IMS 2025 | High ALC peak following infusion of cilta-cel predicts delayed neurological toxicities in myeloma

I will discuss a correlation between the absolute lymphocyte count peak and delayed neurological toxicities in patients treated with cilta-cel. So I think the biggest excitement of the past few months’ meetings in multiple myeloma is a long-term follow-up of the CARTITUDE-1 study that showed 33% progression-free survival at five years with cilta-cel in highly refractory and heavily pretreated patient population, which really for the first time gives us such a long tail on the cure in patients with relapsed/refractory myeloma who were not in any maintenance therapy and really gives us a glimpse of hope for cure even in these refractory patients. And as much as this treatment is revolutionary, it still comes with potentially significant adverse events and even treatment-related mortality. And it does come with some very unique toxicities that we were not familiar with before BCMA-directed CAR-T, which are delayed neurotoxicity. And as those toxicities can be really debilitating, it is very important to find a way to prevent and mitigate those toxicities. So particularly in our institutional experience, we focused on analyzing risk factors for delayed neurological toxicities, including cranial nerve palsies, Parkinsonian neurocognitive neurotoxicity and profound peripheral neuropathies. And I would like to also highlight the work of Dr Hosoya, multi-center retrospective analysis of delayed neurotoxicities as well as the work of Dr Lin of Mayo Clinic and Dr Turner of University of Colorado who investigated the same question and across all the studies the conclusions were very very similar. And the bottom line is while some of the risk factors for more difficult increased toxicity scores after cilta-cel we are already aware of such as high disease burden, other things are not as much in our control. So we noticed that patients who had a higher peak of absolute lymphocyte count that correlates with higher CAR T-cell expansion early in the post-infusion course were at high risk for developing neurological toxicities later on down the line. In our institutional experience, overall incidence of toxicities was pretty high. It was over 30 percent. Good news though that most of those toxicities were cranial nerve palsy, specifically CN7 palsy, that were all reversible with treatment with corticosteroids and IVIG. However, even though reversible, those toxicities cannot be completely dismissed because occurrence of cranial nerve palsy commits patients to a steroid taper which by itself puts them at increased risk for infectious toxicity and other issues during CAR-T recovery. In our analysis, there was extremely clear correlation between the peak of ALC, absolute lymphocyte count, that happened And the median time to the peak was day 11 post-CAR-T infusion within day 10 to 12. So this peak highly correlated with the incidence of cranial nerve palsies. Using the threshold of 5,000 per cubic millimeter lymphocyte count, we were able to separate between the population of patients who did not develop, almost did not develop any delayed neurological toxicity and the sub-population of around 35% of patients who were at very high risk of delayed neurological toxicity. And when focusing on the group of patients with and without toxicities, the median peak ALC in the group without toxicity was just over 2,000, while the median peak ALC in the group with high toxicity was around 13,000. So based on this data that’s now coming from several independent studies, we are able to identify population, although not prior to infusion but very early post infusion, that is at a very high risk for developing delayed neurological toxicities. And now we have to be able to use this knowledge in order to mitigate and prevent at least some of those toxicities. And one approach that we are adopting now institutionally and other institutions are adopting as well is the use of prophylactic corticosteroids using ALC threshold in this early post-infusion day, day 10 to 12, as indication to use limited course of prophylactic dexamethasone, visible to harness this uncontrolled expansion and prevent some of the toxicities that are caused by the rapid expansion. And in the near future we will see if this approach results in better outcomes.

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