Hematopoietic Cell Transplantation in Rare Hematologic Malignancies

Systemic Mastocytosis

Systemic mastocytosis (SM) is a rare disease characterized by infiltration of clonal abnormal mast cells in the skin and internal rgans, such as the bone marrow, spleen, lymph nodes, and the gastrointestinal (GI) tract. Symptoms are caused by the release of vasoactive mediators, and clinicians should have a high index of suspicion for recurrent anaphylaxis, flushing, osteoporosis, and GI symptoms such as cramping and diarrhea. Pigmented urticarial skin lesions are found in most patients; however, once infiltration is discovered in extracutaneous tissue, the diagnosis of SM should be suspected.

The World Health Organization (WHO) 2016 classification defines five categories of SM, including indolent SM (ISM), smoldering SM (SSM), SM with an associated hematologic neoplasm (SM-AHN), aggressive SM (ASM), and mast cell leukemia (MCL). ASM and MCL show increasing infiltration in the bone marrow accompanied by cytopenias, hepatosplenomegaly, malabsorption because of GI involvement, and skeletal disease. SSM is intermediate in this spectrum. Overall median survival in SM-AHN is shorter at 24 months, and clinical course is determined by the underlying malignancy including myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPNs), chronic myelomonocytic leukemia (CMML), or chronic lymphocytic leukemia (CLL).

The initial diagnostic approach is based on bone marrow biopsy, as this is the commonest site of involvement following the skin, serum tryptase levels (>20 ng/mL), CD25 expression by immunohistochemistry or flow cytometry, and molecular testing. SM is associated in 90% of cases with an activating KIT D816V mutation in a tyrosine kinase receptor (KIT). Other oncogenic mutations identified in SM and SM-AHN include TET2, NRAS, SRSF2, ASXL1, EZH2, CBL, and RUNX1 and are usually associated with inferior survival.

The International Prognostic Scoring System for Mastocytosis model was developed from over 100 patients with nonadvanced and advanced SM. Other systems include the Mutation Adjusted Risk Score and Mayo Advanced Prognostic System. Most prognostic systems encompass cytopenias, leukocytosis, serum biomarkers including tryptase, beta2microglobin, alkaline phosphatase, and high-risk mutations.

While symptoms- and organ-directed treatment along with surveillance is the mainstay of treatment in ISM and SSM, advanced SM requires systemic therapy. Treatment selection is influenced by transplant eligibility, rate of progression, and site of involvement. Tyrosine kinase inhibitors such imatinib and dasatinib have been used for the 10% of aggressive SM cases with imatinib sensitive or unknown KIT mutations. Midostaurin, a multikinase inhibitor, was approved based on a phase II trial in 116 adults with previously treated or untreated ASM, SM-AHN, or MCL where it induced response rates of 40% to 60% and a subset were durable. Avapritinib, a kinase inhibitor highly selective to activation-loop mutants of KIT (including KIT D816V) and platelet-derived growth factor receptor A (PDGFRA) kinases was recently U.S. Food and Drug Administration (FDA) approved based on the results of a Phase 2 study in advanced SM (ASM, SM-AHN, or MCL) with objective response rates of 57% and median duration of response of 38 months. Other options include chlorodeoxyadenosine and interferon (IFN)-α, which can alleviate skeletal and histamine-induced symptoms in all SM subcategories.

Allogeneic HCT (Allo-HCT) should be considered after successful debulking and has been shown to prolong overall and progression-free survival (PFS), specifically in SM-AHN. Clinical and pathologic evidence of graft-versus-mast cell effect was initially documented in 2006 in a small prospective study. In 2014, Usten et al. reported the largest retrospective study in 57 patients with advanced SM receiving Allo-HCT in the United States and Europe. Responses were observed in 70% of patients with complete remission (CR) in 28%, and overall survival (OS) and PFS at 3 years was 57% and 51%, respectively, for all patients. Clinical outcomes after Allo-HCT were affected by the SM variants, MCL having the poorest outcomes and conditioning intensity.

Allo-HCT is not recommended for ISM/SSM or low-risk AHN (low-risk MDS, low-risk MPN, favorable-risk CLL, and chronic eosinophilic leukemia [CEL] with PDGFRα rearrangement). In advanced SM patients with a suitable donor, HCT is recommended at the time of best response after KIT inhibition. The use of IFN-α is not recommended given that it may be associated with increased acute graft-versus-host disease (GVHD). For conditioning regimen intensity, myeloablative conditioning (MAC) is favored over reduced-intensity conditioning (RIC) when possible, particularly in younger patients without comorbid conditions. Nonmyeloablative conditioning strategies, including anti-CD117 antibodies, are being evaluated.

Progression after autologous HCT occurs in approximately 20% of patients, and durable responses have been reported with midostaurin and donor lymphocyte infusions (DLIs) in this setting. If active against neoplastic mast cells, CD117 antibodies provide an attractive option for prevention of relapse.

Chronic Myelomonocytic Leukemia

CMML is the most frequent of the myelodysplastic-myeloproliferative overlap syndromes recognized by WHO. CMML is defined by the presence of sustained (>3 months) peripheral blood monocyte count > 1 × 10 ⁹ /L with monocytes accounting for ≥10% of the white blood cell (WBC) count in the absence of reactive etiologies along. The bone marrow has dysplastic features but does not meet criteria for other WHO defined myeloproliferative neoplasms.

CMML is a disease of the elderly with median age at diagnosis of 72 years. CMML cases in young adults can develop on a background of germline mutations in RUNX1, GATA2, ANKRD26, or DDX41 while others arise in the setting of chemotherapy or radiation usually with a latency of around 6 years. Overall prognosis is heterogeneous with median survival abbreviated to 1 to 2 years in high-risk groups, underscoring the importance of recognizing these patients early. Cytogenetic abnormalities are detected in 20% to 30% of patients, most common trisomy 8 and 21, abnormalities of chromosome 7, and Y. Mutations in SRSF2, TET2, and ASXL1 are common and thought to be early drivers.

Based on WHO 2017, a WBC count ≥ 13 × 10 ⁹ g/L discriminates the proliferative MPN-CMML, with activation of RAS/MAPK signaling, from the less aggressive MDS-CMML. The other prognostic factor is blast cell percentage with three groups: CMML-0 (< 2% blasts in peripheral blood [PB] and < 5% in bone marrow [BM]), CMML-1 (2%–4% in PB and/or 5%–9% in BM), and CMML-2 (5%–19% blasts in PB and/or 10%–19% in BM). Several prognostic scoring systems have incorporated cytogenetic and molecular abnormalities. These include Groupe Francophone des Myélodysplasies (GFM) model, the CPSS-mol, the Mayo Molecular Model (MMM), and the MD Anderson prognostic score. High-risk cytogenetics are defined as trisomy 8, complex karyotype, or abnormalities of chromosome 7. Mutation of RUNX1, RAS, SETBP1, and ASXL1 confer a higher molecular risk along with red cell transfusion dependence and CMML 1 or 2 categories. The CPSS-Mol outperformed the MMM and GFM systems and was able to separate patients into four groups with median OS ranging from > 144 to 18 months, and cumulative incidence of leukemic evolution from 0% to 48% at 4 years.

Current therapies are guided by cytopenias or proliferation-associated symptoms. Commonly used drugs include erythropoiesis-stimulating agents in anemic patients, cytoreductive drugs in proliferative diseases, and hypomethylating agents (HMAs) in more severe CMML. Targeted therapies have had limited success. Allo-HCT is the only curative option for patient with CMML but its use is restricted to young/fit patients. One-third of these patients are alive at 5 years and deaths are caused almost equally by treatment-related mortality (TRM) or posttransplant disease relapse. In 2017, Allo-HCT was recommended by an international panel, as upfront treatment in cases of CPSS intermediate-2 or high-risk CMML. Owing to lack of prospective data, these recommendations are based on expert opinion rather than evidence.

Disease status at the time of transplant is a major predictor of transplant outcomes.

In 2015, a large retrospective study of 513 CMML patients treated with Allo-HCT demonstrated improved outcomes for the 26% of patients transplanted in CR. A 4-year estimated relapse-free survival (RFS) was 27% and OS was 33%. A retrospective study of 83 CMML patients supported the use of HMA compared with conventional intensive chemotherapy (IC) before transplant with lower relapse rate and superior PFS. While the goal of IC is to reduce bone marrow blasts and aim for CR before transplant, this should be weighed against the risk of complications (infections and organ damage). A Center for International Blood and Marrow Transplant Research (CIBMTR) analysis of 209 patients undergoing transplant showed CPSS scores, Karnosfsky performance status, and graft source were predictors of survival. Five-year survival for low/intermediate-1 patients was 44% compared to 19% for intermediate-2/high-risk patients. In 2021, a multicenter retrospective study in Germany compared outcomes in 261 patients who underwent autologous HCT compared with those who did not according to CPSS. Higher-risk patients (int-2/high) benefited significantly with a 37% reduced hazard for death with transplant. Timing is critical, as a matched propensity score analysis of 70 patients showed a 5-year OS of 51% in chronic-phase CMML versus 19% in blast-transformation CMML.

Prophylactic DLI strategies are suggested strategies in patients at high risk of posttransplant relapse. Immune modulation by DLI strategies or second transplant is a consideration if relapse occurs beyond 6 months posttransplant.

Hypereosinophilic Syndrome

Hypereosinophilic syndrome (HES) refers to a heterogeneous, poorly defined group of disorders characterized by a sustained peripheral blood hypereosinophilia (AEC > 1.5 × 10 ⁹ /L) and eosinophilic tissue infiltrate responsible for organ damage or dysfunction.

The incidence and prevalence of HES is not well characterized, but the age-adjusted incidence is approximately 0.036 per 100,000. In the Surveillance, Epidemiology and End-Result (SEER) database, incidence increased with age, to peak between 65 and 74 years. Retrospective reviews have documented a 5-year survival rate of 80%, decreasing to 42% at 15 years with cardiac dysfunction as the main cause of death.

An exhaustive workup for secondary causes of HES should be undertaken before a primary myeloid disorder is considered. Peripheral blood smear, vitamin B12, tryptase levels, bone marrow biopsy, cytogenetics, immunochemistry, and molecular assays are part of the initial workup. Molecular analysis for KIT mutations can help exclude mast cell disease. To assess end-organ damage, laboratory and imaging should precede tissue diagnosis.

Recurrent cytogenetic alterations and eosinophil-associated molecular abnormalities lead to the WHO classification, “Myeloid/Lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB or FGR1 or with PCM1-JAK2.” FIP1L1-PDGFRA (F/P) rearrangement is the most common molecular abnormality associated with primary myeloid HES (10%–20%). The PDGFRA-rearranged neoplasm can manifest as chronic eosinophilic leukemia, T-cell lymphoblastic lymphoma, or acute myeloid leukemia (AML). PDGFRB-rearranged neoplasms are less frequent and manifest as MPN or CMML. In the novel targeted therapy era, imatinib with or without steroids is considered definitive treatment for PDGFRA/B rearranged neoplasm with eosinophilia. Durable remission after imatinib discontinuation has been reported. FGFR1- and JAK2-rearranged cases may manifest as MPNs or aggressive lymphoma/leukemia and historically have had a dismal prognosis. FGFR1 inhibition (pemigatinib), JAK2 (ruxolitinib), and FLT3 tyrosine kinase inhibitors are being clinically evaluated.

In the absence of one of these translocations, if there is evidence of a clonal marker or cytogenetic abnormality, a diagnosis of CEL-NOS can be considered. It accounts for < 2% of all patients presenting with hypereosinophilia and is characterized by nonspecific cytogenetic/molecular abnormalities and/or increased myeloblasts. Hydroxyurea is effective as cytoreductive therapy. IFN-α has demonstrated hematologic responses and reversion of organ damage. Vincristine, cyclophosphamide, etoposide, and cladribine have shown efficacy in CEL-NOS.

Idiopathic HES is considered after primary (neoplastic) and secondary causes are excluded in the presence of eosinophil-associated end-organ damage. Most patients with idiopathic HES initially respond to steroid monotherapy with initial high-rate response (85% after 1 month); however, many become refractory over time. Imatinib has been used with variable responses (20%–40% response rates). Given the central role played by interleukin (IL)-5 as a differentiation, activation, and survival of eosinophils, drugs targeting the IL-5 axis have been investigated for HES. Mepolizumab, an IL-5 antibody, was approved by the FDA for the treatment of steroid-responsive HES while other antibodies in clinical testing include reslizumab and enralizumab.

IC followed by Allo-HCT should be considered for treatment-refractory disease, specifically FGFR1-rearranged and JAK2-rearranged neoplasm, and CEL-NOS.

The outcomes of transplant in HES are limited to case reports for patients with aggressive disease. Cooper et al. reported 13 cases of successfully treated HES with autologous HCT with disease-free survival ranging from 8 months to 5 years. While the majority of the cases underwent MAC, nonmyeloablative conditioning regiment has also been successful. Improved cardiac function has been reported following transplant.