IMMUNOCYTIC OR PRIMARY SYSTEMIC AMYLOIDOSIS

Table of contents :


  • Epidemiology
  • Pathogenesis
  • Symptoms & signs
  • Laboratory examinations
  • Prognosis
  • Therapy
  • Response criteria


  • Epidemiology : the incidence of amyloidosis is 8 patients per million per year.
    Pathogenesis : the immunoglobulin free light chain (FLC) is the protein precursor of the amyloid formed in primary systemic amyloidosis (AL)ref1, ref2, and recent literature suggests that the amyloidogenic FLC may be directly toxic in patients with ALref : amyloid infiltrates organs and causes their dysfunction. The 4 most common organs involved in amyloid include: heart, kidney, liver, and the peripheral nerve.
    Symptoms & signs : the symptoms of amyloidosis are vague and include fatigue, edema, and weight loss and are not helpful in formulating the correct differential diagnosis. Occasionally, patients are recognized because of their monoclonal protein and are diagnosed as atypical multiple myeloma because they have a light chain present but < 10% bone marrow plasma cells. Since there is no diagnostic blood test, radiograph, or scan procedure, awareness of the diagnosis is essential to correctly identify patients early in the course. The physical findings of amyloidosis include enlargement of the tongue, periorbital purpura, and the shoulder pad sign. Although very specific for the diagnosis, these are easily overlooked and are seen in < 20% of patients with AL. Reliance on symptoms and signs alone without being aware of the possibility of amyloid will inevitably result in an overlooked diagnosis Laboratory examinations : An accurate diagnosis of amyloidosis and its subtype classification is essential prior to treatmentref. The early recognition of amyloidosis using the algorithm listed below and the careful distinction between immunoglobulin light chain amyloid and the non-immunoglobulin forms of amyloid is critical because systemic therapyref and transplantationref1, ref2 will not have any benefit in the other forms of amyloidref1, ref2 :
    Organ involvement : biopsy of affected organ or biopsy at alternate site
    kidney 24hr urine protein > 0.5 g/day, predominantly albumin
    heart echo : mean wall thickness > 12 mm, no other cardiac cause
    liver total liver span > 15 cm in the absence of heart failure or alkaline phosphatase > 1.5 times institutional upper limit of normal
    nerve peripheral : clinical; symmetric lower extremity sensorimotor peripheral neuropathy
    autonomic : gastric emptying disorder, pseudo-obstruction, voiding dysfunction, not related to direct organ infiltration
    gastrointestinal tract direct biopsy verification with symptoms
    lung direct biopsy verification with symptoms. Interstitial radiographic pattern
    soft tissue tongue enlargement, clinical
    arthropathy
    claudication, presumed vascular amyloid
    skin
    myopathy by biopsy or pseudohypertrophy
    lymph node (may be localized)
    carpal tunnel syndrome
    Alternate sites available to confirm the histologic diagnosis of amyloidosis : fine needle abdominal fat aspirate and/or biopsy of the minor salivary glands, rectum or gingiv. 

    Prognosis : the median survival is approximately 2 years and is < 6 months when there is significant cardiac disease. 10-yr OS = 22%;

    Therapy : the 2 keys to effective treatment of AL amyloidosis are early diagnosis and correct typing. Ideally, treatment should be started before irreversible organ damage has occurred. The current therapeutic approach to systemic amyloidosis is based on the observation that amyloid deposits can be reabsorbed and organ function restored if the synthesis of the amyloidogenic protein precursor is shut down. Therefore, the aim of therapy in AL amyloidosis is to rapidly reduce the supply of amyloid-forming monoclonal free light chains by suppressing the underlying plasma cell dyscrasia while using supportive measures to sustain and possibly preserve organ functions. Hematologic response usually translates into clinically improved organ function and is associated with a substantial survival advantage and improved quality of life. However, if the organ damage is advanced it may be irreversible despite suppression of the amyloid precursor. Most hematologically responding patients show a clinical response after 3–6 months although later responses up to 12 months have been recorded. Importantly, a complete clonal response is not a prerequisite for clinical response and clinical improvement may still occur in patients with a partial clonal response. However, the rate of clinical response is higher in patients with a complete hematologic response than in those with a partial one. Criteria for hematologic response : Assessing the response in amyloidosis : most centers define responses in amyloidosis based on suppression of the precursor immunoglobulin light chain. Patients who achieve hematologic response by electrophoresis, immunofixation, and bone marrow biopsy have higher organ response rates and longer survivalref1, ref2, ref3, ref4, ref5. The measurement of "hematologic response" in patients with AL, however, is difficult because of the inherent low tumor burden. Often the small changes that constitute a "hematologic response" in patients with AL are within the variability of the assays employed. Documenting a response in a cohort of patients who start with a median bone marrow plasmacytosis of 5-7% and median serum M-spike of 1 g/L is a challenge Effective treatments : Investigational therapies : Treatment of localized AL amyloidosis : local production of amyloidogenic light chains and their deposition as amyloid fibrils can occur along the respiratory tract and in the bladder, urethra, head, neck and skin.

    Supportive treatment aimed at improving or palliating organ function, maintaining quality of life, and prolonging survival whilst specific therapy has time to take effect 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.

    Treatment strategies : the availability of several effective regimens allows a better tailoring of treatment aimed at obtaining the most rapid and best suppression of the synthesis of the offending light chain at the minimum toxicity cost. In designing the therapeutic strategy, we must consider that although complete hematologic remission may seem the therapeutic target, reducing the amyloidogenic serum FLC concentration by 50–75% is often sufficient to lead to stabilization or regression of amyloid deposits, with potential for improved organ function and extended survivalref. However, the final outcome will be determined by changes in organ function, which occur over a longer period. In order to minimize the toxicity associated with chemotherapy and gain precious time for possible alternative treatments, an aggressive follow-up with serial measurements of the monoclonal protein is recommended. In the case of PBSCT, monthly measurements could allow responses to be detected quickly, although it can take several months to reach the best response. In our experience, only 1 of the 7 patients who failed to show a hematologic response at +3 months obtained partial response at +12 months, suggesting that patients who do not respond by 3 months should be considered for alternative therapy, avoiding potentially harmful delay. Non-myeloablative therapy, if tolerated, should be pursued to best response or plateau. It may be appropriate to discontinue chemotherapy if the monoclonal protein (a) is no longer detectable by high resolution immunofixation and with normal FLC ratio; (b) has fallen to a plateau level by 50% or more, for at least 3 months, and, despite signs of organ response, toxicity renders further chemotherapy undesirable; (c) has not fallen, or has increased after 2–3 courses of treatment, suggesting that an alternative regimen should be considered. The main effective chemotherapy regimens for systemic AL amyloidosis have advantages and disadvantages. Unfortunately, there are no data yet from prospective randomized trials to support the use of one agent over another, and the choice of strategy is mostly based on nonrandomized studies and personal experience. This accounts for discrepancies in the strategies proposed by different investigators. It is recommended that patients should be treated in the context of clinical trials whenever possible. Based on these considerations some suggestions can be made. Primary treatment of AL: advantages and disadvantages of main regimens :
    regimen
    hematologic 
    response % 
    (CR)
    organ 
    response %
    median time to 
    hematologic 
    response (mo)
    TRM %
    advantages
    disadvantages
    PBSCT 45–60 (14–36) 34–55 3-4 13–14
  • high response rate,
  • improved quality of life,
  • prolonged survival
  • TRM and morbidity still significant
  • limited patient eligibility
  • melphalan and dexamethasone (MDex) 67 (33) 48 4.5 4
  • significant response rate,
  • low toxicity
  • applicable to most AL patients
  • limited experience
  • depletion of stem cells
  • vincristine, doxorubicin, dexamethasone (VAD) 54 (NR) 50 NR 7
  • significant response rate
  • no depletion of stem cells
  • patient selection (vincristine is a poor choice in amyloid neuropathy and doxorubicin in amyloid cardiomyopathy)
  • significant TRM
  • high-dose dexamethasone (HD-Dex) 40–53 
    (16–24) (data from the SWOG study using intensive HD-Dex induction followed by maintenance with HD-Dex and interferon)
    12–45 4 7
  • significant response rate
  • no depletion of stem cells

  •  
  • response rate improvable
  • low response rate in cardiac amyloid
  • significant heart-related TRM
  • melphalan and prednisone (MP) 28–36 
    (uncommon)
    25-30 7–11 low ~ 2
  • low toxicity
  • well tolerated
  • can be applied in virtually all patients

  •  

     
     
     
     
     
     
     
     
     
     
     
     
     
     
     
     
     
     
     
     
     
     
     
     
     
     
     

     

  • low response rate
  • unacceptably long time to achieve a response
  • thalidomide (in the study conducted at the Pavia Centre thalidomide was associated with intermediate dose dexamethasone; in the study conducted at the London Centre 51 patients were treated with thalidomide alone, and 29 patients were treated with thalidomide in association with dexamethasone and/or other alkylating agents) 25–69 
    (0–19)
    25-30 4 low 0–3
  • significant response rate
  • likely less marrow suppression

  •  
  • limited tolerability due to severe toxicity
  • Strategy for AL treatment : patients who fulfill the criteria for high-dose melphalan (200 mg/m2), with normal NT-proBNP and cardiac troponins serum concentration, may have stem cells harvested and may be offered the transplantation procedure. Patients who attain a partial hematologic response, not followed by organ response, can be considered for a second PBSCT or for any of the other regimens without melphalan. It is recommended that PBSCT be performed in units with expertise with AL amyloidosis. Patients who are at intermediate risk should have stem cells harvested, and then may be treated with melphalan and high-dose dexamethasone (MDex). This regimen showed rapid action and hematologic complete response rates comparable to those obtained in PBSCT performed with modified melphalan (100–140 mg/m2), but with very low toxicity. Alternatively, regimens not affecting the stem cell reservoir can be considered, keeping in mind that their toxicity is not negligible (7% TRM): a) VAD-like high-dose Dex induction followed by maintenance with Dex (and interferon, which might deplete stem cells) b) patients < 70 years of age, without symptomatic heart involvement, autonomic neuropathy or polyneuropathy can be treated with VAD. Patients who attain a hematologic response and improvement of organ function and become eligible for PBSCT (melphalan 200 mg/m2) can be considered for this procedure in case of hematologic relapse. Patients who are considered at poor risk should be treated with MP or, preferably, included in investigational trials with the aim of improving the rate of response and its rapidity. In fact, these patients are those in most need of a rapidly effective treatment. For this reason at our center we offer these patients a trial with intermediate dose Dex (20 mg orally, days 1–4, every 4 weeks), melphalan (0.25 mg/kg, adjusted to moderate mid-cycle myelosuppression, days 1–4, every 4 weeks) and thalidomide (100–200 mg/day continuously). Patients relapsing after alkylating-based chemotherapy may be offered intermediate-dose Dex and thalidomide. Supportive therapy remains important in all patients. Sequential solid organ and stem cell transplantation should be considered in selected patients.
    Response criteria (Gertz, 2005) :
    Organ response


    Organ disease progression :
     


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