Real world study of safety and efficacy of lorlatinib as second line and beyond in ALK-rearranged advanced non-small cell lung cancer patients in India - a multicentre chart review study (ROSELAND).

Background: Lorlatinib, an anaplastic lymphoma kinase (ALK)-inhibitor, is approved as frontline as well as subsequent line of therapy in ALK-rearranged advanced non-small cell lung cancer (NSCLC). There is limited literature about safety and efficacy of lorlatinib in Indian patients. Materials and methods: This was a retrospective multicentre study on patients with ALK-rearranged advanced NSCLC received lorlatinib as second line and beyond between May 2017 and December 2021. ALK was tested either by immunohistochemistry or fluorescent in-situ hybridisation. Clinicopathologic features, treatment details, toxicity and outcomes were analysed. Results: A total of 38 patients were enrolled with a median age of 54 years (range: 30-72) and male: female ratio of 20:18. Fifteen (44%) patients had brain metastases at baseline. Lorlatinib use was - second line in 11 (29%), third line in 21 (55%) and fourth line in 4 (11%) of patients, respectively. The best radiologic response to lorlatinib was - complete response in 9 (24%), partial response in 17 (46%), stable disease in 9 (24%) and progressive disease in 2 (5%) of patients, respectively. After a median follow-up of 76.6 months (95% CI: 68.9-100), the median progression-free survival (PFS) of lorlatinib was not reached (95% CI: 24.3-not reached) and median overall survival (OS) of the whole cohort was 93.1 months (95% CI: 62-not reached). Both median PFS (p = 0.48) and median OS (p = 0.74) was similar between second line and later line use of lorlatinib. Thirty-three (87%) patients experienced treatment-related toxicity and six (16%) patients required dose modification. Conclusion: Lorlatinib was highly efficacious in terms of overall response rate, median PFS and median OS in this small real-world cohort of advanced ALK+ve NSCLC with a manageable safety profile.

Canakinumab Versus Placebo in Combination With First-Line Pembrolizumab Plus Chemotherapy for Advanced Non-Small-Cell Lung Cancer: Results From the CANOPY-1 Trial.

PURPOSE: The addition of checkpoint inhibitors to first-line treatment has prolonged survival of patients with non-small-cell lung cancer (NSCLC), but prognosis remains poor, with new treatment options needed. Canakinumab, a human, monoclonal anti-interleukin (IL)-1ß antibody, has potential to enhance the activity of PD-L1 inhibitors and chemotherapy (CT) by inhibiting protumor inflammation. METHODS: CANOPY-1 was a phase III, randomized, double-blind study comparing canakinumab (200 mg subcutaneously once every 3 weeks) versus placebo, both combined with pembrolizumab (200 mg intravenously once every 3 weeks) and platinum-based doublet CT, as first-line treatment for advanced/metastatic NSCLC without EGFR or ALK mutations. The primary end points were progression-free survival (PFS) and overall survival (OS). The secondary endpoints included overall response rate, safety, and patient-reported outcomes. RESULTS: Overall, 643 patients were randomly assigned to canakinumab (n = 320) or placebo (n = 323). With a median study follow-up of 6.5 months, the median PFS was 6.8 months with canakinumab versus 6.8 months with placebo (hazard ratio [HR], 0.85; 95% CI, 0.67 to 1.09; P = .102). With a median study follow-up of 21.2 months, the median OS was 20.8 months with canakinumab versus 20.2 months with placebo (HR, 0.87; 95% CI, 0.70 to 1.10; P = .123). No unexpected safety signals were observed for canakinumab combination. Infection rates were comparable between treatment and control arms. A higher frequency of neutropenia and ALT increase (grade ≤2) were reported in the treatment arm. Higher baseline C-reactive protein and IL-6 levels were associated with shorter PFS and OS. Patients treated with canakinumab had clinically meaningful delays in deterioration of lung cancer symptoms, including chest pain and coughing per LC13 and dyspnea per LC13 and C30. CONCLUSION: The addition of canakinumab to first-line pembrolizumab and CT did not prolong PFS or OS in patients with NSCLC.

Characteristics and outcomes of gallbladder cancer patients at the Tata Medical Center, Kolkata 2017-2019.

BACKGROUND: The north and north-eastern regions of India have among the highest incidence of gallbladder cancer (GBC) in the world. We report the clinicopathological charateristics and outcome of GBC patients in India. METHODS: Electronic medical records of patients diagnosed with GBC at Tata Medical Center, Kolkata between 2017 and 2019 were analyzed. RESULTS: There were 698 cases of confirmed GBC with a median age of 58 (IQR: 50-65) years and female:male ratio of 1.96. At presentation, 91% (496/544) had stage III/IV disease and 30% (189/640) had incidental GBC. The 2-year overall survival (OS) was 100% (95% CI: 100-100); 61% (95% CI: 45-83); 30% (95% CI: 21-43); and 9% (95% CI: 6-13) for stages I-IV, respectively (p = <0.0001).   For all patients, the 2-year OS in patients who had a radical cholecystectomy followed by adjuvant therapy (N = 36) was 50% (95% CI: 39-64), compared to 29% (95% CI: 22-38) for those who had a simple cholecystectomy and/or chemotherapy (N = 265) and 9% (95% CI: 6-14) in patients who were palliated (N = 107) (p = <0.0001). CONCLUSION: The combined surgical/chemotherapy approach for patients with stage II GBC showed the best outcomes. Early detection of GBC remains problematic with the majority of patients presenting with stage III-IV and who have a median survival of 9.1 months. Our data suggests that the tumor is chemoresponsive and multi-center collaborative clinical trials to identify alternative therapies are urgently required.

Efficacy of cyclin-dependent kinase 4/6 inhibitors in patients with metastatic hormone positive breast cancer: a single institutional study from India.

Purpose: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have shown marked benefit in the treatment of hormone positive metastatic breast cancer (HR+ MBC). There are limited real-world studies with palbociclib and ribociclib. Here we report our experience with CDK4/6 inhibitors in these groups of patients. Material and methods: Patients with HR+ MBC who have received either palbociclib or ribociclib during the course of their treatment from January 2017 to January 2022 were included in the study. The baseline demographic features, treatment details and toxicity were recorded. Patients who received at least 1 month of therapy were included in the survival analysis. Results: A total of 144 patients received CDK4/6 inhibitors during the time period. The median age of the population was 53 (30-80) years. Ninety-eight (71.4%) patients presented with de novo metastatic disease. The most common site of metastasis was to the skeleton (74.2%). Most patients (75%) received palbociclib as their therapy. At a median follow-up of 20.2 months, the median progression free survival (PFS) of the whole population was 16.5 (95% confidence interval (95% CI): 11.6-25.5) months and the median overall survival (OS) was 29.7 (95% CI: 21.7-44.6) months. The presence of liver metastases, low progesterone receptor positivity (Allred score < 6) and prior systemic treatment were poor prognostic factors for both PFS and OS in multivariate analysis. Drug was discontinued for only 2.1% of the patient population. Conclusions: Use of CDK4/6 inhibitors has led to improvement in PFS and OS in patients with HR+ MBC and it is well tolerated. The presence of liver metastases and low progesterone receptor positivity (Allred score < 6) and prior treatment are poor prognostic factors.

Ramucirumab in Indian Patients with Advanced Gastric Cancer-Does Borderline Performance Status and Heavy Burden of Disease in Real World Practice Impact Clinical Benefit?

Vikas OstwalBackground Ramucirumab is considered a standard of care as second-line therapy (CT2) in advanced gastric cancers (AGCs). The aim of this study was to assess practice patterns and outcomes with ramucirumab among Indian patients with AGCs. Materials and Methods A computerized clinical data entry form was formulated by the coordinating center's (Tata Memorial Hospital) medical oncologists and disseminated through personal contacts at academic conferences as well as via email for anonymized patient data entry. The data was analyzed for clinical characteristics, response rates, and survival outcomes. Results A total of 26 physicians contributed data, resulting in 55 patients receiving ramucirumab and being available for analysis. Median age was 53 years (range: 26-78), 69.1% of patients had greater than two sites of disease, and baseline Eastern Cooperative Oncology Group's performance score (ECOG PS) ≥ 2 was seen in 61.8% of patients. Ramucirumab was used as monotherapy in 10.9% of patients, while the remaining 89.1% received ramucirumab combined with chemotherapy. Median event-free survival (EFS) and median overall survival (OS) with ramucirumab were3.53 months (95% CI: 2.5-4.57) and 5.7 months (95% CI: 2.39-9.0), respectively. Common class specific grade adverse events seen with ramucirumab included gastrointestinal (GI) hemorrhage (9.1% - all grades) and uncontrolled hypertension (Grade 3/4 - 3.6%). Conclusions Ramucirumab appears to have similar efficacy in Indian AGC patients when compared with real-world data from other countries in terms of median EFS, but OS appears inferior due to more patients having borderline ECOG PS and high metastatic disease burden. GI hemorrhages appear more common than published data, although not unequivocally related to ramucirumab.

First-line Rucaparib Plus Bevacizumab Maintenance Completed One-Year in Germline BRCA1-Mutated Advanced Ovarian Cancer.

The present case study showed the novel approach of Rucaparib and Bevacizumab as first-line maintenance therapy in germline BRCA 1 mutated advanced high-grade serous carcinoma of the ovary. A 56-year-old female with high-grade serous carcinoma of the ovary (ECOG PS1) was treated with carboplatin and paclitaxel in combination with Bevacizumab (CPB), followed by interval debulking surgery. Since the patient was germline BRCA 1 positive, after completion of adjuvant chemotherapy, she was kept on Rucaparib along with Bevacizumab. The patient achieved a complete response and has been leading a disease-free life for the past one year with maintenance therapy of Rucaparib + Bevacizumab, though the patient did experience a few adverse events, including one episode of grade 3 anaemia, occasional grade 3 asthenia, and grade 2 diarrhoea (CTCAE V-4) which was managed by gradual dose reduction of Rucaparib from 600 mg twice daily dose to 300mg twice daily dose. With dose alteration of rucaparib along with bevacizumab as maintenance, the patient continues to tolerate rucaparib and stay relapse-free from disease.

Early Experience with Dabrafenib-Trametinib Combination in Patients with BRAF-Mutated Malignant Melanoma-A Single-Center Experience.

Background Combination of dabrafenib-trametinib is one of the standard treatments in patients with BRAF-mutated advanced malignant melanoma (MM). Real-world data on the usage of this combination is scarce, especially from India. Here, we are reporting our early experience with the usage of this combination therapy. Materials and Methods This is a single institutional data assessment of patients with BRAF-mutated MM registered and treated with BRAF-MEK inhibitors in our hospital. Clinico-pathological features and treatment details were reviewed for all patients. Results A total of seven patients with BRAF-mutated MM treated with this combination therapy with a median age of 66.5 years (range: 49-72 years) and a male:female ratio of 3:4. Six (85.7%) patients had metastatic disease at presentation. In total, 80% of our patient population had two or less than two sites of metastasis at presentation. The initial response rate of the study population was 71%. The drug was well tolerated with fever being the most common side effect which was seen in two (28.5%) of the patients. Conclusion Combination of dabrafenib-trametinib is effective in patients with BRAF-mutated MM with good tolerability. Further studies are required to look for improvement in outcome in this group of patients.

Multidisciplinary management of ovarian germ cell tumours-a single institutional study from India.

BACKGROUND: Ovarian germ cell tumours constitute a heterogeneous group of neoplasm with malignant potential being seen in 5% of cases. There is limited data on treatment outcomes of patients with malignant ovarian germ cell tumours (MOGCT). Here, we present our hospital audit of patients with MOGCT. MATERIAL AND METHODS: This is a retrospective data review of patients with MOGCT treated between May 2011 and December 2019. Patients were treated with staging laparotomy and adjuvant chemotherapy, wherever applicable. Surveillance was allowed for those at low risk for recurrence. Clinicopathologic features and treatment details were recorded, and survival analysis was performed. RESULTS: Sixty-five patients with a median age of 25 years (range: 11-52 years) were treated during the study period. The most common histology was immature teratoma in 35.3% of cases. International Federation of Gynecology and Obstetrics stage IC was the most common stage of presentation (47%). Surveillance was advised for 12.3% of cases. Systemic therapy was given in 51 (78%) patients. At a median follow-up of 46 months (range: 1-109 months), the median progression-free survival (PFS) was not reached. Five-year PFS was 79.3% (95% CI: 65.8-88). The most common toxicity was febrile neutropenia (22%) among those who received systemic therapy. CONCLUSION: Immature teratoma was the most common histology in our series. The majority presented in the early stage. MOGCT is a highly curable disease with surgery and systemic therapy.

Clinicopathological characteristics, prognostic factors and treatment outcomes of seminomatous germ cell tumours from a tertiary cancer centre in eastern India.

Background: . Seminomatous germ cell tumour (SGCT) is a rare but curable malignancy of young adults. The literature on management and outcome of SGCT is scarce from India. We report the demography and treatment outcome of SGCT at our centre. Methods: . We did a retrospective analysis of patients with SGCT treated from March 2011 to December 2018. Patients were staged appropriately with imaging, and pre- and postoperative tumour markers. High inguinal orchiectomy was performed in all with a testicular primary and received subsequent stage-adjusted adjuvant treatment. Patients were monitored for metabolic syndrome during follow-up after completion of treatment. Results: . We treated 85 patients with a median age of 37 (range 20-68) years. The primary site of the tumour was the testis in 80 (94%) and mediastinum in 5 (6%) patients. Cryptorchidism was present in 20 (25%) patients and testicular violation was present in 11 (14%) patients. Stage of the disease was I in 61, II in 13 and III in 6 patients. Adjuvant treatment in stage I disease was single-agent carbo-platin (area under the curve ×7) in 38 (62%), surveillance in 20 (33%) and radiotherapy in 3 (5%) patients. Five patients in the surveillance group relapsed. The 7-year mean (SD) relapse-free survival and overall survival were 83.1% (8%) and 98.7% (1.3%), respectively. Thirty-one patients (n = 52, 60%) had features of metabolic syndrome. Conclusions: . SGCTs have a high cure rate. Long-term follow-up is essential for monitoring toxic effects. Early diagnosis, avoidance of testicular violation and multidisciplinary management are the key features for better long-term outcome in SGCT.

Outcome of COVID-19 in Solid Organ Malignancies: Experience From a Tertiary Cancer Center in Eastern India.

PURPOSE: The COVID-19 pandemic has imposed a unique challenge to oncology patients. Outcome data on COVID-19 in patients with cancer from the Indian subcontinent are scarce in the literature. We aimed to evaluate the outcome of patients with COVID-19 on active systemic anticancer therapy. MATERIALS AND METHODS: This is a retrospective study of patients with solid organ malignancies undergoing systemic therapy with a diagnosis of COVID-19 between March 2020 and February 2021. COVID-19 was diagnosed if a reverse transcriptase polymerase chain reaction assay from oropharyngeal or nasopharyngeal swab was positive for severe acute respiratory syndrome coronavirus 2. The objectives were to evaluate the outcome of COVID-19 and factors predicting the outcome. RESULTS: A total of 145 patients were included with a median age of 58 years (range, 20-81 years). Treatment was curative in 60 (42%) patients. Of all symptomatic cases (n = 88, 61%), 50 had mild, 27 had moderate and 19 had severe COVID-19-related symptoms as per WHO criteria. Fifty (34%) patients required hospitalization with a median duration of hospital stay of 12 days (range, 4-25 days); five patients required intensive care unit admission. The rest were treated with home isolation and did not require further hospitalization. Twenty-two (15%) patients died, and the risk of death was significantly associated with severity of symptoms (odds ratio, 91.3; 95% CI, 9.1 to 919.5, P = .0001) but not with any other clinical factors. Drug holiday was given to 63 (44%) patients with a median duration of 25 days (range, 7-88 days). The median duration to reverse transcriptase polymerase chain reaction-negative was 16 days (range, 7-62 days). CONCLUSION: COVD-19-related death rate was 15% among patients with solid organ malignancies. The severity of the symptoms was related to mortality. The majority of patients with mild symptoms were treated at home isolation.

PDL1 expression and its correlation with outcomes in non-metastatic triple-negative breast cancer (TNBC).

PURPOSE: Triple-negative breast cancer (TNBC) has a poor outcome compared to other subtypes, even in those with early disease. Immune checkpoint inhibitors (ICIs) have been approved in metastatic diseases and are being tested as a neoadjuvant strategy also. The response to ICIs is largely determined by the programmed death ligand 1 (PDL1) score, which also acts as a prognostic marker for outcomes. Here, we report the proportion of PDL1 expression in non-metastatic TNBC and its correlation with response to chemotherapy and outcomes. METHODS: We included all patients who had non-metastatic TNBC treated with neoadjuvant chemotherapy, followed by surgery with/without adjuvant radiotherapy between September 2011 and November 2017. PDL1 testing was carried out on pre-treatment tumour cells with immunohistochemistry (Ventana SP142) and was correlated with pathological response, relapse-free survival (RFS) and overall survival (OS). PDL1 staining was interpreted as negative or positive (more than 1% staining). RESULTS: A total of 107 patients were included for analysis with a median age of 47 years (28-65 yrs). The PDL1 expression of more than 1% was seen in 31 (28.97%) patients. After a median follow-up of 55 months (range: 4-93 months), median RFS and OS were not reached. PDL1 expression did not affect the achievement of pathological complete response (pCR). However, PDL1 expression improved OS (p = 0.016) and trend towards RFS (p = 0.05). Patients who achieved pCR had better RFS and OC compared to those who did not. CONCLUSION: Our study shows PDL1 expression in 29% of the cases. PDL1 expression leads to better RFS and OS. Also, pCR improves survival.

Outcome of testicular non-seminomatous germ cell tumours: report from a tertiary cancer centre in eastern India.

Non-seminomatous germ cell tumour (NSGCT) is a rare but highly curable malignancy. The literature on the management and outcomes of NSGCT is scarce from India. Here, we report the demography and treatment outcomes of NSGCT treated at our centre. This is a retrospective analysis of testicular and retroperitoneal NSGCT patients treated from March 2011 to December 2019. Patients were staged appropriately with imaging, pre- and post-operative tumour marker. Patients received stage adjusted adjuvant treatment after high inguinal orchiectomy. Patients with advanced disease were risk stratified as per International Germ Cell Cancer Collaborative Group (IGCCCG) classification. A total of 100 patients were treated with a median age of 28 years (Range: 18-51). Primary site was testis in 92 and retroperitoneum in 8 patients. Testicular violation was present in 17 (18%) patients. The stage of the disease was I in 32, II in 19 and III in 49 patients, respectively. IGCCCG risk groups were good in 29 (46%), intermediate in 13 (21%) and poor in 21 (33%) patients. Eleven patients (24%) underwent retroperitoneal lymph node dissection amongst 45 with post-chemotherapy residual disease. After a median follow-up of 26.6 months (range: 2.2-100.7), 3-year event-free survival and overall survival (OS) were 70.7% ± 5.6% and 78.2% ± 5.4%, respectively. S3 tumour marker (p = 0.01) and non-pulmonary visceral metastasis (p < 0.001) emerged as independent poor prognostic factors for OS in multivariate analysis. To conclude, testicular NSGCT has very high cure rate. Two-third patients present with advanced disease and one-third of them had poor risk disease. S3 tumour marker and non-pulmonary visceral metastasis are poor risk factors for OS.

Outcomes of metastatic neuroendocrine carcinoma of the gallbladder.

BACKGROUND: Neuroendocrine carcinoma of the gallbladder (NECGB) is a rare pathological entity. They are found to be aggressive cancers. Treatment strategies are based largely on extrapolation from other small cell cancers. Survival is poor compared to adenocarcinoma. Data from low- and middle-income countries are sparse. METHODS: All patients with metastatic NECGB treated in our centre were identified. Their treatment details were captured from electronic medical records. Baseline characteristics were noted and survival was estimated using Kaplan-Meir method. RESULTS: A total of 15 patients were included. The median age was 55 years. Large cell comprises 2/15 and small cell was found in 13/15 patients. Chemotherapy was platinum-based in 12 patients. The response to first-line chemotherapy was partial in 3 (20%), stable disease in 2 (13.3%) and progressive disease in 10 (66.6%). After a median duration of follow-up of 12 months, the median progression free survival was 3 months and the median overall survival was 5 months. CONCLUSION: The outcomes of small cell gallbladder cancer are dismal, despite good response rate. More prospective data are required.

Not so 'rare'-an example of malignant melanoma in India: report from a tertiary cancer centre.

PURPOSE: Malignant melanoma (MM) is rare in India. Indian data on demography and treatment outcome on advanced MM is very limited in the literature. MATERIALS & METHODS: This is a retrospective study of advanced MM treated between January 2013 and December 2020. We evaluated the clinicopathologic features, mutational profiles, survival outcome and prognostic factors in advanced MM patients. RESULTS: Out of a total 460 patients, 185 (42%) had metastatic disease at presentation and were enrolled in this study with a median age of 63 years (range: 28-93) and male:female ratio of 94:91. The mucosal primary was predominant (n = 110, 59%) than cutaneous primary (38%) and anorectum was the most common site (n = 84, 45%). Tumour mutational analysis was performed in 65 (35%) patients. BRAF mutations were detected in 12 patients and KIT mutations in 7 patients. Thirteen patients didn't have any mutations and 22 patients had mutations other than KIT & BRAF. Only 59 (32%) patients took any systemic treatment - immune checkpoint inhibitors (ICIs) in 17, temozolomide in 18 and paclitaxel/carboplatin in 18, tyrosine kinase inhibitors in 6 patients. After a median follow-up of 26 months (95% confidence interval (CI): 11.6-not reached), median progression-free survival (PFS) was 7.1 months (95% CI: 4.4-9.1) and median overall survival was 14.8 months (95% CI: 7.7-18.2 months). The use of ICI emerged as an only significant good prognostic factor (p ≤ 0.001) for PFS, on multivariate analysis. CONCLUSION: Mucosal origin was more common than cutaneous primary with anorectum being the most common site. BRAF mutation was less as compared to published literature. Very few patients received systemic therapy and the use of ICI showed superior PFS.

Multimodality treatment outcome in patients with primary malignant mediastinal germ cell tumor in adults.

BACKGROUND: Malignant mediastinal germ cell tumor (MGCT) is rare and has poor outcomes even after multimodality treatment. Data from resource-poor countries are scarce in the literature. AIMS: To evaluate the clinicopathologic features and treatment outcome of primary malignant MGCT at our center. METHODS AND RESULTS: Single institutional data review of patients aged ≥18 years, treated with a diagnosis of malignant MGCT between Nov'2013 and Nov'2019. Risk stratification was done as per International Germ Cell Cancer Collaborative Group (IGCCCG) classification. Patients were treated with platinum based chemotherapy and surgical resection for the residual disease was performed in non-seminomatous histology.28 patients had MGCT with a median age of 25 years (range:18-36) and all were male. Seven patients had superior vena cava obstruction (SVCO) at diagnosis and pre-treatment histological diagnosis was available in 23 (82%) patients. Seven (25%) patients had seminoma histology, all were of good risk as per IGCCCG risk criteria, whereas others had non-seminoma histology with poor-risk group. Seven patients with seminoma histology achieved a complete response after initial treatment. Six patients with non-seminoma histology underwent complete resection of residual disease post-chemotherapy and five revealed residual viable tumors. After a median follow-up of 10.8 months (range:2.9-75), 3-year progression-free survival (PFS) and overall survival (OS) estimate was 61.2% and 94.7% in the whole cohort, respectively and 3-year PFS and OS estimate was 100% in patients with seminoma histology. CONCLUSIONS: This is the largest data set of MGCT patients' outcomes reported from India with multi-modality treatment. All patients were male and one-fourth had SVCO at presentation. Seminoma histology patients had a 100% outcome after initial platinum based chemotherapy. But, those with non-seminoma histology had a poor outcome even with chemotherapy and surgery.

Management of Refractory Pediatric Sarcoma: Current Challenges and Future Prospects.

Paediatric sarcomas are a heterogeneous group of disorders constituting bone sarcoma and various soft tissue sarcomas. Almost one-third of these presents with metastasis at baseline and another one-third recur after initial curative treatment. There is a huge unmet need in this cohort in terms of curative options and/or prolongation of survival. In this review, we have discussed the current treatment options, challenges and future strategies of managing relapsed/refractory paediatric sarcomas. Upfront risk-adapted treatment with multidisciplinary management remains the main strategy to prevent future recurrence or relapse of the disease. In the case of limited local and/or systemic relapse or late relapse, initial multimodality management can be administered. In treatment-refractory cases or where cure is not feasible, the treatment options are limited to novel therapeutics, immunotherapeutic approach, targeted therapies, and metronomic therapies. A better understanding of disease biology, mechanism of treatment refractoriness, identifications of driver mutation, the discovery of novel targeted therapies, cellular vaccine and adapted therapies should be explored in relapsed/refractory cases. Close national and international collaboration for translation research is needed to fulfil the unmet need.