Survival outcome

The mean and median duration of follow-up of study patients was 38.04 months and 26.7 months, respectively. The 2-year EFS of the entire cohort was 62.6%. The 2-year EFS for patients with BL, DLBCL, and ALCL was 72.0%, 27.5%, and 55.8%, respectively.

Among the 12 patients with diagnosis of DLBCL, 4/12 received CHOP chemotherapy, 1/12 received oral cyclophosphamide, and 7/12 received LMB-89 protocol. Among the 7 patients who received LMB-89 protocol, 3/7 had disease relapse and 2/7 died due to neutropenic sepsis. Among the 5 patients who received CHOP or oral cyclophosphamide, 3/5 had disease relapse. Ten of the 12 patients with DLBCL had Stage III disease at presentation, and 1 patient each had Stage I and II, respectively.

On univariate analysis, factors that significantly predicted poor EFS included non-BL histological subtype, poor PS, not achieving complete response (CR) on interim assessment, malnutrition, and use of less intensive chemotherapy [Figure 1] and [Figure 2]. [Table 2] shows the univariate analysis for various parameters. On multivariate analysis, interim radiological response and PS were significantly associated with EFS. Gender, serum albumin, elevated LDH, hemoglobin, and delay in presentation of more than 1 month did not significantly predict EFS.

Univariate analysis of parameters for event-free survival

Events

The total number of events among the 102 patients was 37. Disease relapse or progression contributed to 27/37 events; 8/37 events were due to treatment-related toxicity death, 1/37 due to a patient developing colonic adenocarcinoma, and 1/37 patient died due to unknown cause in remission.

There were 8/102 (7.8%) treatment-related deaths, 3/8 deaths in patients with BL, 3/8 in patients with ALCL, and 2/8 in patients with DLBCL. The most common protocol associated with treatment-related mortality was LMB-89, which was used in 6/8 patients, 2/8 patients received BFM-90 ALCL protocol and MCP-842 protocol, respectively. All the eight treatment-related deaths were due to neutropenic sepsis.

The mean and median duration of disease relapse/progression was 5.28 and 5.97 months, respectively (range: 0?10.57 months). Three patients expired before treatment could be started and 2/3 had BL and 1/3 had ALCL. Six patients were treated with oral cyclophosphamide and steroids as they were moribund at presentation, 4/6 have expired, and status of the remaining 2/6 patients is not known as they were lost to follow-up. To summarize, definitive treatment for NHL could not be given to 9/102 patients.

Salvage chemotherapy and stem cell transplantation

Salvage chemotherapy was offered to 6 patients, 4/6 patients had DLBCL, 1 patient each had BL and ALCL, respectively. Two patients with DLBCL underwent autologous peripheral blood hematopoietic stem cell transplantation (ASCT) after achieving CR with salvage chemotherapy; they are well on follow-up and are currently in CR. The remaining 4/6 patients had disease progression after salvage and have died; they did not undergo ASCT.

Discussion

There is a paucity of published literature on pediatric NHL from developing countries.[7],[8] The 2-year EFS in patients with BL in our cohort was 72%, whereas the 5-year EFS in the LMB-89 trial was 91%.[1] Patients with Stage I and II BL had 100?S. Advani?et al. from Mumbai, India, reported an EFS of 68% in patients with small noncleaved and large cell lymphoma using MCP-842 protocol.[2] Bakhshi?et al. reported a progression-free survival of 72.8% in a cohort of 38 nonblastic NHL patients at a median follow-up of 20.3 months.[9] Our results in BL are comparable to reports from other centers in India. The 2-year EFS in patients with DLBCL in our cohort is 27.5% which is inferior compared to what has been reported in the literature. Patients with DLBCL were treated with either intensive LMB-89 protocol (n?= 7) or less intensive CHOP protocol (n?= 4) or oral cyclophosphamide (n?= 1) based on physician preference. However, the events in LMB-89 and CHOP group were similar. The poor outcome in the DLBCL cohort compared to BL or ALCL group in our study cannot be explained. The 2-year EFS in patients with ALCL in our study was 55.8%. Lakshmaiah?et al. reported an EFS of 66.7% in pediatric patients with ALCL at a median follow-up of 36 months.[10] Advanced stage, malnutrition, treatment-related toxicity, and poor general condition contribute toward the inferior outcome in our cohort.

None of the patients in our study abandoned treatment. We could not ascertain the overall survival (OS) status because majority of the patients who relapsed or progressed were sent home on best supportive care and their survival outcome could not be ascertained by postal or telephonic contact.

In our study, BL was the most common histology followed by ALCL and DLBCL. We had excluded patients with lymphoblastic lymphoma from our study because they are treated with acute lymphoblastic leukemia protocols rather than the short course intensive chemotherapy protocol used in nonblastic NHL. In a study of 252 pediatric NHL patients from Christian Medical College, Vellore, India, the most common subtype of NHL was lymphoblastic lymphoma (43.2%) followed by BL (22.2%), ALCL (11.5%), and DLBCL (8.7%).[11] The distribution of nonlymphoblastic subtypes seen at Vellore is similar to our study.

The most common reason of events in our cohort was disease relapse or progression; all the relapses occurred within first 10 months of treatment. We did not modify the treatment protocols to reduce the intensity, and therefore, this could not be a reason for higher relapse rate. About 7.8% of patients died due to febrile neutropenia, which is high compared to western settings. Patients have access to broad spectrum antibiotics and intensive care facilities at our hospital. We feel that the neutropenic deaths were because of the patient's poor nutritional status rather than access to adequate facilities. Tumor lysis syndrome (TLS) was effectively managed with hydration and allopurinol. No child required dialysis. Only one child with TLS was given rasburicase; she presented in a moribund condition and died before definitive treatment could be started.

Epidemiologically, our patients had features of sporadic BL unlike the endemic BL seen in Africa. Abdominal mass was the most common presentation and none of our patients with BL had jaw tumor.

Our study has limitations; these include the retrospective nature and lack of OS data. However, there are few curative options after progression or relapse in pediatric nonblastic NHL, especially in BL, and therefore, the EFS should reflect the OS.

Conclusion

Malnutrition and poor physical condition at presentation are important factors responsible for the inferior outcomes seen with pediatric nonblastic NHL at our center when compared to the western data. Patients with DLBCL had inferior outcomes in comparison to patients, with BL or ALCL.

Conflict of Interest

There are no conflicts of interest.

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