Real-world experience of chronomodulated prescription of cyclin-dependent kinases 4/6 inhibitor palbociclib in reducing hematological toxicity – A case series

Case 1

A 42-year-old female patient, diagnosed case of Ca Left Breast ypT3N1M1, invasive ductal carcinoma (IDC) grade 2 underwent wide local excision surgery on 21/6/2017, immunohistochemistry (IHC): Estrogen receptor (ER) +, progesterone receptor (PR) +, human epidermal growth factor receptor 2 (Her2) Neu followed by axillary lymph node (LN) dissection as correction surgery, suggestive of: 1/13 LN metastatic deposit. She defaulted on further management and took Ayurvedic medications. She suffered recurrent lesion in left breast, for which simple mastectomy was done; her histopathology was reported as IDC grade II, p (pathological), T3 (tumour stage 3), LVI (lymphovascular invasion) PNI (perineural invasion). She further defaulted for 7 months. Her IHC done on 6/08/22 was suggestive of ER+ve (Allred score 3+3=6); PR -ve her 2/neu negative. Her positron emission tomography (PET) scan done on August 09, 2022, Small fluorodeoxyglucose (FDG) avid (2.6) left interpectoral LN, FDG avid (11.9) prevascular, bilateral lower paratracheal, precarinal, left infrahilar nodes in mediastinum l/m 9 × 12 mm in precarinal, FDG avid (10.54) left supraclavicular node ms 21 × 21 mm, Small FDG avid (7.3) aortocaval nodes. There were FDG avid (21.1) diffuse pleural thickening lesions along upper lobe of right lung and FDG avid (4.65) smaller pleural-based soft tissue lesions along left upper and lower lobe lung and along left diaphragmatic pleura. PET suggested of FDG avid (10.46) lytic destructive lesion at L2 vertebra causing collapse of vertebral body and large lytic FDG avid (16.7) expansile lesion involving entire sternum. She received 20 Gy in 5# palliative radiation therapy (RT) to dorsolumbar spine (DL) spine (Last Dose: August 18, 2022).

She received 6 cycles Inj. Adriamycin (50 mg/m²) 70 mg + Inj. Cyclophosphamide (500 mg/m²) 700 mg with Inj. Zoledronic Acid 4 mg (LD: January 2, 2023). Her FDG-PET CT done on 9 th January 2023 was suggestive of moderate reduction in size, extent and FDG avidity of previous metastatic lesions suggestive of favourable response. The patient was started on Inj. Leuprolide 22.5 mg depot IM every 84 days, T. Letrozole 2.5 mg OD, and C. Palbociclib 125 mg OD × 21 days (patient was taking morning) from February 12, 2023. The patient was going into neutropenia after starting C. Palbociclib 125 mg after 2^nd cycle of chemotherapy.

As shown in Table 1, she was having grade 1 neutropenia, on chronomodulation her absolute neutrophil count improvised. Her endurance response is also highlighted in the Table 1.

Her serial follow up imaging was sggestive of favourable response. Her PET CT scan done on 17 January 2024 was suggestive of Stable disease. She is now post 11 cycles of tablet Palbociclib 125 mg. Patient is tolerating treatment well.

Case 2

A 51-year-old female patient, diagnosed with case of Ca Left Breast cT4bN2aM1 (skeletal metastasis), ultrasonography-guided biopsy done on January 04, 2023, from left breast revealed IDC, Grade II. Her PET CT scan done on January 10, 2023, revealed FDG avid (5.4) soft tissue lesion m/s 27 × 41 × 32 mm in upper inner quadrant of left breast. Her pet scan further revealed FDG avid specific uptake value (SUV) of 6.1 in multiple Lymph Nodes in left axillary, retropectoral and internal mammary lymph nodes of size 29 × 21 millimetre . FDG avid SUV of4.5 in prevascular, pretracheal, paratracheal, precarinal, and subcarinal nodes lymoh nodes of size 23 × 18 mm. FDG avid multiple lytic lesions; Bilateral scapulae and clavicles (SUV 4.1), multiple pelvic bones (SUV 8.1) and multiple dorsolumbar vertebrae (SUV 8.4). IHC has done on September 18, 2023, ER + (Allred score 3 + 2 = 5), PR negative, Her2/neu negative. The patient received three doses weekly and two cycles three weekly Inj. Paclitaxel (175 mg/m²) and Inj. Carboplatin (area under the curve 5) with Inj. Zoledronic acid 4 mg (LD: March 15, 2023). Her PET CT done on March 23, 2023, was suggestive of favorable response to treatment. The patient received 6^th three weekly cycle chemotherapy with Inj. Paclitaxel (310 mg) and Inj. Carboplatin 650 mg with Inj. ZA 4 mg on last dose May 19, 2023. Her PET CT report on routine follow-up scan done on June 19, 2023, suggestive of reduction in size, extent, and FDG avidity of previous soft tissue primary lesion and LNs. Furthermore her PET scan revealed complete metabolic resolution of metastatic bone lesions Suggestive of favourable response to treatment. The patient was started on C. Palbociclib 125 mg OD and T. Letrozole 2.5 mg OD from July 03, 2023. After 1^st cycle of Palbociclib 125 mg, the patient went into severe pancytopenia. As shown in Table 2, she was having grade 4 neutropenia and thrombocytopenia. She was treated with granulocyte colony stimulation factor, blood component, and antibiotic support. After she recovered, she was prescribed palbociclib although at a lower dose of 100 mg in the afternoon time (chronomodulated prescription of palbociclib), and as shown in Table 2, she not only recovered of the neutropenia but also recovered from thrombocytopenia as well.

The patient has now received 4^th cycle chemotherapy with C. Palbociclib 100 mg OD × 21 days and T. Letrozole 2.5 mg OD. The patient is tolerating treatment well.

Case 3

A 46-year-old lady, diagnosed case of carcinoma left breast, IDC, yrpT3N1M1 with skeletal and Lymph nodal metastasis with no comorbidities, presented to oncology outpatient department (OPD) at PMT, Loni with chief complaints of lump in left breast for 1 month. There is no significant family history. On June 9 2017 Bilateral Sonomammograpywas done which was suggestive of 21 × 18 mm lesion in left breast. Wide local excision of left breast lump was done on June 21 2017. IHC suggestive of ER + PR+ HER 2 NEU not amplified, defaulted treatment of 4 years presented with bony mets and pleural mets, the patient received external beam radiation therapy for symptomatic bony mets in dorsolumbar spine. The patient received 6 cycles Inj AC + Inj ZA. Whole body PET CT was suggestive of favourable respone. She was started on Inj Leuprolide depot 22.5 mg IM every 84 days with T. Letrozole 2.5 mg and Palbociclib 125 mg OD post 3 cycles whole body PET scan was suggestive of favourable response. The patient received 15 cycles of chronomodulated Palbociclib 125 mg (3 weeks on, 1 week off) + T. Letrozole 2.5 mg OD (LD: November 26, 2024) with PET s/o stable disease. As shown in Table 3, during these 15 cycles, she had grade 1 neutropenia which was reversible and limited which was reversible and was induced by co-morbid viral induced myelosuppression, which was reversed in the very next cycle.

Case 4

A 47-year-old lady, diagnosed case of carcinoma bilateral breasts, IDC, yrcT4bN3cM1 with multiple satellite nodules, with no comorbidities, presented to oncology OPD with complaints of lump in right breast for 2 years. There is no significant family history. FDG Pet was suggestive of dermal metastasis, subpleural mets. For which T. Letrozole 2.5mg OD and tab. Palbociclib 125mg (3 weeks on, 1 week off) was started. The patient received 12 cycles C. Palbociclib 125 mg (3 weeks on, 1 week off) + T. Letrozole 2.5 mg OD (LD: November 30, 2024). As shown in Table 4 she had just one episode of grade 1 neutropenia which was reversible.

Case 5

A 74-year-old lady, diagnosed case of carcinoma of left breast, IDC, cT4bN1M0, and a known case of hypertension for 2 years, presented to oncology OPD with chief complaints of lump in left breast for 1 year. There is no significant family history. Bilateral sonomammography with axillary lymph node was done on August 16 2024 which was suggestive of 3.5 × 2.9 × 3.3 cm irregular, lobulated region involving nipple areola complex (NAC) and upper outer quadrant (UOQ) of left breast. Biopsy histopathology report (HPR) was suggestive

Case 6

A 46-year-old lady, diagnosed case of carcinoma left breast, IDC, pT2N1M1 with skeletal metastasis, with no comorbidities, presented to oncology OPD at PMT, Loni with complaints of lump in left breast for 5 months. There is no significant family history. On August 3 2023, Fine needle aspiration cytology (FNAC) was done which was suggestive of infiltrating duct carcinoma (IDC). Her Contrast enhanced computed tomography (CECT) Thorax revealed a 41 × 39 × 42 mm soft tissue lesion in retro areolar region in outer upper quadrant (OUQ) and lower outer quadrant (LOQ) of left breast with minimal nipple retraction. CT revealed sclerotic foci in L2 vertebral body and right humeral head. Her CT scan further revealed a lytic focus in L1 vertebral body. Immuno histochemistry (IHC) was suggestive of estrogen receptor ER+ve, Progesterone receptor PR+ve HER 2/NEU-ve.

Her Whole Body PET CT revealed FDG avid lobulated soft tissue lesion involving retro areolar region in upper outer quadrant (UOQ) and lower outer quadrant (LOQ) of left breast mass measuring 41 × 40 × 42 mm (SUV 14.1) left axillary and retropectoral lymph node (LN) measuring 13 × 10 mm (SUV 3.1), lytic lesion involving D12 vertebral body (SUV 8.11). Patient received Tab Pabociclib 125mg (3 weeks on, 1 week off) + T. Letrozole 2.5 mg OD + 3 monthly Inj Zolendroni acid (ZA) 4 mg.

The patient has received 4 cycles C. Palbociclib 125 mg (3 weeks on, 1 week off) + T. Letrozole 2.5 mg OD (Last Dose: November 27, 2024). As shown in Table 6, she never had neutropenia.