fludarabine
Regulatory sources consulted
Approved indications
- B-cell chronic lymphocytic leukemia in adults with sufficient marrow reserve; first-line only for advanced or progressive Rai III/IV (Binet C) disease or Rai I/II (Binet A/B) with symptoms or progression.
Contraindications
Absolute
- Hypersensitivity; CrCl <30 mL/min; decompensated hemolytic anemia; breastfeeding.
Clinical warnings
- Monitor blood counts before each cycle and through the nadir. Delay or modify the cycle for myelosuppression; infections and bleeding may be severe or fatal. — CIMA/AEMPS, ficha técnica 64900
- It may cause severe neurotoxicity, opportunistic infections, and autoimmune hemolytic anemia. Use irradiated blood for transfusions to prevent transfusion-associated graft-versus-host disease. — CIMA/AEMPS, ficha técnica 64900
Drug interactions
- ModeratePentostatin
Mechanism: The combination was associated with unacceptable fatal pulmonary toxicity.
Recommendation: Do not combine fludarabine with pentostatin.
CIMA/AEMPS, ficha técnica 64900
- HighLive vaccines
Mechanism: Immunosuppression may cause disseminated vaccine infection.
Recommendation: Live vaccines are not recommended during immunosuppression.
CIMA/AEMPS, ficha técnica 64900
- HighDipyridamole or other adenosine-uptake inhibitors
Mechanism: They may reduce the therapeutic efficacy of fludarabine.
Recommendation: Avoid concomitant use when possible and review the regimen with the oncology team.
CIMA/AEMPS, ficha técnica 64900
Pregnancy and lactation
Fludarabine may impair fertility in women and men. If a later pregnancy is planned, offer genetic counseling and consider sperm preservation before treatment. Breastfeeding is contraindicated.
Recent literature (PubMed)
Whether fixed-duration acalabrutinib-venetoclax (with or without obinutuzumab) would result in better progression-free survival than chemoimmunotherapy in patients with untreated chronic lymphocytic leukemia (CLL) is unknown. In this phase 3, open-label trial, we included patients 18 years of age or older who had an Eastern Cooperative Oncology Group performance-status score of 0 to 2 (range, 0 to 5, with higher numbers indicating greater disability) and who did not have a 17p deletion or TP53 mutation. Patients were randomly assigned, in a 1:1:1 ratio, to receive acalabrutinib-venetoclax (acalabrutinib, cycles 1 to 14; venetoclax, cycles 3 to 14), acalabrutinib-venetoclax-obinutuzumab (as above, plus obinutuzumab, cycles 2 to 7), or chemoimmunotherapy with the investigator's choice of fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab (cycles 1 to 6). The primary end point was progression-free survival (acalabrutinib-venetoclax vs. chemoimmunotherapy) in the intention-to-treat population, assessed by blinded independent central review. A total of 867 patients underwent randomization: 291 were assigned to receive acalabrutinib-venetoclax, 286 acalabrutinib-venetoclax-obinutuzumab, and 290 chemoimmunotherapy (of whom 143 received fludarabine-cyclophosphamide-rituximab and 147 bendamustine-rituximab). The median age of the patients was 61 years (range, 26 to 86), 64.5% were men, and 58.6% had unmutated IGHV. Estimated 36-month progression-free survival at a median follow-up of 40.8 months was 76.5% with acalabrutinib-venetoclax, 83.1% with acalabrutinib-venetoclax-obinutuzumab, and 66.5% with chemoimmunotherapy (hazard ratio for disease progression or death with acalabrutinib-venetoclax vs. chemoimmunotherapy, 0.65 [95% confidence interval {CI}, 0.49 to 0.87], P = 0.004; for the comparison of acalabrutinib-venetoclax-obinutuzumab with chemoimmunotherapy, P<0.001). Estimated 36-month overall survival was 94.1% with acalabrutinib-venetoclax, 87.7% with aca
Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia, hepatosplenomegaly, lymphadenopathy, and rarely hyperviscosity. The presence of IgM monoclonal protein associated with ≥ 10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis. The L265P mutation in MYD88 is detectable in more than 90% of patients and is found in most IgM MGUS patients. MYD88 is not required for the diagnosis. Age, albumin, hemoglobin level, platelet count, β2 microglobulin, Lactate dehydrogenase (LDH), and monoclonal IgM concentrations are characteristics that are predictive of outcomes. Not all patients who fulfill WM criteria require therapy; these patients can be observed until symptoms develop. Rituximab-monotherapy is inferior to combination regimens. Recommended first-line therapy can be chemoimmunotherapy or a covalent Bruton tyrosine kinase inhibitor. The preferred Mayo Clinic induction is either rituximab and bendamustine (without rituximab maintenance) or zanubrutinib. Bortezomib, cyclophosphamide, fludarabine, thalidomide, everolimus, pirtobrutinib, carfilzomib, lenalidomide, bendamustine, and venetoclax have all been shown to have activity in relapsed WM. Given WM's natural history, the reduction of therapy toxicity is an important part of treatment selection. Most patients succumb to causes unrelated to macroglobulinemia.
Randomized trials of venetoclax plus anti-CD20 antibodies as first-line treatment in fit patients (i.e., those with a low burden of coexisting conditions) with advanced chronic lymphocytic leukemia (CLL) have been lacking. In a phase 3, open-label trial, we randomly assigned, in a 1:1:1:1 ratio, fit patients with CLL who did not have TP53 aberrations to receive six cycles of chemoimmunotherapy (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab) or 12 cycles of venetoclax-rituximab, venetoclax-obinutuzumab, or venetoclax-obinutuzumab-ibrutinib. Ibrutinib was discontinued after two consecutive measurements of undetectable minimal residual disease or could be extended. The primary end points were undetectable minimal residual disease (sensitivity, <10-4 [i.e., <1 CLL cell in 10,000 leukocytes]) as assessed by flow cytometry in peripheral blood at month 15 and progression-free survival. A total of 926 patients were assigned to one of the four treatment regimens (229 to chemoimmunotherapy, 237 to venetoclax-rituximab, 229 to venetoclax-obinutuzumab, and 231 to venetoclax-obinutuzumab-ibrutinib). At month 15, the percentage of patients with undetectable minimal residual disease was significantly higher in the venetoclax-obinutuzumab group (86.5%; 97.5% confidence interval [CI], 80.6 to 91.1) and the venetoclax-obinutuzumab-ibrutinib group (92.2%; 97.5% CI, 87.3 to 95.7) than in the chemoimmunotherapy group (52.0%; 97.5% CI, 44.4 to 59.5; P<0.001 for both comparisons), but it was not significantly higher in the venetoclax-rituximab group (57.0%; 97.5% CI, 49.5 to 64.2; P = 0.32). Three-year progression-free survival was 90.5% in the venetoclax-obinutuzumab-ibrutinib group and 75.5% in the chemoimmunotherapy group (hazard ratio for disease progression or death, 0.32; 97.5% CI, 0.19 to 0.54; P<0.001). Progression-free survival at 3 years was also higher with venetoclax-obinutuzumab (87.7%; hazard ratio for disease progression or death, 0.42; 97.5% CI, 0.26 to
Sixty percent of newly diagnosed patients with acute myeloid leukemia (ND-AML) receiving frontline therapy attain a complete response (CR), yet 30%-40% of patients relapse. Relapsed or refractory AML (R/R-AML) remains a particularly adverse population necessitating improved therapeutic options. This phase Ib/II study evaluated the safety and efficacy of fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin combined with the B-cell lymphoma-2 inhibitor venetoclax in ND-AML and R/R-AML. The phase IB portion (PIB) enrolled patients with R/R-AML using a 3 + 3 dose escalation and de-escalation algorithm for identification of maximum tolerated dose and dose-limiting toxicities. The phase II portion enrolled patients into two arms to evaluate response and time-to-event end points: phase IIA (PIIA): ND-AML and phase IIB (PIIB): R/R-AML. Sixty-eight patients have enrolled to date (PIB, 16; PIIA, 29; PIIB, 23). Median age was 46 years (range, 20-73). Grade 3 and 4 adverse events occurring in ≥ 10% of patients included febrile neutropenia (50%), bacteremia (35%), pneumonia (28%), and sepsis (12%). The overall response rate for PIB, PIIA, and PIIB was 75%, 97%, and 70% with 75%, 90%, and 61%, respectively, achieving a composite CR. Measurable residual disease-negative composite CR was attained in 96% of ND-AML and 69% of R/R-AML patients. After a median follow-up of 12 months, median overall survival (OS) for both PII cohorts was not reached. Fifty-six percent of patients proceeded to allogeneic hematopoietic stem-cell transplantation (ND-AML, 69%; R/R-AML, 46%). In R/R-AML, allogeneic hematopoietic stem-cell transplantation resulted in a significant improvement in OS (median OS, NR; 1-year OS, 87%). One-year survival post-HSCT was 94% in ND-AML and 78% in R/R-AML. Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin + venetoclax represents an effective intensive treatment regimen in ND-AML and R/R-AML patients, associated with
An interim analysis of progression-free survival in this trial showed that ibrutinib-venetoclax was superior to fludarabine-cyclophosphamide-rituximab (FCR) among patients with chronic lymphocytic leukemia (CLL). Whether ibrutinib-venetoclax is more effective than ibrutinib alone is unclear. In this phase 3, multicenter, open-label trial, we randomly assigned patients with CLL to receive ibrutinib-venetoclax, ibrutinib alone, or FCR. The primary end points were undetectable measurable residual disease (MRD) in bone marrow within 2 years in the ibrutinib-venetoclax group as compared with the ibrutinib-alone group and progression-free survival in the ibrutinib-venetoclax group as compared with the FCR group. A powered secondary end point was progression-free survival in the ibrutinib-venetoclax group as compared with the ibrutinib-alone group. Other secondary end points included overall survival. A total of 172 of the 260 participants (66.2%) in the ibrutinib-venetoclax group had undetectable MRD in bone marrow within 2 years, as compared with none of the 263 participants in the ibrutinib-alone group (P<0.001) and 127 of the 263 participants (48.3%) in the FCR group. With a median follow-up of 62.2 months, disease progression or death occurred in 18 participants (6.9%) in the ibrutinib-venetoclax group, as compared with 59 (22.4%) in the ibrutinib-alone group (hazard ratio, 0.29; 95% confidence interval [CI], 0.17 to 0.49; P<0.001) and 112 (42.6%) in the FCR group (hazard ratio, 0.13; 95% CI, 0.08 to 0.21; P<0.001). Progression-free survival at 5 years was 93.9% with ibrutinib-venetoclax, 79.0% with ibrutinib alone, and 58.1% with FCR. Death occurred in 11 participants (4.2%) in the ibrutinib-venetoclax group, as compared with 26 (9.9%) in the ibrutinib-alone group (hazard ratio, 0.41; 95% CI, 0.20 to 0.83) and 39 (14.8%) in the FCR group (hazard ratio, 0.26; 95% CI, 0.13 to 0.50). Sudden death occurred in 3, 8, and 4 participants in the ibrutinib-venetoclax, ibrutini