4.1. Therapeutic indications

MINJUVI is indicated in combination with lenalidomide followed by MINJUVI monotherapy for the treatment of adult patients with relapsed or refractory diffuse large B‑cell lymphoma (DLBCL) who are not eligible for autologous stem cell transplant (ASCT).

MINJUVI is indicated in combination with lenalidomide and rituximab for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) (Grade 1-3a) after at least one line of systemic therapy.

4.2. Posology and method of administration

MINJUVI must be administered by a healthcare professional experienced in treatment of cancer patients.

Recommended premedication

A premedication to reduce the risk of infusion-related reactions should be administered 30 minutes to 2 hours prior to tafasitamab infusion. For patients not experiencing infusion-related reactions during the first 3 infusions, premedication is optional for subsequent infusions.

The premedication may include antipyretics (e.g. paracetamol), histamine H1 receptor blockers (e.g. diphenhydramine), histamine H2 receptor blockers (e.g. cimetidine), and/or glucocorticosteroids (e.g. methylprednisolone).

Treatment of infusion-related reactions

If an infusion-related reaction occurs (Grade 2 and higher), the infusion should be interrupted. In addition, appropriate medical treatment of symptoms should be initiated. After signs and symptoms are resolved or reduced to Grade 1, MINJUVI infusion can be resumed at a reduced infusion speed (see Table 1).

If a patient has experienced a Grade 1 to 3 infusion-related reaction, premedication should be administered before subsequent tafasitamab infusions.

Combination with lenalidomide

As MINJUVI is indicated in combination with lenalidomide, please refer to the lenalidomide Summary of Product Characteristics (SmPC) for the recommendations on prophylactic antithrombotic medicines.

Posology

Recommended dose for the treatment of adult patients with relapsed or refractory DLBCL

The recommended dose of MINJUVI is 12 mg per kg body weight administered as an intravenous infusion according to the following schedule:

• Cycle 1: infusion on day 1, 4, 8, 15 and 22 of the cycle.

• Cycles 2 and 3: infusion on day 1, 8, 15 and 22 of each cycle.

• Cycle 4 until disease progression: infusion on day 1 and 15 of each cycle.

Each cycle has 28 days.

In addition, patients should self-administer lenalidomide capsules at the recommended starting dose of 25 mg daily on days 1 to 21 of each cycle. The starting dose and subsequent dosing may be adjusted according to the lenalidomide SmPC.

MINJUVI plus lenalidomide in combination is given for up to twelve cycles.

Treatment with lenalidomide should be stopped after a maximum of twelve cycles of combination therapy. Patients should continue to receive MINJUVI infusions as single agent on day 1 and 15 of each 28‑day cycle, until disease progression or unacceptable toxicity.

Recommended dose for the treatment of adult patients with relapsed or refractory FL after at least one line of systemic therapy

The recommended dose of MINJUVI is 12 mg per kg body weight administered as an intravenous infusion according to the following schedule:

• Cycle 1 to 3: infusion on day 1, 8, 15 and 22 of each cycle.

• Cycles 4 to 12: infusion on day 1 and 15 of each cycle.

Each cycle has 28 days.

The recommended starting dose of rituximab is 375 mg/m2 administered as an intravenous infusion according to the following schedule:

• Cycle 1: on days 1, 8, 15 and 22.

• Cycles 2 to 5: on day 1 of each cycle.

Each cycle has 28 days. Please refer to the SmPC of rituximab intravenous formulations for information on its method of administration and premedication and prophylactic medications.

In addition, patients should self-administer lenalidomide capsules at the recommended starting dose of 20 mg daily on days 1 to 21 of each 28-day cycle. The starting dose and subsequent dosing may be adjusted according to the lenalidomide SmPC.

MINJUVI in combination with lenalidomide plus rituximab is given for up to twelve cycles for MINJUVI and lenalidomide, and five cycles for rituximab. Treatment with rituximab should be stopped after five cycles of combination therapy. Patients should continue to receive MINJUVI infusions in combination with oral lenalidomide up to cycle twelve. Treatment with tafasitamab plus lenalidomide should be stopped after a maximum of twelve cycles.

Dose modifications

Table 1 provides dose modifications for MINJUVI in case of adverse reactions. For dose modifications regarding lenalidomide, please also refer to the lenalidomide SmPC.

Table 1: Dose modifications in case of adverse reactions

Adverse reaction

Severity

Dosage modification

Infusion-related reactions

Grade 2 (moderate)

• Interrupt MINJUVI infusion immediately and manage signs and symptoms.

• Once signs and symptoms resolve or reduce to Grade 1, resume MINJUVI infusion at no more than 50% of the rate at which the reaction occurred. If the patient does not experience further reaction within 1 hour and vital signs are stable, the infusion rate may be increased every 30 minutes as tolerated to the rate at which the reaction occurred.

Grade 3 (severe)

• Interrupt MINJUVI infusion immediately and manage signs and symptoms.

• Once signs and symptoms resolve or reduce to Grade 1, resume MINJUVI infusion at no more than 25% of the rate at which the reaction occurred. If the patient does not experience further reaction within 1 hour and vital signs are stable, the infusion rate may be increased every 30 minutes as tolerated to a maximum of 50% of the rate at which the reaction occurred.

• If after rechallenge the reaction returns, stop the infusion immediately.

Grade 4 (life-threatening)

• Stop the infusion immediately and permanently discontinue MINJUVI.

Myelosuppression

Platelet count of less than 50,000/µL

• Withhold MINJUVI and lenalidomide and monitor complete blood count weekly until platelet count is 50,000/µL or higher.

• Resume MINJUVI at the same dose and lenalidomide at a reduced dose if platelets return to ≥ 50,000/µL. Refer to the lenalidomide SmPC for dosage modifications.

Neutrophil count of less than 1,000/µL for at least 7 days

or

Neutrophil count of less than 1,000/µL with an increase of body temperature to 38 °C or higher

or

Neutrophil count less than 500/µL

• Withhold MINJUVI and lenalidomide and monitor complete blood count weekly until neutrophil count is 1,000/µL or higher.

• Resume MINJUVI at the same dose and lenalidomide at a reduced dose if neutrophils return to ≥ 1000/µL. Refer to the lenalidomide SmPC for dosage modifications.

Special populations

Paediatric population

The safety and efficacy of MINJUVI in children under 18 years have not been established.

No data are available.

Elderly

No dose adjustment is needed for elderly patients (≥ 65 years).

Renal impairment

No dose adjustment is needed for patients with mild or moderate renal impairment (see section 5.2). There are no data in patients with severe renal impairment for dosing recommendations.

Hepatic impairment

No dose adjustment is needed for patients with mild hepatic impairment (see section 5.2). There are no data in patients with moderate or severe hepatic impairment for dosing recommendations.

Method of administration

MINJUVI is for intravenous use after reconstitution and dilution.

• For the first infusion of cycle 1, the intravenous infusion rate should be 70 mL/h for the first 30 minutes. Afterwards, the rate should be increased to complete the first infusion within a 2.5‑hour period.

• All subsequent infusions should be administered within a 1.5 to 2‑hour period.

• In case of adverse reactions, consider the recommended dose modifications provided in Table 1.

• MINJUVI must not be co-administered with other medicinal products through the same infusion line.

• MINJUVI must not be administered as an intravenous push or bolus.

For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Infusion-related reactions

Infusion-related reactions may occur and have been reported more frequently during the first infusion (see section 4.8). Patients should be monitored closely throughout the infusion. Patients should be advised to contact their healthcare professionals if they experience signs and symptoms of infusion‑related reactions including fever, chills, rash or breathing problems within 24 hours of infusion. A premedication should be administered to patients prior to starting tafasitamab infusion. Based on the severity of the infusion-related reaction, tafasitamab infusion should be interrupted or discontinued and appropriate medical management should be instituted (see section 4.2).

Myelosuppression

Treatment with tafasitamab can cause serious and/or severe myelosuppression including neutropenia, thrombocytopenia and anaemia (see section 4.8). Complete blood counts should be monitored throughout treatment and prior to administration of each treatment cycle. Based on the severity of the adverse reaction, tafasitamab infusion should be withheld (see Table 1). Refer to the lenalidomide SmPC for dosage modifications.

Neutropenia

Neutropenia, including febrile neutropenia, has been reported during treatment with tafasitamab. Administration of granulocyte colony-stimulating factors (G‑CSF) should be considered, in particular in patients with Grade 3 or 4 neutropenia. Any symptoms or signs of developing infection should be anticipated, evaluated and treated.

Thrombocytopenia

Thrombocytopenia has been reported during treatment with tafasitamab. Withholding of concomitant medicinal products that may increase bleeding risk (e.g. platelet inhibitors, anticoagulants) should be considered. Patients should be advised to report signs or symptoms of bruising or bleeding immediately.

Infections

Fatal and serious infections, including opportunistic infections, occurred in patients during treatment with tafasitamab. Tafasitamab should be administered to patients with an active infection only if the infection is treated appropriately and well controlled. Patients with a history of recurring or chronic infections may be at increased risk of infection and should be monitored appropriately.

Patients should be advised to contact their healthcare professionals if fever or other evidence of potential infection, such as chills, cough or pain on urination, develops.

Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) has been reported during combination therapy with tafasitamab. Patients should be monitored for new or worsening neurological symptoms or signs that may be suggestive of PML. The symptoms of PML are nonspecific and can vary depending on the affected region of the brain. These include altered mental status, memory loss, speech impairment, motor deficits (hemiparesis or monoparesis), limb ataxia, gait ataxia, and visual symptoms such as hemianopia and diplopia. If PML is suspected, further dosing of tafasitamab must be immediately suspended. Referral to a neurologist should be considered. Appropriate diagnostic measures may include MRI scan, cerebrospinal fluid testing for JC viral DNA and repeat neurological assessments. If PML is confirmed, tafasitamab must be permanently discontinued.

Tumour lysis syndrome

Patients with high tumour burden and rapidly proliferative tumour may be at increased risk of tumour lysis syndrome. Tumour lysis syndrome has been reported during treatment with tafasitamab. Appropriate measures/prophylaxis in accordance with local guidelines should be taken prior to treatment with tafasitamab. Patients should be monitored closely for tumour lysis syndrome during treatment with tafasitamab.

CD19-negative or CD20-negative disease

There are no data available on patients with CD19-negative or CD20-negative FL treated with tafasitamab in combination with lenalidomide and rituximab, and it is possible that patients with CD19-negative or CD20-negative FL may have less benefit compared to patients with CD19-positive and CD20-positive FL. The potential risks and benefits associated with treatment of patients with CD19-negative or CD20-negative FL with tafasitamab in combination with lenalidomide and rituximab should be considered.

Immunisations

The safety of immunisation with live vaccines following tafasitamab therapy has not been investigated and vaccination with live vaccines is not recommended concurrently with tafasitamab therapy.

Excipient

This medicinal product contains 37.0 mg sodium per 5 vials (the dose of a patient weighing 83 kg), equivalent to 1.85% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

This medicinal product contains 5.0 mg of polysorbate 20 per 5 vials. Polysorbate 20 may cause allergic reactions.

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

4.6. Fertility, pregnancy and lactation

Treatment with tafasitamab in combination with lenalidomide should not be initiated in female patients unless pregnancy has been excluded. Please also refer to the SmPC of lenalidomide.

Women of childbearing potential/Contraception in females

Women of childbearing potential should be advised to use effective contraception during and for at least 3 months after end of treatment with tafasitamab.

Pregnancy

Reproductive and developmental toxicity studies have not been conducted with tafasitamab.

There are no data on the use of tafasitamab in pregnant women. However, IgG is known to cross the placenta and tafasitamab may cause foetal B‑cell depletion based on the pharmacological properties (see section 5.1). In case of exposure during pregnancy, newborns should be monitored for B‑cell depletion and vaccinations with live virus vaccines should be postponed until the infant's B‑cell count has recovered (see section 4.4).

Tafasitamab is not recommended during pregnancy and in women of childbearing potential not using contraception.

Lenalidomide can cause embryo-foetal harm and is contraindicated for use in pregnancy and in women of childbearing potential unless all of the conditions of the lenalidomide pregnancy prevention programme are met.

Breast-feeding

It is not known whether tafasitamab is excreted in human milk. However, maternal IgG is known to be excreted in human milk. There are no data on the use of tafasitamab in breast-feeding women and a risk for breast-feeding children cannot be excluded. Women should be advised not to breast-feed during and for at least 3 months after the last dose of tafasitamab.

Fertility

No specific studies have been conducted to evaluate potential effects of tafasitamab on fertility. No adverse effects on male and female reproductive organs were observed in a repeat-dose toxicity study in animals (see section 5.3).

4.7. Effects on ability to drive and use machines

MINJUVI has no or negligible influence on the ability to drive and use machines. However, fatigue has been reported in patients taking tafasitamab and this should be taken into account when driving or using machines.

4.8. Undesirable effects

Summary of the safety profile

Patients with relapsed or refractory DLBCL

The safety of tafasitamab in patients with DLBCL was evaluated in the open-label, multicentre, single-arm phase 2 study L-MIND in 81 patients with relapsed or refractory DLBCL. Patients received tafasitamab 12 mg/kg intravenously in combination with lenalidomide for a maximum of 12 cycles, followed by tafasitamab monotherapy until disease progression or unacceptable toxicity.

The median duration of exposure to tafasitamab was 7.7 months.

The most common adverse reactions were: infections (73%), neutropenia (51%), asthenia (40%), anaemia (36%), diarrhoea (36%), thrombocytopenia (31%), cough (26%), oedema peripheral (24%), pyrexia (24%), decreased appetite (22%).

The most common serious adverse reactions were infection (26%) including pneumonia (7%), and febrile neutropenia (6%).

Permanent discontinuation of tafasitamab due to an adverse reaction occurred in 15% of patients. The most common adverse reactions leading to permanent discontinuation of tafasitamab were infections and infestations (5%), nervous system disorders (2.5%), and respiratory, thoracic and mediastinal disorders (2.5%).

The frequency of dose modification or interruption due to adverse reactions was 65%. The most common adverse reactions leading to tafasitamab treatment interruption were blood and lymphatic system disorders (41%).

Patients with relapsed or refractory FL after at least one line of systemic therapy

The safety of tafasitamab in patients with FL was evaluated in the randomised, double-blind, placebo-controlled multicenter phase 3 study inMIND in 652 patients, including 546 participants with relapsed or refractory (R/R) follicular lymphoma and 106 participants with R/R marginal zone lymphoma. Patients received tafasitamab 12 mg/kg (n = 327) or placebo (n = 325) intravenously in combination with rituximab 375 mg/m2 intravenously (for a maximum of 5 cycles) and lenalidomide 20 mg orally (for a maximum of 12 cycles). Tafasitamab treatment was stopped after 12 cycles. Among patients who received tafasitamab, 83% were exposed for 6 months or longer. The median duration of exposure to tafasitamab was 322 days.

In the inMIND study, the most common adverse reactions were infections (68%), including viral infections (41%) and bacterial infections (27%); neutropenia (57%), rash (36.4%), asthenia (34.9%), pyrexia (19%), thrombocytopenia (17%), anaemia (17%), infusion related reaction (15.9%), pruritus (15.6%) and headache (10.4%).

The most common serious adverse reactions were infections (26%), including viral infections (13%), and bacterial infections (6%); febrile neutropenia (2.8%), acute kidney injury (2.8%) and pyrexia (1.8%).

Permanent discontinuation of tafasitamab due to an adverse reaction occurred in 11.6% of patients. The most common adverse reactions leading to permanent discontinuation of tafasitamab were viral infections (2.4%), including COVID-19 (1.5%) and COVID-19 pneumonia (1.2%), infusion-related reaction (0.9%) and pyrexia (0.9%).

The frequency of tafasitamab dose modification or interruption due to adverse reactions was 74.9%. The most common adverse reactions leading to tafasitamab dose modification and interruption were neutropenia (38.8%) and viral infections (23.9%) including COVID-19 (21.1%) and COVID-19 pneumonia (3.7%).

Tabulated list of adverse reactions

Adverse reactions reported for tafasitamab in clinical trials are listed by MedDRA System Organ Class and by frequency.

The adverse reaction frequencies from clinical trials are based on all-cause adverse event frequencies, where a proportion of the events for an adverse reaction may have other causes than the medicinal product, such as the disease, other medicines or unrelated causes.

Frequencies are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2: Adverse reactions in patients with relapsed or refractory DLBCL who received tafasitamab in combination with lenalidomide in the clinical trial MOR208C203 (L‑MIND)

System organ class

Frequency

Adverse reactions

Infections and infestations

Very common

Bacterial, viral and fungal infections+, including opportunistic infections with fatal outcomes (e.g. bronchopulmonary aspergillosis, bronchitis, pneumonia and urinary tract infection)

Common

Sepsis (including neutropenic sepsis)

Neoplasms benign, malignant and unspecified (incl. cysts and polyps)

Common

Basal cell carcinoma

Blood and lymphatic system disorders

Very common

Febrile neutropenia+, neutropenia+, thrombocytopenia+, anaemia, leukopenia+

Common

Lymphopenia

Immune system disorders

Common

Hypogammaglobulinaemia

Metabolism and nutrition disorders

Very common

Hypokalaemia, decreased appetite

Common

Hypocalcaemia, hypomagnesaemia

Nervous system disorders

Common

Headache, paraesthesia, dysgeusia

Respiratory, thoracic and mediastinal disorders

Very common

Dyspnoea, cough

Common

Exacerbation of chronic obstructive pulmonary disease, nasal congestion

Gastrointestinal disorders

Very common

Diarrhoea, constipation, vomiting, nausea, abdominal pain

Hepatobiliary disorders

Common

Hyperbilirubinaemia, transaminases increased (includes ALT and/or AST increased), Gamma-glutamyltransferase increased

Skin and subcutaneous tissue disorders

Very common

Rash (includes different types of rash, e.g. rash, rash maculopapular, rash pruritic, rash erythematous)

Common

Pruritus, alopecia, erythema, hyperhidrosis

Musculoskeletal and connective tissue disorders

Very common

Back pain, muscle spasms

Common

Arthralgia, pain in extremity, musculoskeletal pain

Renal and urinary disorders

Common

Blood creatinine increased

General disorders and administration site conditions

Very common

Asthenia++, oedema peripheral, pyrexia

Common

Mucosal inflammation

Investigations

Common

Weight decreased, C-reactive protein increased

Injury, poisoning and procedural complications

Common

Infusion related reaction

+Further information on this adverse reaction is provided in the text below.

++ Asthenia includes asthenia, fatigue and malaise.

Compared with the incidences on combination therapy with lenalidomide, the incidences of non-haematological adverse reactions on tafasitamab monotherapy decreased by at least 10% for decreased appetite, asthenia, hypokalaemia, constipation, nausea, muscle spasms, dyspnoea and C-reactive protein increased.

Table 3: Adverse reactions in patients with relapsed or refractory FL who received tafasitamab in combination with rituximab and lenalidomide in INCMOR 0208-301 (inMIND)

System organ class / Adverse reaction

All grades frequency

Grade 3-4a frequency

Infections and infestations

Viral infectionsb

Very common

Very common

Bacterial infectionsc

Very common

Common

Pneumonia

Very common

Common

Bronchitis

Common

-

Sepsis

Common

Uncommon

Blood and lymphatic system disorders

Neutropeniad

Very common

Very common

Thrombocytopeniae

Very common

Common

Anaemiaf

Very common

Common

Febrile neutropenia

Common

Common

Leukopenia

Common

Uncommon

Metabolism and nutrition disorders

Tumour lysis syndrome

Uncommon

Uncommon

Nervous system disorders

Headache

Very common

Uncommon

Gastrointestinal disorders

Diarrhoea

Very common

Uncommon

Constipation

Very common

Uncommon

Abdominal paing

Very common

-

Skin and subcutaneous tissue disorders

Rashh

Very common

Common

Pruritus

Very common

Uncommon

General disorders and administration site conditions

Astheniai

Very common

Common

Pyrexia

Very common

Common

Chills

Common

-

Investigations

ALT increased

Common

Uncommon

AST increased

Common

Uncommon

Injury, poisoning, and procedural complications

Infusionrelated reaction

Very common

Uncommon

a The severity of adverse drug reactions was assessed based on the CTCAE, defining grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4=life threatening, and 5=death.

b Includes viral infection, COVID-19, COVID-19 pneumonia, coronavirus infection, coronavirus test positive, cytomegalovirus chorioretinitis, cytomegalovirus infection reactivation, gastroenteritis rotavirus, genital herpes, Hepatitis B, herpes ophthalmic, herpes simplex, herpes simplex reactivation, herpes virus infection, herpes zoster, herpes zoster reactivation, influenza, laryngitis viral, nasal herpes, norovirus infection, oral herpes, parainfluenzae virus infection, pneumonia viral, progressive multifocal leukoencephalopathy, respiratory syncytial virus infection, respirovirus test positive, rhinovirus infection, skin papilloma, varicella zoster pneumonia, varicella zoster virus infection, and viral upper respiratory tract infection.

c Includes bacterial infection, abdominal infection, abscess, appendicitis, asymptomatic bacteriuria, atypical pneumonia, bacteraemia, bacterial sepsis, breast abscess, bronchopulmonary aspergillosis, campylobacter gastroenteritis, campylobacter infection, carbuncle, catheter site infection, cellulitis, cholecystitis, chronic sinusitis, clostridium difficile colitis, clostridium difficile infection, corynebacterium infection, device related infection, diverticulitis, ear infection, ear lobe infection, empyema, enterobacter bacteraemia, erysipelas, erythrasma, escherichia infection, escherichia sepsis, eye infection, folliculitis, furuncle, hemophilus bacteraemia, hemophilus infection, helicobacter gastritis, helicobacter infection, infected cyst, infected dermal cyst, lower respiratory tract infection, moraxella infection, mycobacterium chelonae infection, myopericarditis, myringitis, otitis externa, otitis media, perineal infection, periodontitis, peritonitis bacterial, pneumocystis jirovecii pneumonia, pneumonia moraxella, pneumonia pneumococcal, pneumonia streptococcal, postoperative wound infection, proctitis, prostatitis, pseudomonal sepsis, pseudomonal skin infection, pseudomonas infection, pulmonary sepsis, pulpitis dental, pyelonephritis, salmonellosis, septic shock, sinusitis, skin infection, soft tissue infection, staphylococcal bacteraemia, staphylococcal infection, tooth abscess, tooth infection, urinary tract infection, urosepsis, vaginal infection, and wound infection.

d Includes neutropenia and neutrophil count decreased.

e Includes thrombocytopenia and platelet count decreased.

f Includes anaemia and haematocrit decreased.

g Includes abdominal pain, abdominal discomfort, abdominal pain lower, abdominal pain upper, and gastrointestinal pain.

h Includes rash, rash erythematous, rash maculo-papular, rash papular, rash pruritic, rash pustular, rash vesicular, and urticaria.

i Includes asthenia, malaise, and fatigue.

Description of selected adverse reactions

Myelosuppression

Treatment with tafasitamab can cause serious or severe myelosuppression including neutropenia, thrombocytopenia and anaemia (see sections 4.2 and 4.4).

In the L‑MIND study, myelosuppression (i.e. neutropenia, febrile neutropenia, thrombocytopenia, leukopenia, lymphopenia or anaemia) occurred in 65.4% of patients treated with tafasitamab. Myelosuppression led to interruption of tafasitamab in 41% and to tafasitamab discontinuation in 1.2%.

In the inMIND study, myelosuppression (i.e. neutropenia, febrile neutropenia, thrombocytopenia, leukopenia, lymphopenia or anaemia) occurred in 63.3% of patients treated with tafasitamab, lenalidomide, and rituximab (tafasitamab group) and 63.1% of patients treated with lenalidomide and rituximab (placebo group). Grade 4 haematological adverse reactions included neutropenia, thrombocytopenia and febrile neutropenia. Myelosuppression led to interruption of tafasitamab in 42.8% and to tafasitamab discontinuation in 1.5%.

Myelosuppression was managed by reduction or interruption of lenalidomide, interruption of tafasitamab and/or rituximab. In addition, severe neutropenia was managed by the administration of G‑CSF (see sections 4.2 and 4.4).

Neutropenia/febrile neutropenia

In the L‑MIND study, incidence of neutropenia was 51%. Incidence of Grade 3 or 4 neutropenia was 49% and of Grade 3 or 4 febrile neutropenia was 12%. Median duration of any adverse reaction of neutropenia was 8 days (range 1 – 222 days); median time to onset to first occurrence of neutropenia was 49 days (range 1 – 994 days).

In the inMIND study, incidence of neutropenia was 56.9% in the tafasitamab group (tafasitamab, lenalidomide and rituximab) and 54.2% in the placebo group (lenalidomide and rituximab). Incidence of Grade 3 or 4 neutropenia was 46.8% in the tafasitamab group and 45.5% in the placebo group. Incidence of Grade 3 or Grade 4 febrile neutropenia was 4.3% in the tafasitamab group and 3.4% in the placebo group. Median duration of any adverse reaction of neutropenia was 11 days (range 1 – 433 days). Median duration of febrile neutropenia was 5 days (range 1 – 57 days); median time to onset to first occurrence of neutropenia was 57 days (range 1 – 338 days); median time to onset to first occurrence of febrile neutropenia was 77 days (range 3 – 304 days).

Thrombocytopenia

In the L‑MIND study, incidence of thrombocytopenia was 31%. Incidence of Grade 3 or 4 thrombocytopenia was 17%. Median duration of any adverse reaction thrombocytopenia was 11 days (range 1 – 470 days); median time to onset to first occurrence of thrombocytopenia was 71 days (range 1 – 358 days).

In the inMIND study, incidence of thrombocytopenia was 17.1% in the tafasitamab group (tafasitamab, lenalidomide and rituximab) and 20.6% in the placebo group (lenalidomide and rituximab). Incidence of Grade 3 or Grade 4 thrombocytopenia was 6.4% in the tafasitamab group and 9.8% in the placebo group. Median duration of thrombocytopenia was 16 days (range 2 – 434 days); median time to onset to first occurrence of thrombocytopenia was 33 days (range 1 – 324 days).

Anaemia

In the L‑MIND study, incidence of anaemia was 36%. Incidence of Grade 3 or 4 anaemia was 7%. Median duration of any adverse reaction of anaemia was 15 days (range 1 – 535 days); median time to onset to first occurrence of anaemia was 49 days (range 1 – 1129 days).

When patients in the L‑MIND study were switched from tafasitamab and lenalidomide in the combination therapy phase to tafasitamab alone in the extended monotherapy phase, the incidences of haematological events decreased by at least 20% for neutropenia, thrombocytopenia and anaemia; no incidences of febrile neutropenia were reported with tafasitamab monotherapy (see sections 4.2 and 4.4).

In the inMIND study, incidence of anaemia was 17.1% in the tafasitamab group (tafasitamab, lenalidomide and rituximab) and 14.5% in the placebo group (lenalidomide and rituximab). Incidence of Grade 3 or 4 anaemia was 6.4% in the tafasitamab group and 6.5% in the placebo group. Median duration of any adverse reaction of anaemia was 23 days (range 1 – 432 days); median time to onset to first occurrence of anaemia was 49 days (range 1 – 274 days).

Infections

In the L‑MIND study, infections occurred in 73% of patients. Incidence of Grade 3 or 4 infections was 28%. The most frequently reported Grade 3 or higher infections were pneumonia (7%), respiratory tract infections (4.9%), urinary tract infections (4.9%) and sepsis (4.9%). Infection was fatal in < 1% of patients (pneumonia) within 30 days of last treatment.

Median time to first onset of Grade 3 or 4 infection was 62.5 days (4 – 1014 days). Median duration of any infection was 11 days (1 – 392 days).

Infection led to dose interruption of tafasitamab in 27% and tafasitamab discontinuation in 4.9%.

In the inMIND study, infections occurred in 52.3% of patients in the tafasitamab group (tafasitamab, lenalidomide and rituximab) and in 45.2% of patients in the placebo group (lenalidomide and rituximab). Viral infections occurred in 41.3% of patients in the tafasitamab group and 32% in the placebo group. Bacterial infections occurred in 27.2% of patients in the tafasitamab group and 25.2% in the placebo group. Incidence of Grade 3 or 4 viral infections was 11.6% in the tafasitamab group and 4.6% in the placebo group. Incidence of Grade 3 or 4 bacterial infections was 7.6% in the tafasitamab group and 7.7% in the placebo group. Infections were fatal in 3 patients in the tafasitamab group (two cases of COVID-19 and one of sepsis).

Median time to first onset of any infection ≥ Grade 3 was 10 days (2 – 311 days).

Recommendations for management of infections are provided in section 4.4.

Infusion-related reactions

In the L‑MIND study, infusion-related reactions occurred in 6% of patients. All infusion related reactions were Grade 1 and resolved on the day of occurrence. Eighty percent of these reactions occurred during cycle 1 or 2.

In study inMIND, infusion-related reactions occurred in 15.9% of patients in the tafasitamab group (tafasitamab, lenalidomide and rituximab) and 15.1% in the placebo group (lenalidomide and rituximab). Grade 3 infusion-related reactions occurred in 6.1% of patients in the tafasitamab group. In the tafasitamab group infusion-related reactions occurred in 15.3% of patients during cycle 1, in 1.3% of patients during cycle 2 and in 0.3% of patients during cycle 3.

Symptoms included chills, flushing, dyspnoea, hypertension and rash (see sections 4.2 and 4.4).

Immunogenicity

In 245 patients treated with tafasitamab in the initial clinical studies, no treatment-emergent or treatment-boosted anti-tafasitamab antibodies were observed. Pre‑existing anti-tafasitamab antibodies were detected in 17/245 patients (6.9%) with no impact on pharmacokinetics, efficacy or safety of tafasitamab.

Anti-drug antibodies (ADAs) were tested in 327 patients with relapsed or refractory follicular lymphoma or relapsed or refractory marginal zone lymphoma who received tafasitamab in study inMIND. The incidence of tafasitamab treatment-emergent ADAs was 0.9% (3/327) using a bridging enzyme-linked immunosorbent assay.

No neutralizing antibodies were detected. There was no apparent clinically meaningful effect of ADAs on the pharmacokinetics, pharmacodynamics, safety, or effectiveness of tafasitamab over the median treatment duration of 322.5 days.

Special populations

Elderly

Among 81 patients treated in the L‑MIND study, 56 (69%) patients were > 65 years of age. Patients > 65 years of age had a numerically higher incidence of serious treatment emergent adverse events (TEAEs) (55%) than patients ≤ 65 years (44%).

Among the 274 patients with FL treated with tafasitamab in study inMIND, 50% were ≥ 65 years of age and 20% were ≥ 75 years of age. No clinically meaningful differences in safety or effectiveness were observed between these patients and younger patients but greater sensitivity of some older individuals cannot be ruled out.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme: Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

In the case of an overdose, patients should be carefully observed for signs or symptoms of adverse reactions and supportive care should be administered, as appropriate.