Safety and Efficacy of Propylene Glycol-Free Melphalan in Patients with AL Amyloidosis Undergoing Autologous Stem Cell Transplantation: Results of a Phase II Study.

Patients with systemic light chain (AL) amyloidosis undergoing treatment with high-dose melphalan and autologous stem cell transplantation (HDM/SCT) may develop renal and cardiac toxicities potentially exacerbated by the co-solvent propylene glycol in conventional melphalan formulations. We investigated the safety and efficacy of propylene glycol-free melphalan (PGF-Mel) during HDM/SCT in patients with AL amyloidosis (ClinicalTrials.gov identifier NCT02994784). The primary objective of this phase II, open-label study was evaluation for renal dysfunction, new cardiac arrhythmias, and postural hypotension related to autonomic dysfunction. Secondary objectives included time to neutrophil and platelet engraftment, treatment-related mortality (TRM), overall hematologic response, organ response, and number of peritransplantation hospitalizations. Twenty-eight patients with AL amyloidosis enrolled, of whom 27 underwent HDM/SCT. PGF-Mel at 140 to 200 mg/m2 was administered i.v. in 2 equally divided doses. Patients were monitored for up to 30 days after the last administration of PGF-Mel to assess for treatment-related toxicity. Patients were followed for 12 months from the time of treatment with HDM/SCT for evaluation of hematologic and organ responses. Kaplan-Meier analysis was used to estimate progression-free survival. Two patients (7%) developed renal dysfunction, 5 (19%) experienced new cardiac arrhythmias, and 3 (11%) developed orthostatic hypotension. All patients achieved neutrophil and platelet engraftment, at a median of 10 days and 17 days post-HDM/SCT, respectively. TRM on day +100 was 0%. Peritransplantation hospitalization was required for 23 patients (85%). The most common nonhematologic adverse events were diarrhea (93%), fatigue (82%), and nausea (74%). At 6 months post-HDM/SCT, hematologic complete response or very good partial response occurred in 66% of the patients. At 12 months post-HDM/SCT, renal response occurred in 12 of 23 (52%) patients with renal involvement, and cardiac response occurred in 3 of 11 (27%) patients with evaluable cardiac involvement. Our data indicate that PGF-Mel is safe and efficacious as a high-dose conditioning regimen for autologous SCT in patients with AL amyloidosis.

WHIM Syndrome: First Reported Case in a Patient of African Ancestry.

Background: Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare, primary immunodeficiency syndrome characterized by warts, hypogammaglobulinemia, immunodeficiency, and characteristic bone marrow features of myelokathexis. The pathophysiology of WHIM syndrome is due to an autosomal dominant gain of function mutation in the CXCR4 chemokine receptor resulting in increased activity that impairs neutrophil migration from the bone marrow into the peripheral blood. This results in bone marrow distinctively crowded with mature neutrophils whose balance is shifted towards cellular senescence developing these characteristic, apoptotic nuclei termed myelokathexis. Despite the resultant severe neutropenia, the clinical syndrome is often mild and accompanied by a variety of associated abnormalities that we are just beginning to understand. Case Report. Diagnosis of WHIM syndrome is incredibly difficult due to phenotypic heterogeneity. To date, there are only about 105 documented cases in the scientific literature. Here, we describe the first case of WHIM syndrome documented in a patient of African ancestry. The patient in question was diagnosed at the age of 29 after a comprehensive work-up for incidental neutropenia discovered at a primary care appointment at our center in the United States. In hindsight, the patient had a history of recurrent infections, bronchiectasis, hearing loss, and VSD repair that could not be previously explained. Conclusions: Despite the challenge of timely diagnosis and the wide spectrum of clinical features that we are still discovering, WHIM syndrome tends to be a milder immunodeficiency that is highly manageable. As presented in this case, most patients respond well to G-CSF injections and newer treatments such as small-molecule CXCR4 antagonists.

Modified High-Dose versus High-Dose Melphalan Conditioning in Older Patients Undergoing Autologous Stem Cell Transplantation for Immunoglobulin Light Chain Amyloidosis.

High-dose melphalan and autologous stem cell transplantation (HDM/SCT) induces deep hematologic responses (HR) in patients with newly diagnosed systemic immunoglobulin light-chain (AL) amyloidosis. Modifying melphalan conditioning dose (mHDM <140 mg/m2) is considered in older patients because of concerns regarding tolerability. Age does not predict frailty, and dose modification could compromise responses in an era where effective non-transplant regimens are available. We analyzed 43 patients ≥ 65 years with AL amyloidosis who underwent SCT at Boston University Amyloidosis Center between 2011 and 2020. Median age was 66 years (range 65-68) versus 69 years (range 65-76) in the HDM and mHDM groups, respectively. HR of ≥ very good partial response at 12 months was 66.7% versus 42.3% for patients treated with HDM versus mHDM. Median progression-free survival (PFS) from day 0 of SCT was not reached versus 12.0 months (P =.13); grade ≥ 3 non-hematologic transplant-related toxicities occurred in 87.5% versus 76.9%; and transplant-related mortality was 0% versus 2.3% in the HDM versus mHDM group, respectively. In carefully selected older patients with AL amyloidosis, HDM is well tolerated. Use of mHDM results in reduced HR and PFS; an important consideration with the advent of highly effective non-transplant therapies.

Phase 1a/b study of monoclonal antibody CAEL-101 (11-1F4) in patients with AL amyloidosis.

Systemic immunoglobulin light-chain amyloidosis is characterized by pathologic deposition of immunoglobulin light chains as amyloid fibrils in vital organs, leading to organ impairment and eventual death. That the process is reversible was evidenced in an in vivo experimental model in which fibril-reactive chimeric monoclonal antibody (mAb) 11-1F4 directly targeted human light-chain amyloid deposits and affected their removal via a phagocyte-mediated response. To determine the tolerability and potential amyloidolytic effect of this agent (now designated mAb CAEL-101), we conducted a phase 1a/b study involving 27 patients, most of whom had manifestations of organ involvement. This was an open-label study in which phase 1a patients received mAb CAEL-101 as a single intravenous infusion with escalating dose levels from 0.5 mg/m2 to 500 mg/m2 to establish the maximum tolerated dose (MTD). In phase 1b, the antibody was administered as a graded series of 4 weekly infusions. For both phases, there were no drug-related serious adverse events or dose-limiting toxicities among recipients, and the MTD was not reached. The majority of patients had deep hematologic responses but persistent organ disease prior to treatment. Fifteen of 24 patients (63%) who manifested cardiac, renal, hepatic, gastrointestinal, or soft tissue involvement had a therapeutic response to mAb CAEL-101 as evidenced by serum biomarkers or objective imaging modalities with a median time to response of 3 weeks. Infusions of mAb CAEL-101 were well tolerated and, for the majority, resulted in improved organ function, notably for those with cardiac impairment. This trial was registered at www.clinicaltrials.gov as #NCT02245867.