Chronic lymphocytic leukemia C91.1.

Chronic lymphocytic leukemia (CLL) is the most common leukemic disease in Central Europe. In the WHO classification, chronic lymphocytic leukemia (CLL) is described as indolent (lymphocytic) B-cell lymphoma, which is characterized by a leukemic course. According to WHO, CLL is always a B-cell neoplasia. Only when the proportion of prolymphocytes in the microscopic differential blood count exceeds 55% is a B-PLL present.

For staging according to Binet (Binet JL et al. 1981), only a physical examination and a blood count analysis are necessary. The results of apparative examinations (organomegaly in sonography, CT) are not relevant for staging.

A:

• Hemoglobin ≥ 10 g / dl;
• Platelets ≥ 100,000 / µl;
• < 3 enlarged lymph node regions.

B

• Hemoglobin ≥ 10 g / dl.
• platelets ≥ 100,000 / µl
• ≥ 3 affected lymph node regions

C

• Hemoglobin < 10 g / dl
• platelets < 100.000 / µl
• Lymph node status irrelevant
• Note: regions (n=5) include cervical, axillary, inguinal LK enlargements (unilateral or bilateral), and liver and spleen enlargements (detected by physical examination only).

CLL is the most common form of leukemia in Western industrialized countries. The incidence is 4/100,000/year. There are increasing incidences in older age. In the 8th decade of life, the incidence is 30/100,000. m:w=2:1.

The median age at death with cause of death CLL is 78 years (men,) and 83 years (women). The median age at death is thus equal to the current average life expectancy at birth. Nevertheless, the disease shortens life expectancy.

Risk factors: The risk of developing CLL is increased by the following factors:

Acquired: organic solvents, e.g. benzene according to the German Occupational Diseases Ordinance (No. 1318).

Hereditary: First-degree relatives of CLL patients have an 8.5-fold increased risk of developing CLL and a 1.9-2.6-fold increased risk of developing another indolent lymphoma . Due to the low incidence of these lymphoid neoplasms, the absolute risk of disease in relatives is nevertheless low.

A small group of patients come from families with a strikingly high incidence of CLL and other indolent lymphomas. The genetic basis of this predisposition has not yet been clarified.

CLL is usually preceded by an undiagnosed, clinically asymptomatic preliminary stage with proliferation of clonal B cells. These cells have the biological characteristics of leukemic cells . The condition is termed monoclonal B lymphocytosis (MBL). MBL is detectable in >5% of people over 60 years of age. The risk of progression to CLL requiring treatment is about 1% / year. It depends on the number of monoclonal B lymphocytes.

The median age of onset is between 70 and 75 years, with a wide age range.

The disease is preceded by monoclonal B lymphocytosis (MBL).

The disease is characterized by lymphocytosis of the blood count, which is usually detected incidentally. As the disease progresses, lymphadenopathy, splenomegaly, hepatomegaly, signs of bone marrow infiltration, and possibly autoimmune cytopenias occur.

Clinical symptoms may further manifest with the appearance of B symptoms as well as an increased tendency to infection.

Skin symptoms are not infrequently part of the clinical symptomatology. The following dermatological disease states are associated with CLL to an above-average extent.

Nonspecific (reactive) skin changes in association with CLL (in 30-50% of cases).

• Pruritus
• Chronic urticaria
• Purpura
• Prurigo nodularis
• Eosinophilic panniculitis (Sernicola A et al 2020).
• Hypereosoinophilic dermatitis (Miljković J et al. 2005).

Acute and chronic skin lesions due to CLL-induced immunodeficiency.

Infections of the skin (due to immunodeficiency in the context of the underlying disease).

• herpes simplex
• Zoster
• Zoster generalisatus
• Dermatomycoses
• Yeast infections of the skin

Neoplastic skin lesions (due to immunodeficiency in the context of the underlying disease)

• Malignant skin tumors: It has been found that the risk of developing skin cancer is 8x higher in CLL- patients than in the healthy population. The most common secondary skin tumors in CLL are basal cell carcinoma, squamous cell carcinoma, melanoma, and Merkel cell carcinoma (Morozova EA et al. 2020). The skin cancers often have increased aggressiveness in patients with CLL and are associated with higher recurrence rates and increased metastasis (Brewer JD et al 2014).

CLL- specific infiltrations of the skin.

• Facies leontina: Especially in untreated chronic lymphocytic leukemia, nodular or even planar infiltrates of the skin may occur. They are observed mainly in the facial region (facies leontina).
• Atypical insect bites: unusual, persistent, vesicular, also papular or nodular reactions to insect bites are described (Walker P et al. 2007).
• Eosinophilic dermatosis in haematologic neoplasms: This previously little-known clinical picture is associated with CLL in a high percentage (>70%). The chronic recurrent , pruritic disease can be small-papular, insect bite-like but also flat plaque-like in a zosteriform arrangement (Lucas-Truyols S et al 2017; Almeida FT et al 2020; Cohen PR 2020).

Immunologically accentuated diseases and CLL:

• Pemphigus diseases: Paraneoplasitic pemphigus is clustered associated with chronic lymphocytic leukemia(Yan Z et al (2010).
• Granuloma anulare (Borda LJ et al 2019).
• Erythema anulare centrifugum (described with a marked blood and histoeosinophilia; Miljković J et al. 2005; Stokkermans-Dubois J et al. 2007).
• Pyoderma gangraenosum (Borda LJ et al. 2019).

The leading finding is lymphocytosis with or without accompanying lymphadenopathy. If CLL is suspected, the following investigations are recommended:

Medical history: poor performance, B symptoms, tendency to infection etc.

Previous blood counts / leukocyte values, family history

Physical examination

• Lymph node status, organomegaly,
• bleeding and anemia signs

Blood count (immunophenotyping)

• Leukocytes with differential blood count (microscopic differentiation), platelets, hemoglobin, reticulocytes (in case of anemia signs)
• Multiparametric immunophenotyping
• Expression of CD19 and CD23
• Co-expression of CD5
• Weak or absent expression of CD20, CD79b, FMC7.
• Igκ or Igλ monoclonality.

Bone marrow aspiration: is usually not required for diagnosis, but may be indicated during disease progression to assess unclear cytopenias or quality of remission

Lymph node biopsy: indicated only in the absence of leukemic washout or suspected transformation to aggressive lymphoma (Richter syndrome)

Additional genetic testing:

• Mutation status: del(17p13), TP53 mutation analysis, IGHV mutation status, complex karyotype.
• In case of atypical phenotype, further genetic analysis is necessary for multiparametric to differentiate from other indolent lymphomas.

Comments: Data on the unfavorable prognosis of patients with deletion 17p13 are based on molecular cytogenetic analyses by FISH. The collective of patients with inactivation of p53 by mutations overlaps very much with that of patients with del 17p13, but is not completely congruent.

Further laboratory analyses (depending on symptoms and planned therapy)

• Haptoglobin and Coombs test if hemolysis is suspected, and prior to initiation of fludarabine-containing therapy.
• Glomerular filtration rate (GFR) in case of planned fludarabine- or venetoclax-containing therapy
• Quantitative determination of immunoglobulins in cases of suspected immunodeficiency
• β2-microglobulin (prognostic parameter)

Sonography abdomen: spleen, liver, lymph nodes

According to the 2018 International Workshop on CLL (IWCLL) criteria, the diagnosis of CLL is defined by meeting the following criteria:

Detection of at least 5,000 clonal B lymphocytes per μl in peripheral blood for at least 3 months (Below this level, monoclonal B lymphocytosis (MBL) can be diagnosed in the absence of signs of disease such as: B symptoms, lymphadenopathy, hepatomegaly, splenomegaly, cytopenia, etc.,.

Small, morphologically mature lymphocytes predominate in the blood smear.

Multiparametric immunophenotyping shows co-expression of the B-cell antigens CD19, CD20, and CD23 with the T-cell antigen CD5. Further characteristic: relatively weak expression of surface immunoglobulin, CD20, and CD79b. Light chain restriction (Igκ or Igλ), preferably by double labeling of CD19/Igκ or CD19/Igλ can be used to detect monoclonality of the cells.

Monoclonal B-lymphocytosis

Reactive lymphocytoses (viral infections, collagenoses)

Leukemic non-CLL lymphomas(follicular lymphoma, lymphoplasmocytic lymphoma, marginal zone lymphoma, B prolymphocytic leukemia (B-PLL)).

Hairy cell leukemia

T-cell leukemia with large granular lymphocytes

Mantle cell lymphoma: Special attention is needed to differentiate it from mantle cell lymphoma due to the similar immunophenotype with co-expression of CD19 and CD5, although unlike CLL, mantle cell lymphomas are usually negative for CD23. In case of non-classical immunophenotype of CLL, FISH analysis to exclude the typical aberration of mantle cell l ymphoma (translocation (11;14), or histological examination of the extirpated lymph node to exclude overexpression of cyclin D1 are indicated.

Lymph node enlargement of other etiology.

Furthermore, an existing pruritus should be differentially diagnosed with regard to another non-CLL-associated genesis (see pruritus below).

Antineoplastic treatment is initiated only when symptoms are present. The choice of drugs depends on the general condition of the patient and relevant comorbidity. Therapy is currently undergoing a transformation. Instead of the previous standard of chemoimmunotherapy, targeted inhibitors that interfere with B-cell receptor signaling or the regulation of programmed cell death are increasingly used. The optimal combinations and sequences of the various drugs have not yet been established. There is a general indication for therapy in stage Binet C as well as in stage Binet B or A, if further criteria for a therapy obligation are fulfilled:

• Occurrence/worsening of anemia/thrombocytopenia.
• Massive (>6 cm below the costal margin), progressive or symptomatic splenomegaly; note: spleen size is individually variable depending on body size and weight.
• massive (>10 cm in diameter), progressive or symptomatic lymphadenopathy
• Lymphocyte doubling time of less than 6 months or 50% increase in 2 months, starting from a baseline of at least 30,000 lymphocytes/µl, and after exclusion of other causes of lymphocytosis
• Autoimmune cytopenia refractory to standard therapy.
• Any of the following constitutional symptoms:
• Unwanted weight loss > 10% in 6 months.
• Fever of unknown cause for more than 2 weeks
• Night sweats for more than one month without evidence of infection

First-line therapy: The choice of therapy in CLL is based on comorbidity, (determined e.g. by the CIRS - Cumulative Illness Rating Scale - score), genetic status, renal function and less on calendar age. Whenever possible, therapy should take place in the context of clinical trials.

Patients without genetic risk factors (good general health with good organ function without deletion del(17p13) or TP53 mutation, complex karyotype, IGHV unmutated).

Ibrutinib/rituximab significantly prolongs progression-free survival (hazard ratio (HR) 0.352) and overall survival (HR 0.168) compared with fludarabine/cyclophosphamide/rituximab (FCR) in patients ≤70 years in the E1912 trial. Ibrutinib was given as continuous therapy until disease progression in this study. Subgroup analysis shows the advantage in favor of ibrutinib/rituximab especially for patients with unmutated IGHV status, so BTKI-based therapy is primarily recommended here.

No long-term therapy: If no long-term therapy is desired by the patient or the patient is unsuitable for BTKI (dual platelet aggregation inhibition, bleeding tendency, cardiac arrhythmia, possibly severe heart failure), BTKI-based therapy is primarily recommended. severe heart failure), the FCR regimen(fludarabine (F)+ cytarabone (C) + rituximab (R ) represents an effective alternative therapy, especially for patients with mutated IGHV status (Hallek M et al. 2010; Stilgenbauer S et al. 2014). The addition of R to FC prolonged progression-free survival by approximately 20 months.

Ibrutinib significantly prolongs progression-free survival (HR 0.39) compared to bendamustine/rituximab (BR regimen) in patients ≥65 years of age, but not overall survival at short follow-up (Woyach JA et al.(2018).

Comparing the BR regimen (bendamustine+ rituximab) to the FCR regimen in first-line therapy (Eichhorst BF et al. 2016), BR has been previously recommended in preference to FCR in fit patients beyond 65 years of age due to its more favorable toxicity profile.

The combination of ibrutinib and rituximab showed no benefit compared to ibrutinib monotherapy. Therefore, ibrutinib is recommended as monotherapy, by analogy also for younger fit patients.

Reduced general condition (unfit patients, slow go )

For patients with impaired renal function and/or increased comorbidity (e.g., CIRS ≥6), several options are also available therapeutically with ibrutinib, aclabrutinib, venetoclax, chlorambucil, or bendamustine/anti-CD20 antibody (obinutuzumab, rituximab).

The BTK inhibitor ibrutinib resulted in significant prolongation of both progression-free survival and overall survival and a significant increase in remission rate (86 vs 35%) in patients ≥65 years of age and comorbidity compared with chlorambucil monotherapy (Burger JA et al. 2015).

Ibrutinib/obinutuzumab resulted in a significant prolongation of progression-free survival compared to chlorambucil/obinutuzumab (Moreno C et al. 2016), but not overall survival. Ibrutinib was effective in this regard, in contrast to chemoimmunotherapies, regardless of IGHV status, so that first-line therapy with ibrutinib is recommended, particularly in patients with prognostically unfavorable, unmutated IGHV status.

Acalabrutinib results in significant prolongation of progression-free survival, but not overall survival at short follow-up, compared with chlorambucil-obinutuzumab in patients ≥65 years of age or in patients <65 years of age with comorbidity (Sharman JP et al (2020).

The acalabrutinib/obinutuzumab combination also significantly prolongs progression-free survival compared with chlorambucil/obinutuzumab. Response rates were significantly higher with acalabrutinib/obinutuzumab than with chlorambucil/obinutuzumab, but the differences in progression-free survival and overall survival were not statistically significant.

Temporary combination therapy consisting of the BCL2 inhibitor venetoclax (12 months) plus obinutuzumab (6 months) was found to be significantly superior to chlorambucil/obinutuzumab-based chemoimmunotherapy in terms of progression-free survival (Fischer K et al. 2019). This advantage was shown to be independent of IGHV mutation status and TP53 aberration.

In immunochemotherapy of elderly patients with comorbidity, the combination chlorambucil/binutuzumab compared to chlorambucil/rituximab leads to an increase in the rate of hematologic remissions as well as a prolongation of progression-free survival (Goede V et al. 2014).

It is recommended to treat comorbid patients with regard to primary therapy with a BTK inhibitor (ibrutinib or acalabrutinib) as oral continuous therapy. Alternatively, venetoclax/binutuzumab can be applied (over a total of 12 months).

Chlorambucil/binutuzumab or bendamustine/rituximab are available as an alternative form of therapy for patients with mutated IGHV status or for patients in whom other reasons prevent this (Goede V et al. 2014).

Poor general condition (frail patients, no go):

For this group of patients (short life expectancy due to comorbidity), supportive therapies are the main focus. If the poor general condition is essentially due to CLL, the use of antineoplastic drugs such as steroids, chlorambucil, bendamustine, ibrutinib, venetoclax or anti-CD20 antibodies is also useful.

Patients with genetic risk factors: With evidence of a del(17p13) or a TP53 mutation and/or a complex karyotype and/or unmutated IGHV status have a lower response rate and shorter progression-free survival and overall survival after chemotherapy and chemoimmunotherapy (chlorambucil, fludarabine-containing regimens, bendamustine, also in combination with rituximab).

In patients with CLL requiring therapy and del(17p13)/TP53 mutation or a complex karyotype, the use of BTKI or alternatively the combination of venetoclax/obinutuzumab (over 12 months) is recommended in first-line therapy, regardless of general condition. Alternative: combination of idelalisib/rituximab. If idelalisib is used, stringent PJP prophylaxis and also CMV viremia screening must be performed.

Second-line therapy:

In second-line therapy, age and comorbidity of the patient, type of primary therapy and its success, altered biological characteristics of CLL (e.g., detection of del(17p13) or TP53 mutation) play an important role. After therapy with BTK or BCL2 inhibitors, specific resistance mutations (in BTK, PLCG2 or BCL2, respectively) may occur, the presence of which precludes repetition of the corresponding therapy. Whenever possible, it is recommended that patients receive therapy in the context of clinical trials.

Progress / refractory / early relapse

Patients refractory to current standard chemoimmunotherapies (FCR, Clb-Obi, BR) or who achieved only a short remission (<2-3 years), or relapsed patients with evidence of a del(17p13) or a TP53 mutation have a poor prognosis. Their median overall survival was 1-2 years prior to the introduction of the new agents, calculated from the time of salvage therapy. Here, stable disease in treatment-naive patients is also considered treatment failure according to the IWCLL 2018 criteria. In this patient population, three effective drugs are available, the BTK inhibitor ibrutinib, the BCL2 inhibitor venetoclax, and the PI3Kdelta inhibitor idelalisib.

The BTK inhibitor ibrutinib significantly prolonged progression-free survival and overall survival when compared with the anti-CD20 antibody ofatumumab (Michallet AS et al. 2018)

The triple combination ibrutinib/bendamustine/rituximab/ was superior to the dual combination bendamustine/rituximab and also resulted in prolonged progression-free survival (Chanan-Khan A et al 2016).

The BTK inhibitor acalabrutinib significantly prolonged progression-free survival in patients after at least one prior therapy compared with therapy with idelalisib/rituximab or bendamustine/rituximab.

The BCL2 inhibitor venetoclax in combination with rituximab led to an increase in progression-free survival and overall survival, as well as an increase in the rate of hematologic remissions and MRD negativity, respectively, in patients starting at first relapse compared with bendamustine/rituximab (Seymour JF et al (2018).

Venetoclax resulted in a remission rate of 79% in patients with relapsed or refractory CLL with evidence of a del(17p13) or a TP53 mutation and after pretreatment with a BCR signal transduction pathway inhibitor as monotherapy in a single-arm study (Stilgenbauer S et al. 2018). Similarly, the PI3Kdelta inhibitor idelalisib in combination with rituximab versus rituximab monotherapy significantly prolonged progression-free survival and overall survival in patients with relapsed CLL and comorbidity. Prophylaxis against Pneumocystis jirovecii and regular clinical monitoring for CMV viremia is recommended in all patients.

In patients with ibrutinib pretreatment, the combination venetoclax/rituximab is the preferred standard of care starting with second-line therapy, regardless of risk factors (TP53 aberration) and fitness, due to its high efficacy and limited duration of therapy (2 years).

In patients with prior therapy with venetoclax plus CD20 antibody, re-treatment with the BCL2 inhibitor appears to be feasible if remission is prolonged (Furman RR et al 2014). BTK inhibitors also show very good efficacy after prior therapy with venetoclax.

In patients after first-line treatment with chemoimmunotherapy, BTK inhibitors are alternatively available in the second-line setting in addition to the venetoclax/rituximab combination.

In patients with ibrutinib pretreatment, the combination of venetoclax/rituximab is the preferred standard of care starting with second-line therapy, regardless of risk factors (TP53 aberration) and fitness, due to its high efficacy and limited duration of therapy (2 years).

In patients with venetoclax/binutuzumab pretreatment, retreatment or a switch to a BTK inhibitor is possible.

Progress or early relapse (12-18 months - exclusion of Richter transformation by PET-CT and histology).

• In case of relapse below the median remission duration: change to a BTK inhibitor or therapy with venetoclax/rituximab, also depending on initial tolerability
• In case of relapse above the median remission duration: therapy with venetoclax/rituximab.

Allogeneic stem cell transplantation is an option in high-risk patients.

Richter transformation: In patients with transformation of CLL into aggressive non-Hodgkin lymphoma (Richter transformation), chemoimmunotherapy based on R-CHOP can be performed. In biologically young patients, consolidative allogeneic stem cell transplantation is recommended, especially if NHL and CLL are clonally related (no independent second lymphoma). In the absence of suitability for allogeneic transplantation, autologous stem cell transplantation may be performed instead (S3 Guideline 2018).

In addition, if there are contraindications to allogeneic stem cell transplantation, immunotherapy with the use of checkpoint inhibitors (e.g., pembrolizumab) may be considered (Ding W et al (2016). In patients with transformation to Hodgkin lymphoma, chemotherapy can be administered as for primary Hodgkin lymphoma.

Late relapse

For late relapse (>24 months after therapy), there was superiority of venetoclax/rituximab-based therapy (for a total of 2 years) over bendamustine/rituximab for patients with late relapse after bendamustine/rituximab (>24 months).

Venetoclax/rituximab is presented as the preferred treatment option for patients with late relapse regardless of fitness status (Seymour JF et al 2018).

As an alternative besides venetoclax/rituximab, ibrutinib or acalabrutinib is available for patients unpretreated with BTK inhibitors.

Allogeneic stem cell transplantation

Allogeneic stem cell transplantation remains an option in CLL for patients with an unfavorable prognosis. The indication criteria have currently been revised as follows (Dreger P et al. (2018):

CLL high risk I: resistant to chemoimmunotherapy (if performed), TP53 mutation or deletion, sensitive to pathway inhibitors (BTKI, venetoclax);

CLL high risk II: resistant to chemoimmunotherapy and to at least one pathway inhibitor (BTKI and/or venetoclax).

For patients with high risk II who are refractory to both chemoimmunotherapy and at least one targeted therapy, allogeneic transplantation is an option regardless of TP53 status. Allogeneic transplantation is also recommended for patients with CLL and Richter transformation, if the patient's physical condition and donor situation allow. Transplantation should be performed within clinical trials when possible.

Autologous stem cell transplantation

Autologous stem cell transplantation as a high-dose therapy with autologous blood stem cell transplantation does not lead to an increase in remission and long-term survival rates compared to chemoimmunotherapies, so that this procedure can no longer be recommended for the therapy of CLL. An exception is the Richter transformation, if an allogeneic transplantation is not possible.

Supportive therapy and treatment of complications

CLL patients often present with infectious complications during the course of the disease, which are exacerbated by the decrease in immunoglobulin concentrations and other mechanisms of acquired immunodeficiency. Particularly careful monitoring with intensive general internistic treatment of e.g. chronic or recurrent bronchitis is indicated. Prophylactic substitution with immunoglobulins reduces the risk of severe infections but has no significant impact on mortality . In June 2018, the EMA updated its guideline in the form of a Summary of Product Characteristics and established these criteria for substitution with immunoglobulins for patients with secondary immunodeficiency (Raanani P et al. (2008):

• severe, recurrent infections
• ineffective antimicrobial therapy
• Evidence of absence of specific antibody formation (after vaccination) or serum IgG level <4g/l.
• Age-appropriate vaccinations are recommended, although specific antibody formation may be reduced. Travel vaccinations should only be given after consultation with the specialist in charge, as live vaccines, among others, could endanger the patient.

Survival time is highly variable and depends on the stage of the disease, cytogenetics and laboratory parameters (see above). According to current knowledge, CLL cannot be cured by conventional chemotherapy, antibody-based therapies or specific inhibitors, e.g. against BTK, Pi3K or BCL2. The only potentially curative option is allogeneic stem cell transplantation.

Biological prognostic factors: β2-microglobulins in serum; molecular cytogenetics including TP53 aberration;

Comment: mutational status of variable segments of immunoglobulin heavy chain genes (IGHV)-such as thymidine kinase, SF3B1/NOTCH1 mutations, and other genomic aberrations, among others, currently require prospective validation and are not currently the basis of specific, therapeutic considerations outside of clinical trials.

In order to better assess prognosis prior to initiation of first-line therapy, the so-called CLL-IPI(International Prognostic Index) can be determined, using the following parameters for calculation(https://www.qxmd.com/calculate/cll-ipi) are required: age (≤/> 65 years), Binet stage, β2-microglobulin (</>3.5 mg/dl), IGHV mutation status, deletion 17p (FISH), and TP53 mutation status (The International CLL-IPI working group (2016). However, this prognostic index has only been validated to a limited extent on the basis of the new targeted drugs and is not relevant for the choice of primary therapy.

There is no evidence for effective measures for prevention. Early diagnosis based on the identification of monoclonal B lymphocytosis has not been established. It is also only useful if the early diagnosis of CLL leads to a significant improvement in prognosis.

1. Almeida FT et al (2020) Eosinophilic dermatosis of hematologic malignancy: a case report. Dermatol Online J 26:13030/qt4k8908jb.
2. Bari O et al. (2017) Eosinophilic dermatosis of hematologic malignancy mimicking varicella zoster infection: report in a woman with chronic lymphocytic leukemia and review of the literature. Dermatol Pract Concept 7:6-15.
3. Binet JL et al (1981) A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer 48:198-204.
4. Borda LJ et al. (2019) Unilateral granuloma annulare in association with pyoderma gangrenosum and chronic lymphocytic leukemia. Dermatol Online J 25:13030/qt62c9d1ws.
5. Brewer JD et al (2014) Lymphoma-associated skin cancer: incidence, natural history, and clinical management. Int J Dermatol 53:267-274
6. Burger JA et al (2014) The microenvironment in chronic lymphocytic leukemia and other B cell malignancies: insight into disease biology and targeted therapies. Semin Cancer Biol 24:71-81.
7. Burger JA et al (2015) Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med 373:2425-2437.
8. Chanan-Khan A et al. (2016) Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma (HELIOS): a randomized, double-blind, phase 3 study. Lancet Oncol 17:200-211.
9. Cohen PR (2020) What's in a name? a new nomenclature has been proposed For eosinophilic dermatosis of hematologic malignancy (EDHM): hematologic-related malignancy-induced eosinophilic dermatosis (He Remained). Dermatol Online J 26: 13030/qt1zd6p6z2.
10. Ding W et al (2016) PD-1 Blockade with Pembrolizumab (MK-3475) in Relapsed/Refractory CLL Including Richter Transformation: An Early Efficacy Report from a Phase 2 Trial (MC1485). American Society for Hematology (ASH) Annual Meeting: Abstract 834 https://ash.confex.com/ash/2015/webprogram/Paper84816.html.
11. Döhner H et al (2000) Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 343:1910-1916.
12. Dreger P et al. (2018) for the European Research Initiative on CLL (ERIC) and the European Society for Blood and Marrow Transplantation (EBMT): High-risk chronic lymphocytic leukemia in the era of pathway inhibitors: integrating molecular and cellular therapies. Blood 132:892-902.
13. Eichhorst BF et al (2016) First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol 17:928-942.
14. Fischer K et al (2019) Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med 380:2225-2236.
15. Furman RR et al (2014) Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 370:997-1007.
16. Guideline (2018) Guideline on core SmPC for human normal immunoglobulin for intravenous administration (IVIG). European Medicines Agency. Coming into effect January 1, 2019. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-core-smpc-human-normal-immunoglobulin-intravenous-administration-ivig-rev-5_en
17. Hallek M et al. (2010) First-Line Treatment with Fludarabine (F), cyclophosphamide (C), and Rituximab (R) (FCR) Improves Overall Survival (OS) in Previously Untreated Patients (pts) with Advanced Chronic Lymphocytic Leukemia (CLL): Results of a Randomized Phase III Trial On Behalf of An International Group of Investigators and the German CLL Study Group. Lancet 376:1164-1174.
18. Jin A et al (2019) Eosinophilic dermatosis of hematologic malignancy responding to dupilumab in a patient with chronic lymphocytic leukemia. JAAD Case Rep 5:815-817.
19. Lucas-Truyols S et al (2017) Eosinophilic dermatosis of hematologic malignancy. Actas Dermosifiliogr 108:e39-e44.
20. Michallet AS et al. (2018) Rituximab plus bendamustine or chlorambucil for chronic lymphocytic leukemia: primary analysis of the randomized, open-label MABLE study. Haematologica 103:698-706.
21. Miljković J et al (2005) Hypereosinophilic dermatitis-like erythema annulare centrifugum in a patient with chronic lymphocytic leukaemia. J Eur Acad Dermatol Venereol 19:228-231.
22. Moreno C et al. (2016) Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 20:43-56.
23. Morozova EA et al (2020) Cutaneous manifestations of B-cell chronic lymphocytic leukemia. Int J Hematol 112:459-465.
24. Rai KR et al (1975) Clinical staging of chronic lymphocytic leukemia. Blood 46:219-234.
25. S3 Guideline (2018) S3 guideline on diagnosis, treatment and follow-up for patients with chronic lymphocytic leukemia (CLL), 2018. https://www.awmf.org/leitlinien/detail/ll/018-032OL.html
26. Sernicola A et al (2020) Eosinophilic panniculitis triggered by arthropod bites in chronic lymphocytic leukemia. Clin Ter 171:e369-e370.
27. Seymour JF et al (2018) Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med 378:1107-1120.
28. Sharman JP et al (2020) Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet 395:1278-1291.
29. Stilgenbauer S et al. (2014) Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial. Blood 123:3247-3254
30. Stilgenbauer S et al (2018) Venetoclax for patients with chronic lymphocytic leukemia with 17 deletion: results from the full population of a phase II pivotal trial. J Clin Oncol 36:1973-1980.
31. Stokkermans-Dubois J et al (2007) Erythema annulare centrifugum revealing chronic lymphocytic leukaemia. Br J Dermatol 157:1045-1047).
32. The International CLL-IPI working group (2016) An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol 17:779-790.
33. Walker P et al (2007) Exaggerated insect bite reaction exacerbated by a pyogenic infection in a patient with chronic lymphocytic leukaemia. Australas J Dermatol 48:165-169.
34. Woyach JA et al.(2018) Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med 379:2517-2528.
35. Yan Z et al. (2010) Paraneoplastic pemphigus characterized by polymorphic oral mucosal manifestations--report of two cases. Quintessence Int 41:689-694