Rituxan Plus Chlorambucil as First-Line Treatment for Chronic Lymphocytic Leukemia

Dreyling, Martin, et al. "Phosphatidylinositol 3-kinase inhibition by copanlisib in relapsed or refractory indolent lymphoma

Dreyling et al. (p. 3898-3905) provide a detailed medical study on how copanlisib inhibits Phosphatidylinositol 3-kinase in a situation of recurred lymphoma. The presence of Phosphatidylinositol 3-kinase is an indication of surviving malignant B Cells among the patients.  Copanlisib 60mg inhibits this proliferation among patients to increase their survival rate given that once the B Cells increase beyond a certain threshold, limited options of treatment exist. The copanlisib 60mg was given intravenously for a span of 28 days with seven days interval as a second phase treatment.

In the research study, it was evident that copanlisib usage among pretreated patients with indolent B-Cell lymphoma increased efficacy significantly. This effectiveness works well among patients whose initial treatment include Rituximab and alkylating. Notably, 59% of the patients depicted objective responses that were durable and rapid. The average time for response was estimated to be fifty-three days, and the duration of response is about 22.6 months. This objective response was noted to be 70% among patients with marginal zone lymphoma and 59% among patients with follicular lymphoma.  The durability of the responses among the patients was enhanced by multiple prior lines of treatment, for instance alkylating and rituximab which reveals a possibility of PI3K playing a central oncogenic role in aggressive B-Cell lymphoma.

The most common treatment-related negative event that occurs among patients is transient hyperglycemia since 49% of the patients experienced it. However, this adverse event is self-limiting and does not lead to substantial discontinuation of medication. For patients with diabetes, short span insulin was recommended to manage the situation. Additionally, a low occurrence of GI toxicities like colonic perforations (none seen), colitis, diarrhea or transaminitis were noted with intermittent intravenous use of copanlisib. In conclusion, the use of copanlisib treatment shows a positive risk-benefit profile in malignant B-Cell lymphoma patients (Dreyling et al. p. 3905).

Salar, Antonio, et al. "Comparison of subcutaneous versus intravenous administration of rituximab as maintenance treatment for follicular lymphoma:

The pharmacokinetic model was used in stage I where a fixed 400-mg SC rituximab provides non-inferior c-trough as compared to level IV dosage as noted by Salar et al. (p. 762). This assertion was confirmed in the second stage where a fixed 1,400-mg SC proved non-inferior to IV maintenance dosing for two to three months regimen. Since rituximab offers a wide therapeutic window, 22,25 fixated dosage proved feasible as maintained an acceptable profile and was also sufficient enough to prevent under dosage. Stage I data provided the context of bioavailability of 1,400-mg SC dose that should be used in viewing the dose as ideal.

Based on previous medical investigations, of high dose rituximab, 22,25 the fixed dose of sub-cutaneous administration was not expected to result in any adverse events. Such a claim was supported by post hoc analysis of adverse events by BSA. Additionally, the analysis of AEs, severe SAEs and SAEs revealed a similar occurrence in both subcutaneous and intravenous treatments of patients in any BSA performed in stage I. Notably, in using either SC or IV no adverse events that were noticed that would necessitate the discontinuation of medication among the patients. In essence, there was no significant difference between the intravenous or subcutaneous administration of the rituximab among the patients. The common adverse implications of rituximab include nausea, and arthralgia which were observed but within the safety profile already established. Apparently, some degree of expectancy bias was unavoidable given that SC formulation was administered on an ongoing treatment regimen.

 In conclusion, it would be acceptable to suggest that, based on the research findings, rituximab SC administration improve the drug’s convenience but further research needs to be carried out to determine whether SC routes offer higher efficacy compared to IV ones.

Hillmen, Peter, et al. "Rituximab plus chlorambucil as first-line treatment for chronic lymphocytic leukemia

The purpose of the research study conducted by Hillmen et al. (p. 1236- 1241) is to find out how the addition of Rituximab to chlorambucil would affect the efficacy and safety among patients with chronic lymphocytic Leukemia (CLL). Given that CLL mostly affects elderly patients who have comorbidities that disqualify their eligibility for fludarabine-based treatment. As such, the ideal therapy options for such a population remains chlorambucil monotherapy. However, this treatment has proved ineffective, and the response rates low necessitating as an additional and therapeutic alternative.

The therapy regimen involved treatment of first-line CLL with rituximab (375 mg/m2 on the first day of the cycle I and 500 mg/m2 after that in addition to chlorambucil (10 mg/m2/d for all the cycles from the first to the 7th day for the six twenty-eight-day cycles. Six additional cycles of chlorambucil could be administered to patients not attaining a complete response (CR). The primary goal and end point of this research study was the safety of the patients. The patients received R-chlorambucil treatment for thirty months. The median age of the patients was recorded to be seventy years with a median of seven comorbidities. The most grade for adverse events was ¾ and was attributable to hematologic toxicities with leukopenia occurring in 23% of the patients and lymphopenia and neutropenia occurring in 41% of the patients. It was notable that the objective response was estimated to be 84% with CR attained in 10% of all the patients. Although the median overall survival was not attained, the progression-free survival was 23.5 months. Therefore, in line with other research studies, it would be accurate to conclude that addition of rituximab to chlorambucil monotherapy will improve efficacy without having any negative events. This R-chlorambucil is most beneficial to patients ineligible for fludarabine-based therapies particularly among the elderly.

Pettitt, Andrew R., et al. "Alemtuzumab in combination with methylprednisolone is a highly effective induction regimen for patients with chronic lymphocytic leukemia and deletion of TP53

Pettitt et al. (p. 1647-1655) assert that in chronic lymphocytic leukemia (CLL), TP53 mutation/ deletion is strongly connected with an adverse event and resistance to chemotherapy-based therapies. Nonetheless, TP53 defects are not associated with conflict to the methylprednisolone or anti-CD52 monoclonal antibody alemtuzumab.A multicenter treatment approach was used to improve the treatment of TP53-defective CLL. This study was used to evaluate the effectiveness of combining methylprednisolone and alemtuzumab. The treatment procedure involved 22 previously treated patients and 17 untreated patients with a dose of alemtuzumab 30 mg thrice a week and methylprednisolone 1.0 g/m2 for five consecutive days for four weeks. Additionally, in this treatment, there was the use of antimicrobial prophylaxis consisting of itraconazole, cotrimoxazole, and acyclovir.

The primary objective was response while the secondary endpoints aimed at overall survival (OS), progression-free survival (PFS), and safety. The response rate was incredibly high, that of 85% and the complete response rate was recorded to be 36%.  Notably, the progressive free survival was 11.8 months while the median overall survival was 23.5 months. These outcomes reveal that Alemtuzumab combined with methylprednisolone is the most effective treatment regimen reported in TP53-deleted CLL.

Works Cited

Dreyling, Martin, et al. "Phosphatidylinositol 3-kinase inhibition by copanlisib in relapsed or refractory indolent lymphoma." Journal of Clinical Oncology

35.35 (2017): 3898-3905.

Hillmen, Peter, et al. "Rituximab plus chlorambucil as first-line treatment for chronic lymphocytic leukemia: final analysis of an open-label phase II study." Journal of Clinical Oncology 32.12 (2014): 1236-1241.

Pettitt, Andrew R., et al. "Alemtuzumab in combination with methylprednisolone is a highly effective induction regimen for patients with chronic lymphocytic leukemia and deletion of TP53: final results of the national cancer research institute CLL206 trial." Journal of Clinical Oncology 30.14 (2012): 1647-1655.

Salar, Antonio, et al. "Comparison of subcutaneous versus intravenous administration of rituximab as maintenance treatment for follicular lymphoma: results from a two-stage, phase IB study." Journal of Clinical Oncology

32.17 (2014): 1782-1791.