Hypercalcemia Following Treatment with Lenalidomide in Chronic Lymphocytic Leukemia (CLL).
Authors: Shah Bijal D. , Veliz Marays , Santana Ricardo , Lancet Jeffrey E , Powers John J. , Dubovsky Jason A , Tinsley Sara , Deaver Darcie , Sotomayor Eduardo M. , Pinilla Javier 
Published: October 2019

Abstract
Abstract 4413

BACKGROUND
In concert with emerging effectiveness data, we are learning that the side effect profile of lenalidomide (L) in CLL may be different from that observed with other malignancies, such as multiple myeloma (MM) or myelodysplastic syndrome (MDS). In particular, at lower doses than typically used for MM or MDS, a unique tumor flare response (TFR) has been observed for which the mechanism is still unclear, but may be related to a “cytokine release” phenomenon.

CASE REPORT
Here we would like to describe 3 cases of hypercalcemia that occurred in 3 of 17 patients with fludarabine refractory CLL treated at the Moffitt Cancer Center: 2 patients who were on a clinical trial of lenalidomide plus rituximab (LR), and 1 patient who was treated with L outside of a clinical trial setting.

Case 1
Pt #1 was initiated on (LR) on 12/2007 for CLL with bulky LAN, elevated wbc (110K), and 90% bone marrow (BM) involvement. By day 6, his calcium peaked at 11.78 and was accompanied by a drop in wbc to 15K. He had no other evidence of TFR, and was specifically without complaints of back pain or tender/progressive LAN. He was treated with IV fluids and steroids which promptly corrected his calcium, after which L was resumed. His course has been complicated by neutropenia requiring G-CSF. Although LAN remains stable, he has had an excellent BM response, with only 40% CLL seen on reevaluation in 06/2009.

Case 2
Pt #2 was initiated on LR on 8/2008 for CLL with bulky LAN, mildly elevated wbc (20.5K) and 60% BM involvement. By day 4 his calcium peaked at 16.94, at which time he presented to our urgent care center with weakness, sweats, back pain, nausea and vomiting. No tender or progressive LAN was appreciated. He was treated with IV fluids, pamidronate, calcitonin and steroids which normalized his calcium. An attempt was made to restart L, which again produced hypercalcemia after 4 days. No further attempts were made to resume this medication. A workup performed during the first episode of hypercalcemia was notable for a slight elevation in the PTHrp (8.5).

Case 3
Pt #3 was initiated on L alone on 6/2008 for CLL with bulky LAN, elevated wbc (283.6K), and 95% BM involvement. By day 4, his calcium peaked to 14.64, and was associated with a TFR, including a rise in wbc (306K), LDH (1285), and enlarging/painful LAN. The hypercalcemia was treated with IV fluids, zoledronate, and steroids. Bendamustine was immediately initiated for the treatment of CLL with dramatic improvement on lymph nodes and WBC counts. Following 1 cycle of bendamustine, L was resumed, with stabilization of his disease.
Workup in these patients was unremarkable, with normal VitD/PTH levels, and only a mild elevation of PTHrp in Pt#2 (see table), in whom hypercalcemia had reoccurred upon rechallenge with L. Pt#1 and #3 were successfully retreated without recurrent hypercalcemia, though, Pt#3 received prior cytoreductive therapy with bendamustine.

CONCLUSION
Hypercalcemia is a rare complication of advanced B-cell malignancies seen with lymphokine/cytokine mediated bone disruption. Increased production of l,25-(OH) 2D by lymphocytes may also lead to hypercalcemia, and in CLL it is mainly associated with Ritcher's transformation or presence of osteolytic lesions. Here we report on 3 cases of hypercalcemia, which were identified during L treatment in CLL, and which had not been observed in other studies of L. We hypothesize that the hypercalcemia could be a direct reflection of increased cytokine levels, including IL-6, TNFα, and, MIP-1α, which are known to influence osteoclastogenesis. Interestingly, IL-6 is known to act synergistically with PTHrp in experimental models to drive hypercalcemia, which may be relevant for the patient who developed recurrent hypercalcemia on rechallenge with L. Levels of cytokines at different time points are now under investigation and are anticipated for presentation at the meeting. These events indicate that serum chemistries of patients initiating treatment with lenalidomide should be closely monitored during the first weeks of treatment.

Disclosures:
Off Label Use: Lenalidomide is an immune modulator drug currently being studied for efficacy in conjunction with Rituxan in chronic lymphocytic leukemia. This abstract summarizes a unique side effect, hypercalcemia, seen among a small cohort of patients on this study.. Lancet:Celgene: Research Funding. Pinilla:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding; exelixis: Research Funding.