Amsterdam, the Netherlands. Abstract S1617.}