The remaining case was a 45-year-old female patient who presented with extensive extramedullary hematopoiesis, which aggravated severe neurological complications such as blindness and paraplegia, with ECOG performance grade 4 and HCT-CI score 4. The patient was diagnosed as polycythemia vera (PV) with JAK2 exon 12 mutation accompanying splenomegaly in 2002, and treated with intermittent phlebotomy until 2007. Progressive thrombocytopenia and huge splenomegaly with a longest diameter of 25 cm was identified in 2012, and a follow-up BM study showed MF-3 fibrosis with normal karyotype. Splenectomy was conducted in 2014 due to severe pain. After splenectomy, thrombocytopenia and constitutional symptoms improved transiently but she complained of intermittent headache and diplopia at 5 months after splenectomy. Brain MRI showed diffuse meningeal thickening along parieto-temporal regions (Figure 1A), and dura biopsy revealed an increased number of hematopoietic precursors of all lineages. Diplopia was aggravating, with visual disturbance, and back pain and paraplegia developed despite radiation therapy (Figure 1B). We planned a RIC allo-HCT but the patient's performance status was getting worse due to progressive paraplegia and development of pneumonia. Although we explained that she was not a proper candidate for allo-HCT due to the high expectation of fatality, we finally decided to conduct allo-HCT using NMA conditioning regimen with patient consent and willingness. The patient received a CD34+ stem cell infusion of 18.9 x 106/kg from her younger brother on September 2015. CBC recovered on day 13 and the patient discharged without early complications. Although herpes zoster infection occurred, no GVHD developed, follow-up BM showed improved fibrosis with MF-2 grade, and meningeal lesions on follow-up MRI totally disappeared at 6 months post-HCT (Figure 1C). Despite improved performance status with stable blood counts, WB and donor T-cell chimerism declined progressively; 66% and 62% at 6 months, and 37% and 41% at 18 months post-HCT, respectively. Mutation of JAK2 exon 12 became undetectable at 6 months post-HCT, but re-appeared at 11 months post-HCT. She was scheduled for additional stem cell infusion when the chimerism fell to 47% at 14 months post-HCT, and infusion was conducted at 19 months post-HCT (CD34+ and CD3+, 11.0 x 106/kg and 230.0 x 106/kg, respectively). At 8 months after second stem cell infusion, both WB and T-cell chimerism became 99% and she is alive with full donor chimerism and no evidence of BM fibrosis at 52 months post-HCT. However, her neurological complications still remain. She experienced only mild oral GVHD, which was soon resolved with low dose of prednisolone.
Patients with MF frequently exhibit accompanying extramedullary hematopoiesis within the liver, spleen, or any sites at advanced stage. However, involvements in vital organs, such as cardiovascular system or central nervous system (CNS), are rare manifestations and can sometimes be fatal. Although these manifestations are not included as an adverse-risk parameter in a prognostic scoring system, uncontrolled extramedullary hematopoiesis might be an emergency complication and should be treated by urgent radiation therapy or with allo-HCT in progressive cases. Although RIC regimens allow allo-HCT for patients ineligible for a myeloablative conditioning regimen, we still confront high TRM after transplantation. Therefore, we should cautiously consider NMA conditioning regimens for MF with progressive extramedullary hematopoiesis that aggravates a patients' comorbidities. Among several NMA regimens, low dose TBI plus alemtuzumab for sickle cell anemia showed stable mixed-donor chimerism with reversal of hemoglobinopathy without significant GVHD and TRM. Our experience also showed this NMA regimen can be applied safely in MF patients with severe comorbidity, without producing acute or chronic complications. However, severe viral or fungal infection due to alemtuzumab and poor graft function are the problems most expected, and these should be considered and closely monitored for survival outcome. Thus, a meticulous search for potential focus of infection should be performed prior to HCT. We think the critical difference in treatment outcome between patient #3 and #4 may be the difference in the number of infused stem cells (CD34+, 10.9 x 106/kg and 2.5 x 106/kg, respectively). In addition, our experience also suggested that the time and appropriate procedure for additional stem cell infusion should be studied more, and that NMA conditioning regimen followed by stem cell infusion from unrelated or mismatched donor should be tried cautiously due to poor immune reconstitution and infectious complications. We expect that MF patients with severe comorbidity might be treated successfully with alemtuzumab-based NMA regimen from MSD followed by additional stem cell infusion without significant fatalities.