Spare the Spleen in ALPS: It Is Not an Expendable Vestigial Organ

Background:

Autoimmune lymphoproliferative syndrome (ALPS-FAS) due to inherited and somatic FAS genetic defects is associated with childhood onset lymphadenopathy, splenomegaly, multilineage cytopenias, and an increased life-time risk of B-cell lymphoma. More than two hundred patients with ALPS-FAS and their relatives have been followed at NIH and CHOP since 1993. Though splenectomy was the go to remedy until early 2000s, steroid and spleen sparing immunomodulatory regimens have been the mainstay of long term therapy in recent years for many ALPS patients with refractory cytopenias secondary to autoimmune destruction and splenic sequestration. This included mycophenolate mofetil (n=54), rapamycin (n=17 at NIH and n=22 at CHOP), rituximab (n=25), plaquenil (n=4), and TPO-mimetics (n=4).

Patients and Observations:

In our cohort; 80 patients had a splenectomy before 2005, compared to only 26 patients that endured a splenectomy between 2005 and 2018 among NIH cohort and none at CHOP. Post splenectomy sepsis related morbidity and mortality were noted to be considerable. More ALPS patients in our cohort have perished due to overwhelming post splenectomy sepsis(n=10) and non-availability of timely medical care than all other causes of death cumulatively, including deaths due to lymphoma (n=5). This change of practice was predicated upon the success of regimens containing long term use of mycophenolate mofetil (Rao VK et al. Use of mycophenolate mofetil for chronic, refractory immune cytopenias in children with autoimmune lymphoproliferative syndrome. Br J Haematol. 2005 May; 129(4):534-8) or rapamycin (Bride KL et al. Sirolimus is effective in relapsed/refractory autoimmune cytopenias: results of a prospective multi-institutional trial. Blood. 2016 Jan 7;127(1):17-28. doi: 10.1182/blood-2015-07-657981). Though rapamycin was more potent against the underlying lymphoproliferative process of ALPS, some patients could not tolerate its side effects: mouth ulcers, increased lipids, molluscum, warts, deep vein thrombosis and peripheral edema. Notable toxicities were persistent secondary hypogammaglobulinemia (n=20/25) following rituximab and prolonged use of mycophenolate mofetil.

Conclusion:

1. Splenectomy and rituximab should be avoided in ALPS-FAS. Though successfully used in many patients, we still need to be wary of the short and long-term toxicities of both rapamycin and MMF. Though it may sound self-evident to avoid splenectomy today, even in early 2010s we have had a 1year old child with ALPS-FAS undergoing unwarranted splenectomy. Splenectomy for an enlarged spleen for a diagnostic or therapeutic purpose should be avoided under many circumstances unless indicated as a last resort. (Kristinsson SY et al. Long-term risks after splenectomy among 8,149 cancer-free American veterans: a cohort study with up to 27 years follow-up. Haematologica. 2014 Feb;99(2):392-8. doi: 10.3324/haematol.2013.092460. PMID: 24056815).

2. Experience gained from long term management of nonmalignant lymphoproliferation in rare disorders like ALPS can also be applicable to lymphadenopathy, splenomegaly and hypersplenism in patients with sporadic ITP and other inherited disorders of immune system, due to defects in genes like PIK3CD, PIK3R1, CTLA4, LRBA and STAT3GOF etc. using spleen sparing long term immunosuppressive/immunomodulatory medications.

Future Directions:

1. It is desirable to create an all cause iatrogenic/surgical asplenia registry for all patients (both pediatric and adults) under the auspices of ASH. This registry should prospectively collect data about patients that have undergone splenectomy and follow them for the long term and document their associated life time comorbidities. This will help us in developing standardized prophylactic asplenia care protocols. (A registry for patients with asplenia/hyposplenism reduces the risk of infections with encapsulated organisms. Arnott A, Jones P, Franklin LJ, Spelman D, Leder K, Cheng AC. Clin Infect Dis. 2018 Feb 17. doi: 10.1093/cid/ciy141. [Epub ahead of print])

2. Targeted physiological restoration of the fas or other affected protein function is desirable in symptomatic patients with ALPS and similar inherited disorders of non-malignant lymphoproliferation as a long-term therapeutic approach starting from childhood and continued into late adulthood.