Summary of the EHA-ISA Working Group Guidelines for High-dose Chemotherapy and Stem Cell Transplantation for Systemic AL Amyloidosis.

The European Hematology Association (EHA) and International Society of Amyloidosis (ISA) recently agreed to collaborate on the development of guidelines for high-dose chemotherapy and stem cell transplantation (SCT) for the treatment of systemic light chain (AL) amyloidosis.[1] A working group of key opinion experts of ISA was created, and the guidelines were developed and endorsed by the guidelines committee members of the EHA. The objectives were to provide healthcare professionals with clear guidance on the selection and management of patients with AL amyloidosis undergoing high-dose chemotherapy and SCT. Draft guideline was reviewed and agreed by the members of the writing group and approved by the board members of the ISA. The working group was chaired by Vaishali Sanchorawala, MD.

AL amyloidosis is usually caused by an indolent B-cell clone that produces an immunoglobulin light chain λ in 75%–80% of cases and κ light chains in the remaining cases. A high frequency (~40%–60%) of the chromosomal translocation t(11;14), which juxtaposes the immunoglobulin heavy chain locus (IgH) to the oncogene cyclin D1, characterizes this clone. Somatic mutations in IGLV (encoding the light chain variable region) reduce the fold stability of the native soluble protein and increase protein dynamics, which favors endoproteolysis and the production of soluble aggregates. These soluble aggregates then interact with GAGs and serum amyloid P to lead to amyloid fibrillogenesis. Amyloid fibril deposition occurs in various organs and leads to organ dysfunction, organ failure, and death.[2] Treatment of AL amyloidosis is currently focusing on targeting the plasma cell dyscrasia to achieve a deep and durable hematologic response that would eventually translate to organ response and improve survival.

High-dose intravenous melphalan and autologous SCT was developed for the treatment of AL amyloidosis in the early 1990s and was prompted by its success in myeloma.[3] This application has evolved significantly over the past 3 decades. These guidelines provide a comprehensive assessment of eligibility criteria, stem cell collection and mobilization strategies and regimens, risk-adapted melphalan dosing, role for induction and consolidation therapies, specific supportive care management, long-term outcome with respect to survival, hematologic response and relapse, and organ responses following SCT. There is also specific guidance for performing SCT before/after solid organ transplantation in AL amyloidosis. Success of SCT in AL amyloidosis relies on the shared experience of the center and treatment team in managing complications of a rare disease with multiorgan involvement.

Due to the rarity and heterogeneity of AL amyloidosis, the field still lacks high quality of evidence to develop guidelines. Nevertheless, medical professionals representing the field of AL amyloidosis have put maximum effort to generate a balanced and effective tool to facilitate clinical decision making. These guidelines are therefore expected to be of substantial help to clinicians dealing with rare disease of AL amyloidosis worldwide. Simultaneously, the guideline provides an overview of the areas of uncertainty for and new directions of future research. The endorsement of the EHA is very encouraging and emphasizes the importance of these guidelines for SCT in AL amyloidosis.

Selection of patients for high-dose chemotherapy and SCT is crucial to reduce SCT-related morbidity and mortality. Eligibility criteria vary for centers and their local experience, policies, and operating procedures; however, patients with medically refractory pleural effusions, advanced cardiac involvement with stage IIIb disease, orthostatic hypotension refractory to medical therapy, acquired factor X deficiency with active bleeding and GI involvement with GI bleeding should not be offered SCT. Role of induction therapy before SCT, historically, was questioned due to low level of plasmacytosis as well as clinical deterioration during induction therapy making some patients ineligible to proceed to SCT. However, with development of novel induction therapy regimens and the US Food and Drug Administration (FDA) approval of daratumumab-VCd (bortezomib, cyclophosphamide, and dexamethasone) regimen, 2–4 cycles of induction therapy for those with bone marrow plasmacytosis of >10% before SCT is favored. For patients achieving hematologic complete response after induction therapy, SCT should be delayed at the time of hematologic relapse. Stem cell mobilization should be performed with granulocyte colony-stimulating factor (G-CSF) alone either as a single dose or split dose and plerixafor could be used to reduce capillary leak syndrome associated with G-CSF. Careful management of fluid overload and complications should be performed during this phase. Risk-adapted high-dose melphalan (200 mg/m2 or 140 mg/m2) is the preferred conditioning regimen before SCT for AL amyloidosis (Figure 1). There might be a role for few cycles of consolidation therapy for those who achieve a less than very good partial hematologic response after SCT and did not receive induction therapy prior to SCT; however, the potential benefit of consolidation must be balanced with the risk of toxicity. Long-term lenalidomide-based maintenance therapy after SCT does not have a definitive role in AL amyloidosis. Patients with advanced single organ dysfunction due to AL amyloidosis have a potential to receive solid organ transplantation and can become suitable candidates for consideration of SCT. The considerations in this special group includes fitness for SCT based on criteria for AL amyloidosis after the organ transplant, management of immunosuppression during stem cell harvesting and the impact of function of the transplanted organ on risks of SCT as well as the potential risk of (ir)reversible transplanted organ dysfunction during SCT. A coordinated approach with the organ transplant team is a must for long-term success. Supportive treatment aimed at preventing and minimizing complications during pre, peri, and post-SCT period has an important impact on survival. Supportive care should be considered a fundamental part of an integrated treatment approach to these patients and requires the coordinated expertise of several specialists who are familiar with this disease.

Figure 1.

EHA-ISA guidelines for stem cell transplantation in AL amyloidosis. AKI = acute kidney injury; CR = complete response; DLCO = diffusing capacity for carbon monoxide; ECOG = Eastern Cooperative Oncology Group; eGFR = estimated glomerular filtration rate; EHA-ISA = European Hematology Association and International Society of Amyloidosis; ESRD = end-stage renal disease; G-CSF = granulocyte colony-stimulating factor; NYHA = New York Heart Association; MEL = Melphalan; SCT = stem cell transplantation.

In conclusion, the EHA-ISA guidelines for high-dose chemotherapy and SCT in AL amyloidosis provide practical guidance for clinicians and demonstrate the progress in the stratification and selection of patients, risk-adapted conditioning regimen and appropriate supportive care which can lead to a long-term outcome with respect to hematologic response, organ response and survival with this intensive treatment.

DISCLOSURES

V.S. discloses that she receives research support from Celgene, Takeda, Janssen, Prothena, Caelum, Oncopeptide, Sorrento, Karyopharm, consulting fees from Pfizer, Janssen and is a member of the advisory board of Janssen, Regeneron, Abbvie, Proclara, Protego, Telix, Pharmatrace.