Primary CNS lymphoma

 Reference: Annals of Oncology June 2024

ESMO guidelines

Diagnosis Recommendations

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Contrast-enhanced cranial MRI is the recommended imaging modality for patients with PCNSL [II, A]. The IPCG protocol based on 3T or 1.5T MRI is recommended [V, A].

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PCNSL diagnosis must be confirmed by histopathological examination of tumour biopsy [III, A].

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Corticosteroid therapy before tissue biopsy should be avoided whenever clinically possible [IV, D]. In case of clinical deterioration, urgent biopsy should be carried out before the start of corticosteroids [IV, A].

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Tissue samples should be collected by stereotactic biopsy in patients with brain lesions [IV, A].

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Tumour resection is not recommended, except in carefully selected patients with rapidly increasing intracranial pressure who may benefit from surgical debulking at the time of tumour biopsy [IV, D].

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Diagnosis is based on morphology and immunohistochemistry [minimum stain panel includes cluster of differentiation (CD)20, CD3, CD10, B-cell lymphoma (Bcl)-6, Bcl-2, multiple myeloma 1 (MUM1) and Ki-67 antibodies]. Molecular analysis of Ig heavy and light chain loci can be used in selected cases where diagnosis is difficult [V, A].

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When brain biopsy is contraindicated, CSF examination is a valid option. Flow cytometry, MYD88 L265P mutation analysis and IL-10 levels in CSF samples may support a diagnosis of PCNSL [IV, B].

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Suspicion of PVRL should be confirmed by conventional cytology examination of the vitreous humour and, when possible, by flow cytometry. Although not diagnostic, MYD88 L265P mutation and IL-10 levels may be assessed in the vitreous and aqueous humours as indicators of ocular lymphoma [III, A].

Staging

Recommendations

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Spinal cord imaging should be carried out in symptomatic patients or in case of CSF positivity [V, B].

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Unless lumbar puncture is clinically contraindicated, physical–chemical features of CSF as well as conventional cytology and flow cytometry should be assessed in all patients [IV, B].

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Ophthalmological assessment by slit lamp fundoscopy should be carried out in all patients to exclude intraocular involvement [IV, A]. When available, retinal angiography or tomography is advisable [IV, C].

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All patients should undergo systemic imaging to exclude extra-CNS disease using FDG–PET, preferably combined with contrast-enhanced CT scan [V, B].

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If FDG–PET–CT is not feasible, contrast-enhanced total-body CT scan, bone marrow aspiration and biopsy and testicular US should be carried out [V, B].

Treatment recommendations- Newly diagnosed

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Enrolment in suitable prospective clinical trials should be offered to every patient with PCNSL [I, A].

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When a prospective trial is not available, induction ChT including HD-MTX is recommended at a minimum dose of 3 g/m2 delivered in a 3-h infusion [I, A].

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Combinations of HD-MTX with other cytotoxic agents that cross the blood–brain barrier and have been tested in prospective (preferably randomised) trials are recommended (e.g. MATRix, R–MBVP, rituximab–HD-MTX–carmustine–etoposide–prednisone, R–MPV, R–MT) [I, A].

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The benefit of adding rituximab [not European Medicines Agency (EMA) approved, not Food and Drug Administration (FDA) approved] to induction HD-MTX-based polyChT remains unclear. The balance between tolerability and efficacy should be discussed with patients and their carers [II, B].

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Judicious reduction of MTX dose according to renal function and comorbidities is recommended [III, A].

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Intrathecal ChT is not recommended in routine practice, except for patients with CSF dissemination who are unable to receive ChT including MTX at ≥3 g/m2 or for patients with persistence of CSF or meningeal disease at the end of first-line treatment [III, D].

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Intravitreal ChT is not recommended in routine practice, except for patients with persistent intraocular lymphoma at the end of first-line treatment [III, D].

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HDC–ASCT is recommended as consolidation in fit patients with responsive or stable disease after suitable induction ChT [I, A].

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Fitness for HDC–ASCT should be evaluated dynamically during treatment, especially in older patients who may gain or lose ‘HDC–ASCT fitness’ during induction ChT [III, B].

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Thiotepa-based ASCT conditioning regimens should be used. The dose of thiotepa combined with either busulfan or carmustine should be based on established protocols and informed by patient fitness and comorbidities [III, A].

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Consolidation WBRT at a dose of 36-40 Gy/20 fractions is recommended in young patients who are not suitable candidates for ASCT. Safety profiles (haematological and cognitive toxicities) should be considered for individual therapeutic choice [I, A].

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Consolidation WBRT at a dose of 36-40 Gy/20-22 fractions should be avoided or deferred in elderly patients because of the high risk of disabling neurocognitive impairment [I, D].

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Reduced-dose WBRT (23.4 Gy) is an option for patients with responsive disease after suitable induction ChT, but the longer-term effects on cognitive function remain to be defined, especially in elderly patients [III, B].

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Watchful waiting can be considered in elderly patients in CR after induction with an established drug combination [II, B]. Maintenance with oral drugs, such as alkylating agents or immunomodulators such as lenalidomide (not EMA approved, not FDA approved) can be considered on an individual basis [IV, C].

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There is no established standard of care for patients unfit for HD-MTX-based ChT. Valid (but incompletely investigated) palliative options include upfront WBRT [III, B], corticosteroids, oral alkylating agents with or without rituximab (not EMA approved, not FDA approved), BTK inhibitors and immunomodulators [V, C].

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Assessment of response to treatment should follow modalities and timing proposed by the IPCG criteria.

Relapsed refractory PCNSL treatment recommendations

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Patients with r/r PCNSL should be registered in a prospective clinical trial assessing novel drugs or strategies [III, A].

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Fit patients with refractory or early relapsed PCNSL can be treated with, for example, HD-ifosfamide- or HD-AraC-based combinations, followed by ASCT or WBRT according to previous treatment [III, B].

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Patients with refractory or early relapsed PCNSL unfit for salvage polyChT could be treated with WBRT [V, C] or with a single drug such as ibrutinib, lenalidomide or temozolomide [III, B; not EMA approved, not FDA approved].

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Patients with late relapse of PCNSL could be re-treated with HD-MTX, employing the same or similar ChT regimen used in first-line treatment, and consolidated with ASCT or WBRT in the case of response [IV, B].

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The increased risk of neurotoxicity associated with WBRT should be considered in patients aged >60 years with r/r PCNSL [IV, C].

IPCG guidelines for response assessment

The International Primary Central Nervous System Lymphoma Collaborative Group (IPCG) response criteria combine MRI findings, ophthalmologic examination, cerebrospinal fluid analysis, and corticosteroid use to assess treatment response in primary CNS lymphoma.^[1-2] These criteria were published in 2005 to standardize response assessment across clinical trials.^[2]

Response Categories

The IPCG criteria define the following response categories:^[3-4]

Complete Response (CR):

• Complete disappearance of all gadolinium enhancement on brain MRI
• No corticosteroid use
• Negative CSF cytology
• Normal ophthalmologic examination (if previously involved)

Unconfirmed Complete Response (CRu):

• Either no residual gadolinium enhancement but continued steroid use, OR
• Small residual gadolinium enhancement probably related to biopsy or hemorrhage

Partial Response (PR):

• ≥50% decrease in size of contrast-enhancing tumor on MRI
• Stable or reduced corticosteroid dose
• No new lesions

Progressive Disease (PD):

• ≥25% increase in tumor size on MRI, OR
• Appearance of any new tumor lesion

Stable Disease:

• Situations that do not meet criteria for CR, CRu, PR, or PD

Key Assessment Components

The IPCG criteria require evaluation of multiple disease sites:^[1-2]

• Brain MRI with gadolinium contrast to measure enhancing lesions
• Ophthalmologic examination including slit-lamp examination for vitreoretinal involvement
• CSF analysis with cytology when safely obtainable
• Corticosteroid dose documentation, as steroids can dramatically reduce enhancement independent of tumor response

 

New prognostic system for myeloma

 

Reference: Blood Journal Sept 2025

IMS/IMWG recommendations for the definition of HR MM

Criteria for HR MM
Del(17p) defined by FISH on CD138-purified cells with CCF >20%
TP53 mutation defined with NGS-based methodologies on CD138-purified cells
t(4;14), t(14;16), or t(14;20) if co-occurring with 1q gain/amplification∗ and/or del(1p32)
Monoallelic del(1p32) occurring with 1q gain/amplification
Biallelic del(1p32)
β2M >5.5 mg/dL in the context of preserved renal function and creatinine <1.2 mg/dL

FISH, fluorescence in situ hybridization; NGS, next-generation sequencing.

∗

1q+, gain (3 copies) or amplification (≥4 copies) of the long arm of chromosome 1.

Burkitt's lymphoma

 Reference: ERN Blood Net Lancet Hematology Feb 2025

BL-IPI

• age > 40yr, 
• LDH > ULN
• ECOG 2 or higher
• CNS involvement

Initial diagnosis: excision or bx, fluid or bone marrow aspirate, cytogenetics or FISH ( t ( 8;14) in Burkitt's as opposed to t (14;18) in Follicular.

• EBV and SOX 11 testing on all cases. Then, based on the findings, you divide Burkitt's into 3 groups.
• Initial testing: CBC, CMP, phosphate, uric acid, viral serology, EBV PCR, CT. PET not required. MRI if neurologic symptoms.
• Evaluate risk factors for TLS: Circulating Burkitt cells, serum LDH, bulky disease > 7 cm, bone marrow involvement, III or IV stage, ECOG 2 or higher, Cr Cl < 80

If 1 or more factors present start TLS prophylaxis immediately.

• Prevention include: hydration 2-3 liters/m2 per 24 hr
• Rasburicase
• If person may have G6PD def--> start allopurinol, send G6PD testing before starting rasburicase

First line rx:

Has to include anthracycline.

High risk: ECOC 2 or higher, Ann Arbor III or IV stage, LDH > ULN, tumor > 7 cm

R CODOX/MIVAC

DA R EPOCH with CNS prophylaxis

Low risk 3-6 cycles DA-R EPOCH or 3 cycles CODOX R-M

Prophylaxis:

PJP

Acyclovir

Reference: BCCA https://www.bccancer.bc.ca/chemotherapy-protocols-site/Documents/Lymphoma-Myeloma/LYCODOXMR_Protocol.pdf

Coomb's negative hemolytic anemia

 

Reference : ASH clinical news Sept 2025

1. First step to confirm Coomb's neg:  get enhanced DAT test to rule out Ig A, Ig M, low-affinity Ig G or Ig G antibody that binds to fewer epitopes.

2. Coomb's neg AIHA is rare 3-10 % of AIHA

3. Causes:

•  Acquired: B12 def, infections such as malaria, review oxidative drug hx ( phenazopyridine, dapsone) 
•  Genetic: Wilson's disease, enzymopathies, hemoglobinopathies, and membranopathies.

4. Tests:  smear evaluation, corrected retic count, B12, folate,, PNH, Eosin-5-malemide, Hb electrophoresis, G6PD testing. Some of these may be falsely neg after blood transfusion.

Metastatic TNBC

 Reference: https://ascopubs.org/doi/10.1200/EDBK-25-481154

1. Keynote 355 showed addition of pembro to advanced TNBC with CPS 10 or higher resulted in better OS: In the CPS-10 subgroup, the median overall survival was 23.0 months in the pembrolizumab–chemotherapy group and 16.1 months in the placebo–chemotherapy group. 40% of patients are eligible for pembro upfront. 

2. ASCENT trial: single agent saci versus chemo. Overall survival (12.1 v 6.7 months; HR, 0.48 [95% CI, 0.38 to 0.59]) with sacituzumab govitecan therapy.

3.  DESTINY breast 04- T-DXd improved both PFS and overall survival and led to an objective response rate of 50%.

4. PARP inhibitors for GBRCA 1 or BRCA 2 front line. OlympiaD

In first-line, median OS was numerically longer for olaparib versus TPC (22.6 versus 14.7 months, respectively).  

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In first-line, the 3-year OS rate was 40.8% for olaparib versus 12.8% for TPC.   

EMBRACA trial talazoparib 8.6 m versus 5.6 m PFS

However in 2025 the following protocol has changed.

Front line treatment: new standard of care

• BRCA1 or BRCA 2--> if yes olaparib or talazoparib
• If BRCA neg, check PDL1 CPS > 10--> sacituzumab+ pembro ( ASCENT 04, PFS HR 0.65,Duration of response 16 months)
• If BRCA neg, PDL 1 neg---> Sacituzumab single agent (ASCENT 03, PFS 9 month)

Double refractory CLL and newly diagnosed CLL

 Ref Blood Oct 2025

CLL- 2024 ASH Frontline CLL

Newly diagnosed CLL needing rx

• TP53 status
• IGHV status
• Indication for rx:
• Cardiac hx, HTN, DOAC, bleeding hx or dual antiplatelets

Double refractory 

• Prognosis PFS 7 months, OS 2 yr
• 2 treatment options: pirtobrutinib and anti- CD 19  CAR- T Lisocel

1. Important to differentiate between true refractory versus exposed to these agents for limited time and or intolerance as a reason for stopping.

2. Obtain bx and mutation at progression to rule out Richter

3. Pirtobrutinib has an ORR of80% but responses last 15 months so best to start with this and plan on Lisocel. Lisocel has CR of 20%

4.  Do not discontinue BTK i immediately upon progression until there is access to the next line of treatment

5. For those who progress after CAR-T , allo SCT provided they have at least a PR

Metastatic RCC

 

Antiangiogenic TKI	Indication	Side effects
Sunitinib	TKIs (axitinib, cabozantinib, lenvatinib, tivozanib): These are approved for advanced or metastatic RCC, often as first-line or subsequent therapy. Axitinib and lenvatinib are used in combination with immune checkpoint inhibitors (ICIs) such as pembrolizumab or avelumab ( no OS benefit with avelumab + axitinib) for first-line therapy. Cabozantinib is preferred as a single agent after progression on ICI-based therapy, with robust evidence supporting its use in this setting. Tivozanib is specifically approved for relapsed/refractory RCC after two or more prior systemic therapies	Hypertension, diarrhea, fatigue, hand-foot syndrome, and hepatotoxicity are common. Tivozanib has a lower incidence of severe diarrhea and rash compared to sorafenib, but hypertension and asthenia are notable
Axitinib
Cabozantinib
Lenvatinib
Tovozanib
Pazopanib
Belzutifan	A HIF-2α inhibitor, FDA-approved for advanced RCC after prior PD-1/PD-L1 inhibitor and VEGF-TKI. It is recommended as a subsequent therapy, particularly after IO and VEGF-TKI exposure.	Anemia, fatigue, hypoxia, and dyspnea are most common. It has a favorable safety profile and lower rates of treatment discontinuation compared to everolimus

 

 

	mTOR inhibitor
	Everolimus
Indication	An mTOR inhibitor, used as subsequent therapy after VEGF-TKI failure, especially in heavily pretreated patients
Side effect monitoring	Stomatitis, fatigue, rash, and pneumonitis (<15%) are typical.

 

Combination Therapies:

• TKIs: Frequently combined with ICIs (e.g., axitinib + pembrolizumab, lenvatinib + pembrolizumab, cabozantinib + nivolumab) for first-line therapy, improving response rates and survival.^[6]
• Everolimus: Can be combined with lenvatinib for improved efficacy over monotherapy, but with increased toxicity.
• Tivozanib and belzutifan: Used as single agents in later lines; no established combination regimens in mRCC.

Effectiveness:

• Cabozantinib offers superior PFS, OS, and ORR compared to everolimus and other TKIs in the post-ICI setting.^[2]
• Tivozanib improves PFS over sorafenib in heavily pretreated patients (median PFS 5.6 vs. 3.9 months) with similar OS and lower grade ≥3 AEs.
• Belzutifan shows a significant PFS and objective response rate advantage over everolimus (ORR 22% vs. 3.6%; median PFS 5.6 months for both, but more durable responses with belzutifan), with improved quality of life and tolerability.
• Everolimus provides modest PFS benefit over placebo, but is less effective than newer agents and combinations

 

In summary, cabozantinib is the preferred VEGF-TKI after ICI-based therapy, tivozanib is an option for heavily pretreated patients, everolimus is reserved for refractory cases, and belzutifan is now favored over everolimus for patients progressing after IO and VEGF-TKI, with a better side effect and quality of life profile.