Newly Diagnosed Pernicious Anemia Can be Treated with a Single Megadose of Cobalamin. Results of a Pilot Trial

Introduction: Pernicious anemia is the leading cause of vitamin B12 deficiency worldwide, caused by an autoimmune reaction against parietal cells in the gastric mucosa leading to B12 absorption impairment. The treatment of pernicious anemia is based on replacement of cobalamin, oral and sublingual routes have been described nevertheless its absorption is erratic. The recommended schedules for vitamin B12 replacement is an intramuscular injection of 1000μg every other day for 1 to 2 weeks followed by weekly injections for a month and then tapered to once a month indefinitely (Green.Blood 2017;129(19):2603-2611). Such an approach can limit treatment adherence for patients in a resource-poor setting and may be unnecessary. Furthermore, the toxicity of cobalamin is minimal, while the benefit of larger doses is unknown.

Objective: We aim to demonstrate that a single mega-dose intramuscular (IM) injection of a multivitamin formulation is sufficient to achieve and maintain a complete hematologic response for a six-month period.

Methods: We performed a single center pilot study approved by our ethics committee and registered in Clinicaltrials.gov (NCT03372447). All patients with newly diagnosed, untreated pernicious anemia ≥18 years were included after written informed consent was obtained. A single IM dose of a multivitamin formulation consisting on cobalamin 10,000 μg, thiamin 100 mg, and pyridoxine 50 mg was administered. Complete blood count (CBC) was performed at 15 and 30 days and monthly thereafter for a total of six months. Partial response (PR) was considered when Hb ≥10g/dl, Normal WBC, PLT ≥100x10³/μL, Complete response (CR) was defined as Hb ≥12g/dl, normal WBC and PLT. Our primary outcome was normalization of CBC (CR) at 6 months. As secondary outcomes we evaluated safety and measured levels of methylmalonic acid (MMA), homocysteine (HCY) and B12 levels (B12L) at diagnosis, three and six months after treatment.

Results: Eight patients have been enrolled (5 men and 3 women), median age was 58 years (range 25-77). None had neurological symptoms at presentation. Median laboratory values at diagnosis were Hb 5.9 g/dL (range 3.9-10.7), mean corpuscular volume 113.2 fL (range 94.6-122.9), WBC 2.68x10³/μL (range 1.26-6.08), PLT 93x10³/μL (range 9.75-156,000), lactic dehydrogenase 3082IU/L (range 439-9840), B12L 85 pg/ml (range 83-90), HCY 154.09 μmol/L (range 83.7-182.44), MMA 24435 nmol/L (range 5175-99500). By day 30 all patients achieved PR. At the end of the third month, 100% of patients reached a CR regarding Hb and WBC while 88% of patients reached a complete PLT response. Median Hb increment at 1 month and 3 months was 6.15g/dl (range 3.1-7.74) and 1.8g/dl (range 0.4-3.7) respectively. The difference between Hb concentration at all time-points was statistically significant (ANOVA; p=0.002) particularly in the first 15 days (p=0.025), while post hoc testing revealed that increments in Hb after the second-week post-treatment were not (p>0.05). Until now, 4/8 patients have completed the primary outcome and all of them have maintained CR and normal levels of HCY and B12L without further cobalamin doses, only one patient had an asymptomatic increase of MMA. No adverse events following the administration of multivitamin preparation were documented.

Conclusions: A single dose of a 10,000μg B12 multivitamin was safe and tolerated. Thus far all patients have achieved and maintained a response for at least six months. This simplified single cobalamin administration is an effective option for the treatment of pernicious anemia.

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