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North American Pediatric Aplastic Anemia Consortium Symposium

Introductory image: Dr. Margolis with Young Patient - High Five

This summary was prepared by Kelsie Storm, MD and Phoenix Ho, MD

Challenges Faced in the Diagnosis and Management of Severe Aplastic Anemia

Acquired aplastic anemia is a rare, life threatening disease affecting children and young adults that causes the bone marrow to stop making blood cells.  As with all rare diseases, there is a relative lack of research to develop cures and guide the management of affected patients. The North American Pediatric Aplastic Anemia Consortium (NAPAAC) was formed by leading physician researchers with expertise in bone marrow failure syndromes, including severe aplastic anemia (SAA), in order to collaboratively improve the care of affected patients. In addition to their effort to provide validated guidelines for diagnostic approaches and care, NAPAAC aims to develop an innovative research agenda in this area.  The group convened at Texas Children’s Hospital September 25 – 27th for the “New Directions in Bone Marrow Failure Symposium,” which featured panel discussions in the areas of hematopathology, bone marrow transplant, and supportive care. The related challenges faced in the diagnosis and management of aplastic anemia are highlighted in this summary.

Hematopathology Panel Discussion

The diagnosis of aplastic anemia can be challenging. Unlike other bone marrow failure syndromes that may have characteristic features or testable genetic mutations, aplastic anemia must be distinguished from other diseases causing markedly decreased marrow cellularity primarily by evaluation of the bone marrow.  Expert hematopathologists , Drs. Tarek Elghetany (Baylor College of Medicine), Inga Hoffman (Dana-Farber Cancer Institute), and Michele Paessler (University of Pennsylvania and Children’s Hospital of Philadelphia) presented cases illustrative of diagnostic challenges. One area of controversy lies in the particularly difficult distinction of SAA from refractory cytopenia of childhood (RCC), a subtype of myelodysplastic syndrome (MDS) with potential for progression to more advanced disease and AML.  Both conditions demonstrate a very depleted bone marrow, and both have been reported to show mild dysplasia and patchy areas of red blood cell, or erythroid, precursors. However, in the absence of an MDS defining clone, such as monosomy 7, these overlapping morphologies can make for imprecise diagnoses. Distinguishing SAA and RCC is important because the diseases respond differently to immunosuppressive therapy (IST), with higher rates of no-response, partial response, and treatment failure, including clonal evolution, in children with RCC. Clonal evolution following IST has also been described in children with SAA. However, a subset of patients with SAA who develop clones after IST, may have been misdiagnosed. A study published recently in Histopathology by Bauman, et. al. described the implementation of a central pathologic review of patients with SAA and RCC and adherence to strict criteria for the diagnoses as defined by the recent WHO classification.  The criteria for SAA excluded any patchy cellularity, particularly of erythroid lineage and did not allow any dysplasia in the megakaryocytic lineage. In the patients determined to fit the strict criteria for SAA, there were only 3% that developed a clonal population after IST compared to 14% previously reported to have clonal evolution after IST in populations without such adherence to strict criteria or central pathologic review. These findings emphasize the importance of diagnostic precision in distinguishing SAA and RCC and also highlight the need for research as to the true incidence of clonal evolution in SAA.

Bone Marrow Transplant Panel Discussion

Matched sibling donor bone marrow transplant remains the ideal definitive treatment for severe aplastic anemia. When a matched sibling is not available, the majority of physicians would initiate IST with Cyclosporine and antithymocyte globulin (ATG) as the first line therapy. However, controversy exists, particularly with advances in hematopoietic stem cell transplantation (HSCT). Experts in HSCT, Drs Leslie Lehmann (Dana-Farber Cancer Institute), James Huang (University of California, San Francisco and UCSF Benioff Children’s Hospital), and Timothy Olson (University of Pennsylvania and Children’s Hospital of Philadelphia) discussed outcomes data essential to clinical decision-making. The current overall survival for matched sibling transplant in SAA with a conditioning regimen of Cyclophosphamide and ATG at 3 years is 90%. The typical time to transplant is 4-6 weeks. The ideal stem cell source is generally accepted to be bone marrow as peripheral blood stem cell transplants have been shown to have a higher incidence of chronic graft versus host disease (GVHD) and umbilical cord blood has been limited by graft failure. There is variable outcome data from alternative donor source transplants, largely because studies are typically retrospective and from single institutions. Though donor matching continues to improve, GVHD and graft failure are still significant causes of morbidity and mortality with alternative donor transplants. Furthermore, the ideal conditioning regimen is not agreed upon for alternative donor stem cell transplants in SAA. Though IST is widely accepted as the first line therapy when a matched sibling transplant is not an option, there is some evidence to suggest that exposure to IST prior to transplant increases graft rejection, which is problematic for patients who don’t respond to IST. As donor matching and supportive care within hematopoietic stem cell transplantation continue to improve, prospective, multi-institutional studies are needed to compare outcomes of IST and HSCT, particularly related to treatment of relapse.

Supportive Care Panel Discussion

Supportive care, which encompasses blood production transfusion and the prophylaxis and treatment of infections, is an important component in the management of patients with SAA. As supportive care in the setting of HSCT is often more clearly defined, expert panelists Drs. Anjulika Chawla (Brown University and Hasbro Children’s Hospital), Ulrike Reiss (St. Jude Children’s Research Hospital), Zora Rogers (UT Southwestern Children’s Medical Center at Dallas), and Kelly Walkovich (University of Michigan and C.S. Mott Children’s Hospital) focused on current practice and areas of needed research pertaining to supportive care during IST for SAA based on results of a survey of 18 NAPAAC physicians. Regarding the transfusion of blood products, 88% of responders use the minimum number of transfusions of packed red blood cells (pRBC) that keep patients asymptomatic, while 78% of responders follow the same practice for platelet transfusions. However, the majority report that they would transfuse to keep both parameters above a certain level, which varied in responses. Regarding the prophylaxis of infection during the time of severe neutropenia, 38% report using granulocyte colony stimulating factor (GCSF) in most patients while 69% report using it during an infection if neutropenia has not resolved. A review of the literature revealed seven studies looking at GCSF during IST in SAA and found no difference in overall survival, event free survival, or relapse, but fewer infections in the first 90 days of treatment and fewer days of hospitalization. There is some literature to suggest that GCSF may increase rates of secondary AML. There is also literature to suggest that response to GCSF in the first 10-14 days may predict who responds to IST. The use of antibiotic prophylaxis is also variable. One quarter of responders do not use any antimicrobial prophylaxis. Two thirds use routine prophylaxis against Pneumocystis infection and two thirds use routine antifungal prophylaxis, though the specific antimicrobials varied. Among NAPAAC institutions prophylaxis against bacterial infection varied greatly, but the most commonly used antibiotic was Levoquin. Parameters for initiating and stopping prophylaxis varied. Supportive care practices for patients with SAA are widely extrapolated from oncology patients undergoing chemotherapy, however the etiology of bone marrow failure is extremely different. Prospective, multi-institutional studies are necessary to determine how SAA patients are impacted by supportive care practices.

In conclusion, severe aplastic anemia can present challenges both at diagnosis and throughout treatment. Areas in need of further research include further characterization of clonal evolution in SAA, ongoing optimization of therapy for patients without a sibling matched donor, and the development of evidence based supportive care guidelines. Collaboration among experts, as is demonstrated by NAPAAC, will allow for the prospective multi-institutional studies necessary to achieve progress in severe aplastic anemia and better the outcomes for affected patients.