SAN DIEGOâ€”Patients 70 years old and younger with previously untreated chronic lymphocytic leukemia (CLL) lived longer and had progression of their disease delayed when treated with ibrutinib (an irreversible inhibitor of Brutonâ€™s tyrosine kinase [BTK]) combined with the anti-CD 20 agent rituximab than patients in a control arm receiving standard fludarabine, cyclophosphamide and rituximab (FCR) in a phase three study from the ECOG-ACRIN Cancer Research Group reported to the 2018 annual meeting of the American Society of Hematology (ASH).
The researchers concluded that the findings had immediate practice changing implications establishing ibrutinib-based therapy as the most effective first-line treatment for most patients with CLL. â€œIbrutinib-based therapy is now the preferred initial treatment for the majority of CLL patients around the world independent of age,â€ said lead study author, Tait D Shanafelt MD, Professor of Hematology at Stanford University in Stanford CA, noting that a partner phase three study had also established its superiority in older patients. (Alliance North American Intergroup Study A041202: https://ash.confex.com/ash/2018/webprogram/Paper116653.html )
The â€œgold standardâ€ treatment for younger patientsâ€”aged 70 and belowâ€”with previously untreated CLL (who were fit enough to tolerate aggressive treatment) had been FCR chemotherapy, said Shanafelt. â€œThis trial evaluated whether the combination of ibrutinib and rituximab was similar toâ€”or superior thanâ€”FCR-based therapy for these younger fit patients,â€ he said.
FCR toxic and not curative
At an ASH press briefing to announce the new findings Shanafelt told Oncology Times that although FCR had been the single best initial treatment for CLL, it had still not been a curative therapy.Â â€œAnd itâ€™s also a fairly toxic treatment with extensive side effects,â€ he said. â€œItâ€™s a regimen that can only be tolerated by CLL patients under 70â€”who tend to be more robust.Â So although itâ€™s a good therapy, thereâ€™s room for improved effectiveness and certainly also room for improved side effect profile,â€ he said.
Ibrutinib targets Brutonâ€™s tyrosine kinase (the enzyme that helps mediate cell signaling through the B-cell receptor pathway)â€”known to be an important survival pathway in CLL B-cells, said Shanafelt.Â â€œWe know that it is very effective in relapsed patientsâ€”and can lead to very durable remissions,â€ he said. But itâ€™s recent approval as an option for previously untreated patients had been based on a trial in elderly patients with CLL that compared ibrutinib to chlorambucil.Â â€œThe challenge is that chlorambucil is a pretty ineffective treatment by itself for patients with CLL,â€ he said. â€œAnd the fact that ibrutinib was superior to chlorambucil didnâ€™t really help us understand how it stacked up to our gold-standard treatments for CLL patients such as FCR,â€ he said.Â
In the study the investigators enrolled 529 patients with previously untreated CLL who were aged 70 and younger.Â â€œWe excluded patients with deletion 17p because that subgroup of patients does not respond well to FCR.Â So they were inappropriate to be randomized,â€ said Shanafelt.Â Two out of every three patients were randomized to ibrutinib plus rituximab, the remaining one-third of study patients received standard FCRâ€”six cycles at â€œtraditional dosingâ€, he said (intravenous fludarabine (25 mg/m2Â ) and cyclophosphamide (250 mg/m2) days 1-3 with rituximab (50 mg/m2Â on day 1 of cycle 1; 325 mg/m2Â on day 2 of cycle 1; 500 mg/m2Â on day 1 of cycles 2-6) every 28-days).
After 34 months of follow up the ibrutinab/rituximab combination had conferred a superior progression free survival (PFS) as well as a superior overall survival (OS), he said.Â â€œThe risk of progression was reduced by about two-thirds in the ibrutinib and rituximab arm compared to FCR.Â What was notable was that the ibrutinib and rituximab [regimen] was also less toxic than FCR with respect to the proportion of patients experiencing any grade three or higher toxicity. So we have a circumstance where the novel targeted therapy led to superior progression free survival, better overall survival, with fewer side effects.â€
The researchers reported a benefit for PFS that favored the experimental arm over the FCR treatment arm with a hazard ratio (HR) of 0.352 (â€œp valueâ€ less than <0.0001). The HR for OS also favored the ibrutinib-based regimen with a HR of 0.168 (â€œp-valueâ€ of 0.0003).
When he was asked about the striking benefit in OS from the experimental regimen Shanafelt said that although the improvement had been impressive â€œfrom a hazard ratio point of viewâ€, there had been only a limited number of deaths on the trial. â€œSo we probably need to be somewhat circumspect and desire longer follow up for that end-point,â€ he said. Even so (from the raw data) the risk of death had been reduced five-fold with ibrutinib-based therapy compared FCR, he said. â€œThat difference was statistically significant and it met the criteria for superiority that was specified in the protocol before the trial began.â€
â€œWe were all surprised to see this early difference in the survival curves. And even though weâ€™re encouraged by that I do think that weâ€™re all wanting longer follow up to see how durable that is and whether the curves separate more widely or not,â€ he said.
How significant had been the reduction in PFS of about a 65 per cent by the time of follow up? â€œI think itâ€™s impressive. Itâ€™s notable that the FCR-treated patients in this trial had progression free survival and overall survival exactly as expectedâ€”based on the previous German trials.Â So we see that the FCR patients did as we expected. But the ibrutinib arm was superior,â€ he said.
He added that neither arm of the study had reached the median PFS, and that it would need longer follow up before the researchers could assess medians for the two arms.
When he was asked about toxicities Shanafelt said the ibrutinib regimen had been less toxic overall and had different toxicities from FCR chemotherapy. â€œFor the FCR arm grade three or higher adverse events occurred in a bit over 70 per cent of patients. In the ibrutinib-rituximab arm it was about 58 per cent,â€ he said. â€œIf we look at all grade three and higher adverse events the toxicity [profile] favors ibrutiib and rituximab,â€ he said.
There were big differences in the types of side effects, he said.Â â€œThe grade three and higher adverse events that were more common in the FCR arm were myelo-suppression, neutropenia, low hemoglobin, low platelets and infectious complications.Â In the ibrutinib arm the side effects that were seen more frequently were atrial fibrillation (which occurred in three per cent of patients in the ibrutinib arm compared to no patients in the FCR arm) and hypertension (seven per cent of the patients in the ibrutinib arm compared to no patients in the FCR arm): So a slightly different side-effect profile.â€
Shanafelt said the clinical implications were that ibrutinib-based therapy had been superior to the historical â€œbest therapyâ€ for treatment of CLLâ€”which had been a chemotherapy platform of FCR.Â â€œItâ€™s also less toxic than that historical therapy,â€ he said,
â€œThe other exciting thing at this 2018 ASH meeting is that the Alliance [North American Intergroup Study A041202] presented the results in the plenary session of a companion studyâ€”a phase three trialâ€”that looked at older patients: those age 65 and older, and compared ibrutinib or ibrutinib and rituximab to bendamustine and rituximab,â€ he said. These two trials had been designed in collaboration. And they had both reported reaching their primary endpoints of improving progression free survival with ibrutinib-based therapy over standard chemotherapyâ€”the ECOG trial also showing a survival advantage, he said.Â â€œAnd together those two trials move us fully into the novel therapy era for treatment of CLL, and establish ibrutinib-based therapy as a preferred initial therapy for most patients with this disease.â€