Leukeran (chlorambucil)

P3, N=344, Recruiting, Ascentage Pharma Group Inc. | Not yet recruiting --> Recruiting

P3, N=344, Not yet recruiting, Ascentage Pharma Group Inc.

Chlorambucil and ibrutinib can promote the apoptosis of MCL cell line Jeko-1, and combined application of the two drugs shows a synergistic effect, the mechanism may be associated with the AKT-related signaling pathways.

P3, N=155, Active, not recruiting, AstraZeneca | Trial completion date: Jun 2024 --> Nov 2024 | Trial primary completion date: Jun 2024 --> Nov 2024

P3, N=211, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Apr 2029 --> Apr 2027

Among them, compound 11b exhibited potent anticancer efficacy in cancer cell lines and mouse tumor models with intrinsic resistance to the parent compound FK866 or chlorambucil. Compound 11b caused catastrophic NAD depletion via a synergistic effect between the NAD salvage pathway blockade and DNA damage-triggered NAD consumption. Our findings suggest a new intervention strategy for causing catastrophic NAD depletion in cancer cells and provide basis for the development of new inhibitors targeting NAD metabolism.

After 4 years of follow-up, ibrutinib-venetoclax continues to significantly prolong progression-free survival (vs chemoimmunotherapy) in patients with previously untreated chronic lymphocytic leukaemia, supporting its use as a first-line option.

After 8 cycles, patients with VGPR remission receive Chlorambucil 6mg D1-4,15-18, dexamethasone 20mg D1-4,15-18, cyclophosphamide 300mg, D1-4,15-18 for 4cycles, others receive Zanubrutinib as maintenance. These results demonstrate that zanubrutinib, dexamethasone and or not cyclophosphamide are quickly effective in the treatment of WM, with more deeper response and less toxicity, maybe treatment discontinued by combining with cyclophosphamide after deep remission. Comments*The regimen of ZD: Zanubrutinib 240mg d1-28, dexamethasone 20mg D1-4,15-18. Patients more than 75 years old, Zanubrutinib 160mg d1-28, dexamethasone 10mg D1-4,15-18.

Other non-BTKi/BCL2i therapies received included bendamustine+rituximab, rituximab monotherapy, investigational regimens, chlorambucil+obinutuzumab, and other regimens. Our findings indicate that patients treated with BTKi/BCL2i sequences in 1L and 2L may have experienced improved outcomes relative to patients who received other sequences in the same LOTs. While research is beginning to investigate characteristics and outcomes for patients who received these therapies consecutively (Lew et al. , Blood Adv 2021), future research should further examine these outcomes in a larger patient population and in patients who have already discontinued and relapsed on both BTKis and BCL2is.

We describe the case of a 62-year-old patient diagnosed in 2003 with CLL, previously treated with Chlorambucil, and chemo-immunotherapy with R-CVP regimen. Conclusions. The fixed-duration treatment with Ven-R showed 254 high efficacy and feasibility even in patients with renal failure on dialysis and with high hemorrhagic risk, for which BTK-inhibitors may not represent a safe therapeutic alternative.

The discovery cohort comprised pre-treatment samples from 79 CLL patients enrolled in the NCRI RIAltO trial (NCT01678430) who underwent factorial randomisation to ofatumumab and either bendamustine or chlorambucil, with or without idelalisib. The present study has identified three previously undescribed T-cell subpopulations that appear to influence the risk of infection, SPM, and death in patients with CLL receiving frontline chemo-immunotherapy. Further studies are warranted to validate these findings in the setting of targeted agents and in patients receiving CIT for other haematological malignancies.

The main first-line treatment regimens received were: chlorambucil (37%), dexamethasone, rituximab and cyclophosphamide (DRC)(21%), rituximab monotherapy (13%), bendamustine/rituximab (BR) (9.1%), Bruton tyrosine kinase (BTK) inhibitors (7%), and bortezomib, dexamethasone and rituximab (BDR) (5.5%). There were no significant differences in OS between different times of diagnosis. This Spanish registry for SWM contributes to advancing knowledge and the continual enhancement of treatment strategies for WM.

A Phase III trial comparing I+V (15 months [mo]) with chlorambucil-obinutuzumab led to the approval of I+V. Ibrutinib plus venetoclax significantly improved progression-free and overall survival compared to FCR in untreated CLL. Using MRD to direct the duration of I+V maximizes outcome with 97.2% progression free survival at 3 years The efficacy seen in FLAIR is superior to previous Phase III CLL trials indicating that I+V with duration guided by MRD is a new gold standard for CLL treatment.

With prolonged follow-up of 55 months in the GLOW study, all-oral, once-daily, fixed-duration Ibr+Ven continues to show superior PFS versus Clb+O. Among patients treated with Ibr+Ven, benefit in PFS was particularly observed in patients with uIGHV who achieved uMRD at EOT+3 and in patients with mIGHV regardless of MRD status at EOT+3. Moreover, Ibr+Ven fixed-duration combination treatment continues to demonstrate an OS advantage versus chemoimmunotherapy in patients with previously untreated CLL.

Pts with RT occurring as large B-cell lymphoma who did not previously receive CIT (e.g., fludarabine, cyclophosphamide, bendamustine, chlorambucil) for their CLL/SLL were included...The remaining 14% had been treated with an anti-CD20 monoclonal antibody (MoAb), steroids, lenalidomide, radiation, or alemtuzumab... This is the largest cohort of pts who developed RT having received only SMI with no CIT for their CLL reported, thus reflecting the current treatment landscape. Despite being CIT-naïve, pts in our series who received tx for their CLL/SLL and then developed RT had a short OS, underscoring the need to develop better therapies for these pts. In contrast, as in other published analyses (Wang Haematologica 2020), pts w/o prior tx for CLL/SLL had more favorable outcomes, with a median OS of approximately 5 years.

Patients were randomly assigned to receive bendamustine or chlorambucil plus ofatumumab, with or without idelalisib. To our knowledge, this is the first study to identify correlations between the re-emergence of non-malignant B-cells following anti-CLL therapy and specific clinical endpoints such as haematopoietic recovery, serum Ig levels, TTP and OS. Although further validation is required in the context of targeted agents, our findings suggest that therapy-induced re-emergence of non-malignancy B-cells may have important biological and clinical implications in CLL.

Patients were randomly assigned to receive ofatumumab plus either bendamustine or chlorambucil, with or without idelalisib. CIT results in profound immune changes that persists up to 18.5 [16.1 – 22.6] months following treatment. Furthermore, the overall effect of these changes further differentiates the CLL-associated immune profile from that of HC, deepening the existing T-cell dysfunction irrespective of chemotherapy choice, or the addition of idelalisib. Our study has important potential implications for patients receiving CIT in a range of clinical settings and supports the move towards more targeted agents that are less likely to cause indiscriminate immune perturbation.

Herein, we developed a photosensitizer prodrug (CSP) by conjugating the photosensitizer pyropheophorbide a (PPa) and the DNA-damaging agent Chlorambucil (Cb) with a GSH-responsive disulfide linkage and demonstrated a multifunctional co-delivery nanoplatform (CSP/Ola nanoparticles (NPs)) together with DSPE-PEG and PARP inhibitor Olaparib (Ola). As a consequence, the co-delivery nanoplatform greatly promotes the tumor cell apoptosis and shows a high antitumor performance with combinational chemotherapy and PDT. Overall, this work provides a potential alternative to improve the therapeutic efficiency of triple negative breast cancer cell (TNBC) treatment by synergistically enhancing DNA damage and disrupting DNA damage repair.

Due to the absence of direct head-to-head trials, an indirect Bucher comparison was performed using a common comparator (OBI + chlorambucil). Compared to previously published evaluations, the use of longer follow-up periods with a larger number of events in the calculations demonstrates that AKA compared to VEN+OBI significantly reduces the risk of progression or death by 47% in the overall population and by 56% in the subgroup of patients with unmutated IGHV genes.

In an exploratory analysis, 40 patients enrolled in the CLL14 trial (NCT02242942, N=432) treated with obinutuzumab (G) in combination with chlorambucil (Clb) or Venetoclax (Ven) were selected based on an undetectable MRD status (<10 -4 ) at 3 months after last dose of G and subsequent molecular relapse, defined as MRD ≥10 -4 , within a defined follow-up (FU) time of 24 months. In this small subset of patients with MRD relapse after ClbG or VenG patient groups showed different clonal expansion. Whether the observed results are caused by biological factors or the treatment has to be investigated on larger patient numbers.

The FRE-PIPs conjugated to chlorambucil (FRE-chb) inhibited transcription of TRIB1, causing differentiation in various AML cell lines...Administration of FRE-chb inhibited tumor progression in vivo without remarkable adverse effects. In conclusion, targeting cis-regulatory elements of the FOXO family is a promising therapeutic strategy that induces AML cell differentiation.

P2, N=20, Active, not recruiting, Michele Reni | Recruiting --> Active, not recruiting | N=30 --> 20 | Trial primary completion date: Jun 2021 --> Jan 2023

Regarding first-line therapy, 46.8% received fludarabine, cyclophosphamide, plus rituximab (FCR), followed by chlorambucil (19.9%), and obinutuzumab plus chlorambucil (GC) (12.1%). Age and reimbursement mainly influenced treatment strategies. Greater effort to apply risk stratifications into practice and clinical trials for novel agents could help improve treatment outcomes in Korean patients.

Objective: Impact of baseline genomic aberrations on undetectable minimal residual disease (uMRD) at 3 months after end of treatment (EOT+3) and progression-free survival (PFS) of ibrutinib+venetoclax (Ibr+Ven) and chlorambucil+obinutuzumab (Clb+O) in patients with previously untreated CLL from GLOW (NCT03462719) was evaluated. With approximately 4 years of follow-up, uIGHV status and trisomy-12 were associated with shorter PFS with fixed-duration Ibr+Ven in patients with previously untreated CLL. However, imbalances in early non- progression events and small sample size may limit interpretation. PFS with Ibr+Ven was significantly better than Clb+O across most genomic subgroups.

In the frontline setting, the ELEVATE-TN study compared acalabrutinib, either alone or in combination with obinutuzumab, to chlorambucil plus obinutuzumab...Frontline phase 3 trial data comes from the SEQUOIA study, where zanubrutinib was compared with bendamustine plus rituximab...The combination of ibrutinib plus venetoclax has received frontline approval from the EMA. Ongoing studies may offer future options of time-limited therapy involving covalent BTK, but current approaches with indefinite covalent BTK treatment offer a safe and effective strategy to treat CLL patients at this time.

An improved understanding of the disease biology has contributed to the development of novel agents able to target key pathways in CLL.2 Two classes of targeted agents have been extremely impactful in shaping current treatment of CLL: the BCL2 inhibitor venetoclax and the Bruton's tyrosine kinase inhibitors (BTKi) ibrutinib, acalabrutinib and zanubrutinib...Patients received six 28-day cycles of ibrutinib in combination with fludarabine, cyclophosphamide and rituximab (FCR) followed by 2 years of ibrutinib maintenance...The combination of ibrutinib-venetoclax demonstrated superior progression-free survival (24 months estimated rate 84.4% for patients treated with ibrutinib-venetoclax and 44.1% for patients treated with chlorambucil-obinutuzumab) and superior rates of U-MRD (55.7% vs 21%).15 The time-limited approach with concomitant administration of BTK and BCL2 targeting agents has potential advantages over continuous BTK inhibitor-based therapy in terms of reduced risk for treatment-related side effects due to the prolonged administration and potentially lower costs8 , however, there are still open questions in terms of selection of therapy at time of retreatment and quality and durability of responses to subsequent therapies. It is important to note that treatment with combination of BTKi and venetoclax with or without CD20 monoclonal antibodies is not FDA approved and is still being investigated in clinical trials.

Given the patient’s clinical fragility in a multidisciplinary meeting, we opted for therapy aimed at symptomatic relief and containment of the disease with chlorambucil and prednisolone, with progressive clinical improvement until the 3rd cycle of treatment. This case illustrates the natural history of many cutaneous T-cell lymphomas, which exhibit an initial phase clinically and histologically indistinguishable from eczema. Although, rapid evolution to an aggressive primary cutaneous T-cell lymphoma, as described in our case, is not the commonly described evolutionary pattern. Treatment of PCTCL-NOS includes systemic chemotherapy, autologous bone marrow transplantation, and eventually, brentuximab vedotin or alemtuzumab.

The most common antineoplastic treatment was ibrutinib in 1L (64.8%) and 2L (62.1%), followed by bendamustine + rituximab (12.6%), obinutuzumab + chlorambucil (5.2%), rituximab + chlorambucil (4.8%), and idelalisib + rituximab (3.9%) in 1L and venetoclax (15.5%), idelalisib + rituximab (6.9%), bendamustine + rituximab (3.5%), and venetoclax + rituximab (3.5%) in 2L. This study expands the information available on patients with CLL in Spain, describing the diversity in patient characteristics and therapeutic approaches in clinical practice.

HS-5 human stromal cells were exposed to mitoxantrone (MTX) and chlorambucil (CHL) and, for the first time, were profiled for 80 cytokines using an array. Of particular concern was that some combinations induced micronuclei at levels above the mitomycin C positive control, however most combinations were less than the sum of micronuclei induced following exposure to each cytokine in isolation. These data infer a possible role for cytokines through chemotherapy-induced cytokine storm, in the instigation and support of leukaemogenesis in the BM, and implicate the need to evaluate individuals for variability in cytokine secretion as a potential risk factor for complications such as DCL.

The IC50 behavior of the conjugates of the first and second generations showed anticancer activity against PC-3, HCT-15, and MFC-7 cell lines. The second generation was more active against PC-3, HCT-15 and MFC-7 with IC50 of 3.8±0.5, 3.0±0.2 and 3.7±1.1 M, respectively The new Janus dendrimers with anticancer chlorambucil and nonsteroidal anti-inflammatory Ibuprofen can improve the anticancer activity of chlorambucil with less toxicity.

These favorable physicochemical properties can effectively facilitate gastrointestinal absorption, blood circulation stability, tumor accumulation, cellular uptake, and cytotoxicity, therefore achieving high oral relative bioavailability (358.72%) and significant tumor growth inhibition while decreasing side effects. Thus, this work may open a new avenue for robust oral chemotherapy attractive for clinical translation.

Historically treatment with naked monoclonal antibodies (mAbs) alone or in combination with standard chemotherapy (e.g. anti-CD52, anti-CD20 plus fludarabine/chlorambucil) have yielded significant clinical response in patients with chronic lymphocytic leukemia (CLL) compared to chemotherapy alone. Later developments include chimeric antigen receptor expressing T cells (CAR-T) targeting cell surface proteins (e.g. CD19, ROR1), small molecule inhibitors such as ibrutinib, idelalisib, venetoclax targeting intracellular proteins (e.g. BTK, PI3Kδ, BCl-2) and combinations thereof have shown excellent clinical activity in patients...Together these experiments demonstrated the specificity and potency of anti-FcuR-ADC in vitro, and studies are underway to evaluate its efficacy in vivo using a patient-derived xengograft CLL model. We envisage that anti-FcμR-DVD-ADCs may offer a promising modality for the treatment of CLL.

Patients with previously untreated CLL and coexisting conditions were randomized 1:1 to 12 cycles of venetoclax with 6 cycles of obinutuzumab, or 12 cycles of chlorambucil with 6 cycles of obinutuzumab (Clb-Obi). These long-term data confirm a continued PFS benefit of fixed-duration Ven-Obi treatment compared to Clb-Obi, including patients with high-risk CLL. Five years after cessation of Ven-Obi, over half of the patients of this elderly patient population remained in remission, 8% still had uMRD and over 60% had not required second-line treatment. The 1-year Ven-Obi regimen is an effective fixed-duration option for patients with CLL and coexisting conditions.

In the CLL14 study, symptomatic patients with CLL receiving frontline therapy with VO had longer progression-free survival (PFS) and deeper remissions [more undetectable minimal residual disease (MRDu)] compared with to that seen in patients receiving chlorambucil and obinutuzumab [1]. Current status: At the time of submission, 67 patients have been registered and randomized per protocol. Accrual is ongoing.

International guidelines [1,2] recommend targeted therapies including covalent BTK inhibitors (cBTKi; ibrutinib, acalabrutinib, zanubrutinib) and BCL2 inhibitors (BCL2i; venetoclax) combinations as preferred regimens for most treatment naïve CLL patients...Before 2012 alkylating agents in monotherapy (chlorambucil) were the therapy most frequently used, and from that year onwards, chemoimmunotherapy (FCR, R-Bendamustine) was particularly given (Figure 1)...In the multivariant analysis, age younger than 65 years, female sex, and mutated IGHV were related to better OS. In summary, our data confirm that targeted therapies have become the most used treatment as frontline therapy in CLL, emphasizing the need for treatment algorithms including best sequential treatments and optimal treatment duration.

Among pts treated with TAs, 971 (75%) received continuous therapy with a first-generation Bruton tyrosine kinase inhibitor (BTKi) (ibrutinib [I] monotherapy, 32.7%%; I-obinutuzumab [IO], 11.6%); I-Rituximab [IR], 18.7%; or a second-generation BTKi (acalabrutinib [A] monotherapy, 18.4%; A-obinutuzumab [AO], 18.4%). 322 persons (24.9%) received fixed-duration (FD) therapy with venetoclax (V)-based combinations (V-obinutuzumab: 22.5%; V-Ibrutinib: 10.9%). Patients enrolled in the CT/CIT arms received chlorambucil (C) as a single agent (14.3%), Bendamustine-Rituximab (BR, 19.6%), C-obinutuzumab (CO, 66%)...Nonetheless, the results of this analysis evaluating the upfront administration of TAs on OS suggest these agents have substantially mitigated but not fully eliminated the shorter OS of CLL patients relative to the AGMGP. Continued development of novel treatment approaches to improve outcome for patients with CLL is needed.

Case Description/ 54-year-old male with Stage IVB MZL status-post Rituximab, Vincristine, and Leukeran, presented with 2-week history of significant bouts of bloody diarrhea and general malaise...Five cycles of the Oxaliplatin /Capecitabine regimen were initiated...The latter delayed the approval of Pembrolizumab (a novel therapy for MSI-H positive GA) and Zanubrutinib (a novel BTK inhibitor for refractory MZL)...Hence, more guidance is needed to navigate therapeutics in concurrent malignancies. It is essential to streamline the process for authorizations for chemotherapeutics, especially for the more vulnerable populations which are prone to getting lost to follow-up, causing poorer outcomes.

P3, N=603, Completed, TG Therapeutics, Inc. | Active, not recruiting --> Completed | Trial completion date: Jan 2024 --> Feb 2023 | Trial primary completion date: Nov 2023 --> Feb 2023

Molecular and clinical relapses were less frequent during the first year post-treatment with ibrutinib + venetoclax versus chlorambucil + obinutuzumab regardless of MRD status at EOT+3 and IGHV status. Even for patients not achieving uMRD (<10), PFS rates remained high with ibrutinib + venetoclax; this is a novel finding and requires additional follow-up to confirm its persistence over time.

Alkylating agents in monotherapy (chlorambucil) were the most used until 2012, and from then, chemoimmunotherapy...Patients who received targeted therapies had significantly longer TTNT compared to other regimens. In the multivariable analyses, mutated IGHV genes targeted therapies and chemoimmunotherapy regimens were related to longer TTNT, and sex female, age younger than 65, and mutated IGHV genes were associated with better OS.