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HDL treatment for patient on intermittent hemodialysis

Question

What is the best treatment for a patient with hairy cell leukemia on intermittent hemodialysis?

Search strategies

Pubmed search using the MeSH terms “hairy cell leukemia” AND “hemodialysis,” or “vemurafenib” AND “end stage renal disease”

Background

Hairy cell leukemia (HCL) is an indolent, B-cell malignancy that is fairly uncommon. Patients typically present with pancytopenia, splenomegaly, and circulating hairy cells, which are so named due to the cytoplasmic projections they have, resembling hair. Most hairy cell leukemias (95-100%) have a BRAF mutations (BRAF V600E), a gain of function mutation first described in melanoma.1

Due to it’s indolent nature, not all patients who receive a diagnosis of hairy cell leukemia would be indicated to receive treatment. Reasons to pursue treatment would be unexplained weight loss greater than 10% in the preceding 6 months, excessive fatigue, splenic discomfort, recurrent infections, hemoglobin < 11g/dL, platelets < 100,000/mcL, ANC < 1000/mcL, symptomatic organomegaly, and progressive lymphocytosis/lymphadenopathy. For patients without any of these, the NCCN guidelines would recommend observation alone.2

HCL is not considered a curable malignancy but the treatment goal is to induce a deep-durable response to therapy. Negativity for minimal residual disease (MRD) after initial therapy is associated with longer and more lasting remissions.1

For patients who are indicated for treatment, the NCCN guidelines recommends initial therapy with a purine analog such as cladribine and pentostatin.2 Purine analogs, however, are metabolized to their active form and are excreted in the urine. For patients with end stage renal disease (ESRD) or that are currently on hemodialysis, there is no data available to guide therapy and dosing with these agents, including timing of therapy related to hemodialyisis, need for dose reductions, and overall safety in the ESRD disease population.3 Other regimens for the treatment of HCL that are preferred in the NCCN HCL guidelines include alternative purine analogs with rituximab, vemurafenib, and clinical trial.2 Due to the already rare nature of HCL, data in the end stage renal disease and hemodialysis population is lacking.

Literature Review

Rituximab is a treatment option for HCL patients with ESRD and will no require any dosage adjustments in this population. Because rituximab is a monoclonal antibody, it undergoes antibody degradation just like natural antibodies, and this is not dependent on kidney function.4

Vemurafenib is a BRAF inhibitor, initially studied in melanoma that has now also been implicated in the treatment of HCL due to the characteristic nature of the BRAF mutation within HCL. Vemurafenib’s pharmacokinetics are also not renally dependent, making the need for dosage adjustments in patients with impaired renal function.5 One case report has been published of a patient with melanoma and end stage renal disease on peritoneal dialysis, treated with vemurafenib at the full recommended dose (960mg twice daily). The patient required a dose reduction after several months of therapy for QTc prolongation, a well-known side effect of the medication, but otherwise exhibited tolerability to the medication.6

Another study investigated the dosing of vemurafenib in the HCL setting (in melanoma, it is typically dosed as 960mg twice daily). This study was a retrospective chart review of 21 patients with HCL treated with vemurafenib. Doses were determined by the treating physician, but ranged from 240mg twice daily to 960mg twice daily, with the majority of patients receiving 240mg twice daily. The median duration of treatment within this study was 90 days, but discontinuation of the medication was determined by the treating physician and no data was available as to the reasons for therapy discontinuation. This study also performed pharmacokinetic studies and found that low-dose (240mg twice daily) was sufficient to inhibit BRAF and there were no significant differences in responses between doses. It should be noted, however, that the patient population for each dose was very small. Additionally there was no MRD data available within this trial for evaluation.7

A recent abstract published demonstrates the use of both vemurafenib and rituximab together for the treatment of HCL. This trial treated 31 patients with relapsed/refractory HCL with vemurafenib 960mg twice daily for 8 weeks and rituximab 375mg/m2 every 2 weeks while on vemurafenib and then for an additional 4 doses every 2 weeks after vemurafenib was completed. 96% of these patients were able to achieve a complete response and 65% of patients were MRD-negative. This data represents a therapy option with very promising outcomes and a definitive duration as well.8

Conclusion

The treatment combination of vemurafenib and rituximab represents a feasible option in ESRD patients with HCL. These agents do not require dose adjustments for renal dysfunction or timing with respect to renal replacement therapy such as intermittent hemodialysis. The optimal dosing for vemurafenib remains unclear in the HCL setting with the current available literature. Providers should initiate therapy at the recommended dose of 960mg twice daily if the patient has no other co-morbidities that conflict with therapy, and should adhere to dose reduction recommendations for toxicities as needed for individual patients. For patients who do require dose adjustments, current evidence supports that these patients are likely still deriving full benefit from the medication. At this time, there is not enough long term or MRD data to recommend every patient be initiated or maintained on a lower dose of vemurafenib.

References

1. Maevis V, et al. Hairy cell leukemia: short review, today's recommendations and outlook. Blood Cancer J. 2014 Feb; 4(2): e184.

2. National Comprehensive Cancer Network. Hairy Cell Lekemia. V.1.2020.

3. Cladribine injection [prescribing information]. Lake Surich, IL: Fresenius Kabi; August 2016.

4. Cartron G, et al. Pharmacokinetics of rituximab and its clinical use: Thought for the best use? Critiical reviews in Oncology and Hematology. 2007;62(1):43-52.

5. Zhang W, et al. Clinical Pharmacokinetics of Vemurafenib. Clinical Pharmacokinetics. 2017;56:1033-1043.

6. Iddawela M, et al. Safety and efficacy of vemurafenib in end stage renal failure. BMC Cancer. 2013;13(581).

7. Dietrich S, et al. BRAF inhibition in hairy cell leukemia with low-dose vemurafenib. Blood. 2016;127(23):2847-2855.

8. Tiacci E, et al. The BRAF inhibitor vemurafenib plus rituximab produces a high rate of deep and durable repsonses in relapsed/prefractory hairy cell leukemia: updated results of a phase 2 trial. EHA. 2019. Abstract.

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