Treatment of Patients with Aggressive Systemic Mastocytosis, Mast Cell Leukemia and Mast Cell Sarcoma: A Single Center Experience

Abstract Aggressive systemic mastocytosis (ASM), mast cell leukemia (MCL) and mast cell sarcoma (MCS) are rare, life-threatening mast cell disorders, characterized by an aggressive clinical course, drug resistance and a poor survival. Established disease-modifying therapies include interferon-alpha (INF-A), cladribine (2CdA) and midostaurin (PKC412). However, these treatment approaches are unable to exert curative effects in advanced mastocytosis. Intensive therapy, including poly-chemotherapy and hematopoietic stem cell transplantation (HSCT) have also been suggested for patients with rapidly progressing ASM and MCL (Ustun et al, J Clin Oncol 2014;32:3264-3274). However, little is known about long-term outcome and survival in these patients. We analyzed the clinical course and treatment responses in 24 patients with ASM, MCL and MCS seen at the Medical University of Vienna between May 1994 and December 2017. According to World Health Organization criteria, patients were diagnosed as ASM (n=11), ASM with associated chronic myelomonocytic leukemia (ASM-CMML, n=6), ASM with associated chronic eosinophilic leukemia (ASM-CEL, n=1), MCL (n=4) and MCS (n=2). The median age at diagnosis was 59 years (range 21-90 years) and the f:m ratio was 1:2.4. Patients received first-line therapy with INF-A (3x106 units three times a week, n=8), 2-CdA (0.13 mg/kg, days 1-5, n=5); CLAG (cladribine 5mg/m2, days 1-5, ARA-C 2g/m2 day 1-5, G-CSF, 300 µg from day 6 until recovery; n=2), alternating 2CdA and midostaurin (n=2), midostaurin alone (2x100 mg/day, n=2), FLAG (fludarabine, 30mg/m², days 1-5; ARA-C 2 g/m² days 1-5; G-CSF 300µg from day 6 until recovery, n=1) and brentuximab-vedotin (1.6 mg/kg every 3 weeks, n=1). In 3 patients (ASM, n=1; MCL, n=2) no therapy could be administered because of poor performance status. Detailed information on therapies and responses in our patients are provided in Figure 1. In 17 of 21 patients (81%) a response to therapy was observed, namely a complete remission (CR) in one female MCL patient, age 54 yrs (years) receiving 2 cycles of FLAG; a good partial response (GPR) of the remaining tumor mass (after surgery) in one female patient with MCS aged 33 yrs after 2 cycles of CLAG; a partial response (PR) in 5 additional patients; and a stable disease (SD) in 9 patients (Figure 1). Two patients, one female ASM patient, age 54 yrs with PR after 6 cycles of 2CdA and one female patient with MCS, age 30 yrs, with a GPR after CLAG, underwent HSCT and achieved long-term CR under maintenance with midostaurin. Median survival until loss of response to first-line therapy was 20 months (range: 3-73 months). Interestingly, in all 4 patients who had received both 2CdA and midostaurin, no progression of the disease occurred. In the follow up, 3 patients are still alive, 7 developed a secondary acute myeloid leukemia (sAML) and in one patient with ASM-CMML, the CMML component progressed without overt AML. Three patients died due to unrelated (non-SM) events (age at death: 93, 90, and 67 yrs). The patient with CR following FLAG had a relapse of MCL after 4 months. In 3 patients receiving IFN-A, the disease showed progression under therapy and in 2 patients receiving midostaurin, therapy had to be withdrawn due to treatment-related toxicity prior to response evaluation. Interestingly, the risk to develop sAML was significantly higher in patients with ASM/CMML or ASM/CEL (71.4%) compared to patients with ASM (27.2%) or MCL/MCS without an associated hematologic neoplasm (0%) (p<0.05). Salvage therapy in patients with progressive disease (PD or toxicity under first-line therapy, n=4; PD/relapse following response to first-line therapy in patients eligible for further therapy, n=10) included 2CdA, polychemotherapy, INF-A, azacitidine and hydroxyurea. The median number of treatment lines of salvage therapy was 1.7 (range 1-4) and resulted in a median duration of response of 8 months (range: <1 to 44 months). The median survival of patients developing sAML was 4 months and was markedly shorter compared to patients without sAML (median survival 13 months). In conclusion, treatment of ASM, MCL and MCS remains a clinical challenge and unmet treatment-need. The combination of conventional therapy such as chemotherapy with novel tyrosine kinase inhibitors and/or HSCT may be a new promising approach in these patients and may lead to cure in some of them. However, controlled studies are necessary to confirm this hypothesis. Figure 1. Figure 1. Disclosures Valent: Incyte: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Sperr:Novartis: Honoraria; Pfizer: Honoraria; Daiichi Sankyo: Honoraria.

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Systemic Mastocytosis. A GIMEMA Multicenter Survey.

Blood ◽

10.1182/blood.v108.11.4874.4874 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4874-4874

Author(s):

Livio Pagano ◽

Caterina Giovanna Valentini ◽

Pellegrino Musto ◽

Morena Caira ◽

Michela Rondoni ◽

...

Keyword(s):

Mast Cell ◽

Point Mutation ◽

Systemic Mastocytosis ◽

Response To Treatment ◽

First Line ◽

Kit Mutation ◽

First Line Therapy ◽

Line Therapy ◽

Multicenter Survey ◽

Third Line

Abstract To evaluate clinical and biological features, treatments and outcome of patients(pts) with Systemic Mastocytosis(SM). A retrospective study (1995–2006) about pts with SM admitted in 14 Italian hematology divisions in tertiary cares or university hospitals. 30 cases of SM were collected(median age 62 y.o.; M/F 14/16) and classified according to the WHO criteria: Mast Cell Leukemia in 14 pts, Aggressive SM in 12 and Indolent in 3; the remaining one had SM with associated clonal non-mast cell-lineage hematologic disease. Skin was the principal extramedullary organ involved (19 pts) followed by spleen(15), liver(13), and cardiovascular system(12). Molecular biology studies were performed in 22 pts: 15 showed the c-kit point mutation D816V; in another patient a different c-kit mutation was found while in 3 pts additional gene defects and karyotype abnormalities were recognized. Treatments were heterogeneous, and the same patient could have received different therapies after failure of the previous one. Imatinib(400 mg/day) was used in 17 pts (11 as first line therapy, 5 and 1 as second and third line respectively); interferon-alpha(3×3 MU s.c. weekly) was employed in 7 patients(4 as first line therapy, 2 as second and 1 as third line); 2-CDA(0.14 mg/kg) was administered in 3 pts(1 as first, 1 as second and 1 as third line therapy); 2 patients underwent HSCT as second and third line respectively. Data about response to treatment are reported in the table. The overall response rate to imatinib was of 30%, registering 1 complete remission(CR) and 4 partial remissions. All but one responsive patients did not present c-kit point mutation. Three pts(10%) died for progression of SM; a fourth patient in CR died for accidental causes. The actuarial Kaplan-Meier curve at 10 years showed an overall-survival of 87%. Conclusions: SM is a rare disease, characterized by severe and life-threatening mediator-related symptoms but with a low mortality rate. D816V c-kit mutation is frequent and associated with resistance against imatinib: only 1 patient showed a CR. Of note 2-CDA has shown interesting clinical response: all 3 treated pts showed a clinical improvement. Because of the rarity of SM, an effective standard of care is lacking. More data are needed to find new and successful therapeutic strategies; it is possible that new tyrosine kinase inhibitors could allow to achieve clinical and molecular remission of disease, crossing resistence to imatinib due to c-kit mutation, in order to improve above all quoad valitudinem prognosis of these pts. Response to treatments. DRUGS CR PR Stable Unrespons. N.E. TOTAL Imatinib 1 4 5 3 4 17 INF-alpha 0 1 1 5 0 7 2-CDA 0 3 0 0 0 3 Conventional CTX 0 1 2 4 1 8 Allo-HSCT 2 0 0 0 0 2 Wait & Watch 0 0 6 2 0 8

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Cytoreductive Therapy in Systemic Mastocytosis: Outcome Analysis and Response Prediction in 134 Consecutive Patients.

Blood ◽

10.1182/blood.v112.11.1759.1759 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1759-1759

Author(s):

Ken-Hong Lim ◽

Animesh D. Pardanani ◽

Joseph H Butterfield ◽

Chin Yang Li ◽

Ayalew Tefferi

Keyword(s):

Mast Cell ◽

Imatinib Mesylate ◽

Median Duration ◽

Systemic Mastocytosis ◽

Myeloid Cells ◽

First Line ◽

First Line Therapy ◽

Line Therapy ◽

Duration Of Response ◽

Immature Myeloid Cells

Abstract Background: Current therapy in adult systemic mastocytosis (SM) includes observation alone, topical therapy for cutaneous disease, symptomatic non-cytoreductive therapy and cytoreductive therapy. The latter involves several drugs whose individual merit in the treatment of SM has not been well characterized. Patients and Methods: Diagnosis of SM was according to the 2001 WHO criteria (World Health Organization Classification of Tumours of Hematopoietic and Lymphoid Tissues, p 1–351. Lyon, France: IARC Press; 2001). Response to cytoreductive therapy was assessed by consensus criteria (Eur J Clin Invest.2007;37:435). The study population was selected from a series of 342 adult SM patients referred to our institution and seen between 1964 and 2008. KITD816V mutation analysis was performed by DNA sequencing. Results: A total of 134 study patients received treatment that included at least one cytoreductive drug as either first-line (n=105) or second-line (n=29) therapy. Interferon-alpha with or without prednisone (n=58), hydroxyurea (n=43), imatinib mesylate (n=42) and 2-chlorodeoxyadenosine (n=26) were the most frequently used cytoreductive agents accounting for 120 of the 134 study cases; the remaining 14 patients received other cytoreductive drugs, none of which were effective. i. Interferon-alfa (IFN-a) with or without prednisone IFN-a with or without prednisone (24 and 34 patients, respectively) was given to 12 patients with indolent SM (ISM), 14 aggressive SM (ASM), and 32 SM with associated clonal hematological non-mast cell lineage disease (SM-AHNMD). For all 58 patients receiving therapy, complete (CR), major (MR), and partial (PR) response/regression were achieved in 3, 7, and 14 patients, respectively, for an overall response rate (ORR) of 41%. ORR in ISM, ASM, and SM-AHNMD was 50%, 43%, and 38%, respectively. Median duration of response was 12 months (range, 1–117 months). Anemia and elevated ESR were significantly associated with inferior ORR; 29% vs. 56% (p=0.04) and 14% vs. 57% (p=0.01), respectively. BM detection of KITD816V did not appear to affect response rates (p=0.4). ii. Hydroxyurea (HU) HU was given to 2 ASM, 40 SM-AHNMD and 1 mast cell leukemia (MCL) patients. The drug was used as first-line therapy in 30 patients. MR and PR were achieved in 1 and 8 SM-AHNMD patients, respectively (ORR=21%). Median duration of response was 37 months (range, 5–84 months). iii. Imatinib mesylate (IM) in patients with SM and associated eosinophilia IM was given to 22 SM patients who had associated eosinophilia (SM-eos): 2 had ISM, 2 ASM, and 18 SM-AHNMD. The drug was used as first-line therapy in 9 patients. Ten of the 22 patients with SM-eos were known to harbor the FIP1L1-PDGFRA fusion mutation and all responded to IM (ORR=100%). None of 5 FIP1L1-PDGFRA-negative SM-eos patients had a response to IM. In the remaining 7 patients with unknown mutation status, 4 patients had a response to IM (1 CR, 1 MR, and 2 PR). iv. IM in patients with SM not associated with eosinophilia IM was administered to 20 SM patients without associated eosinophilia (7 ISM, 2 ASM, 10 SM-AHNMD, and 1 MCL). Response was documented in 4 (20%) patients (1 CR, 1 MR, and 2 PR) including 1 with ISM, 2 with ASM and 1 with SM-AHNMD. Median duration of response was 19.5 months (range, 9–69 months). Two patients developed interstitial pneumonitis. v. 2-Chlorodeoxyadenosine (2-CdA) 2-CdA was given to 10 ISM, 3 ASM, and 13 SM-AHNMD patients; the drug was used as first-line therapy in 8 patients. CR, MR and PR were achieved in 1, 7, and 4 patients, respectively (ORR=46%). ORR in ISM, ASM, and SM-AHNMD was 50%, 33%, and 46%, respectively. Median duration of response was 11 months (range, 3–74 months). Presence of leukocytosis (WBC > 10 x 109/L), monocytosis (absolute monocyte count > 0.9 x 109/L) or circulating immature myeloid cells was significantly associated with inferior response; 13% vs. 61% (p=0.02); 11% vs. 69% (p=0.006) and 0% vs. 71%, (p=0.001), respectively. Response was not affected by BM detection of KITD816V (p=1.0). Conclusions: Both IFN-a and 2-CdA are reasonable treatment options, with comparable efficacy, for symptomatic SM including the subcategories of ISM, ASM and SM-AHNMD. IFN-a response was significantly better in the absence of anemia or elevated ESR. 2-CdA response was similarly better in the absence of leukocytosis, monocytosis or circulating immature myeloid cells. The therapeutic value of IM was limited to FIP1L1-PDGFRA-positive disease.

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Not BCL2 mutation but dominant mutation conversation contributed to acquired venetoclax resistance in acute myeloid leukemia

Biomarker Research ◽

10.1186/s40364-021-00288-7 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Xiang Zhang ◽

Jiejing Qian ◽

Huafeng Wang ◽

Yungui Wang ◽

Yi Zhang ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Underlying Mechanism ◽

Lymphocytic Leukemia ◽

First Line ◽

Dominant Mutation ◽

First Line Therapy ◽

Line Therapy ◽

Acute Myeloid

AbstractVenetoclax (VEN) plus azacitidine has become the first-line therapy for elderly patients with acute myeloid leukemia (AML), and has a complete remission (CR) plus CR with incomplete recovery of hemogram rate of ≥70%. However, the 3-year survival rate of these patients is < 40% due to relapse caused by acquired VEN resistance, and this remains the greatest obstacle for the maintenance of long-term remission in VEN-sensitive patients. The underlying mechanism of acquired VEN resistance in AML remains largely unknown. Therefore, in the current study, nine AML patients with acquired VEN resistance were retrospectively analyzed. Our results showed that the known VEN resistance-associated BCL2 mutation was not present in our cohort, indicating that, in contrast to chronic lymphocytic leukemia, this BCL2 mutation is dispensable for acquired VEN resistance in AML. Instead, we found that reconstructed existing mutations, especially dominant mutation conversion (e.g., expanded FLT3-ITD), rather than newly emerged mutations (e.g., TP53 mutation), mainly contributed to VEN resistance in AML. According to our results, the combination of precise mutational monitoring and advanced interventions with targeted therapy or chemotherapy are potential strategies to prevent and even overcome acquired VEN resistance in AML.

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Long‐term outcome comparing histological grades of follicular lymphoma patients treated with immunochemotherapy as first‐line therapy: A retrospective analysis from two institutions

European Journal Of Haematology ◽

10.1111/ejh.13359 ◽

2019 ◽

Vol 104 (3) ◽

pp. 198-206

Author(s):

Santiago Mercadal ◽

Juan‐Manuel Sancho ◽

Fina Climent ◽

Gustavo Tapia ◽

Helena Pomares ◽

...

Keyword(s):

Follicular Lymphoma ◽

Retrospective Analysis ◽

First Line ◽

Term Outcome ◽

Long Term Outcome ◽

First Line Therapy ◽

Line Therapy

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Porcine Mast Cell Leukemia with Systemic Mastocytosis

Veterinary Pathology ◽

10.1177/030098588902600117 ◽

1989 ◽

Vol 26 (1) ◽

pp. 90-92 ◽

Cited By ~ 9

Author(s):

D. E. Bean-Knudsen ◽

C. W. Caldwell ◽

J. E. Wagner ◽

H. F. Stills

Keyword(s):

Mast Cell ◽

Systemic Mastocytosis ◽

Cell Leukemia ◽

Mast Cell Leukemia

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Cost-Effectiveness of Pembrolizumab Plus Chemotherapy Versus Pembrolizumab Monotherapy in Metastatic Non-Squamous and Squamous NSCLC Patients With PD-L1 Expression ≥ 50%

Frontiers in Pharmacology ◽

10.3389/fphar.2021.803626 ◽

2022 ◽

Vol 12 ◽

Author(s):

Qiao Liu ◽

Zhen Zhou ◽

Xia Luo ◽

Lidan Yi ◽

Liubao Peng ◽

...

Keyword(s):

Cost Effectiveness ◽

Life Expectancy ◽

Cost Effective ◽

Base Case ◽

First Line ◽

Term Survival ◽

First Line Therapy ◽

Line Therapy ◽

Nsclc Patients

Objective To compare the cost-effectiveness of the combination of pembrolizumab and chemotherapy (Pembro+Chemo) versus pembrolizumab monotherapy (Pembro) as the first-line treatment for metastatic non-squamous and squamous non-small-cell lung cancer (NSCLC) with PD-L1expression ≥50%, respectively, from a US health care perspective.Material and Methods A comprehensive Makrov model were designed to compare the health costs and outcomes associated with first-line Pembro+Chemo and first-line Pembro over a 20-years time horizon. Health states consisted of three main states: progression-free survival (PFS), progressive disease (PD) and death, among which the PFS health state was divided into two substates: PFS while receiving first-line therapy and PFS with discontinued first-line therapy. Two scenario analyses were performed to explore satisfactory long-term survival modeling.Results In base case analysis, for non-squamous NSCLC patients, Pembro+Chemo was associated with a significantly longer life expectancy [3.24 vs 2.16 quality-adjusted life-years (QALYs)] and a substantially greater healthcare cost ($341,237 vs $159,055) compared with Pembro, resulting in an ICER of $169,335/QALY; for squamous NSCLC patients, Pembro+Chemo was associated with a slightly extended life expectancy of 0.22 QALYs and a marginal incremental cost of $3,449 compared with Pembro, resulting in an ICER of $15,613/QALY. Our results were particularly sensitive to parameters that determine QALYs. The first scenario analysis yielded lower ICERs than our base case results. The second scenario analysis founded Pembro+Chemo was dominated by Pembro.Conclusion For metastatic non-squamous NSCLC patients with PD-L1 expression ≥50%, first-line Pembro+Chemo was not cost-effective when compared with first-line Pembro. In contrast, for the squamous NSCLC patient population, our results supported the first-line Pembro+Chemo as a cost-effective treatment. Although there are multiple approaches that are used for extrapolating long-term survival, the optimal method has yet to be determined.

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