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Leukemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Despite the significant improvement in the therapy of ALL, in particular in children, about 25% of children and 50–60% of adults relapse. Second remissions (CR2) can be achieved in most of these patients, but in many cases, they are not sustained. Factors associated with a poor outcome after relapse include a shorter length of first remission, bone marrow as the initial site of relapse, older age, T-cell ALL, ETP-ALL, BCR-ABL1, and male sex. For patients who relapse more than 2 years after achieving CR, remission may be re-induced with the same drugs that induced the first remission. Clofarabine, a purine nucleoside, was approved over a decade ago for patients who have had two or more relapses, and the drug has had modest success.53 Another useful licensed cytotoxic is the liposomal formulation of vincristine sulfate.
Leukaemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2014
Phase II studies assessing the role of clofarabine, a novel nucleoside analogue developed from fludarabine and cladribine, administered in combination with cytarabine for relapsed and refractory AML patients resulted in a CR rate of 22%.36 Several other trails established clofarabine’s credentials in resulting high CR rates in newly diagnosed older patients, but unfortunately, the overall survival was not improved.37 A similar drug, troxacitabine, is currently in clinical trials.
Acute Myeloid Leukaemia
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
The UK National Cancer Research Institute (NCRI) AML-16 trial attempts to answer some of the topical questions discussed above. The trial compares standard-dose daunrorubicin/Ara-C versus daunorubicin/clofarabine induction, with an additional randomization to receive a modest dose of mylotarg (GO) on day 1 induction, followed by maintenance with a hypomethylating agent, 5-azacytidine, for 12 months, completed accrual in 2012. GO is a calicheamicin conjugated monoclonal antibody directed against the CD33 antigen that is expressed on most AML blast cells. The preliminary results do not suggest an improvement in remission rate or survival; the impact of the maintenance therapy is not yet known. The addition of GO did not appear to make any difference in remission rates, but it accords a significant reduction in subsequent relapse which makes a 15–20% improvement in overall survival. Rare patients also developed a syndrome resembling veno-occlusive disease of the liver. When simultaneously given with induction chemotherapy, the dose is critical to avoid liver toxicity, with a 3 mg/m2 appearing to be safe and not pre-disposing patients to additional risk if receiving a subsequent transplant. A recent individual patient based meta-analysis of all five trials in adults where GO was combined with induction therapy show an overall survival benefit, particularly for those without adverse risk. The drug was licensed for AML by the USFDA in September 2017 for the treatment of adults with newly diagnosed CD33+ AML and for patients aged 2 years and older with CD33+ AML who have experienced a relapse or who have not responded to initial therapy. Also, on 28 July 2017, the US Food and Drug Administration (FDA) granted a ‘breakthrough designation’ for the use of venetoclax, an oral BCL-2 inhibitor, with low-dose cytrabine or a hypomethylating agent for the treatment of newly diagnosed patients with AML who are not eligible for intensive chemotherapy.
Early T-cell precursor acute lymphoblastic leukemia with KRAS and DNMT3A mutations and unexpected monosomy 7
Published in Baylor University Medical Center Proceedings, 2018
Though ETP-ALL was thought to have a particularly poor prognosis, recent studies with more effective therapy have shown less significant differences in outcomes. Nevertheless, it is noted that minimal residual disease rates in ETP-ALL are higher than those seen in other T-ALL cases.1 Our patient had virtually no response to hyper-CVAD (cyclophosphamide, vincristine, Adriamycin, dexamethasone) therapy. He was subsequently switched to a clofarabine/cytarabine regimen more commonly used in acute myeloid leukemia, and repeat biopsy demonstrated <5% marrow cellularity with marked chemotherapeutic effect. However, some residual blasts were present with persistence of monosomy 7 in 11% of cells by FISH studies. A follow-up biopsy 1 week later showed marrow recovery with trilineage hematopoiesis, 6.5% myeloblasts (CD34+, myeloperoxidase+, CD3−), and negative monosomy 7 FISH studies. With absence of monosomy 7, it was hoped that these blasts represented regenerative myeloblasts, though the possibility of residual leukemic blasts with antigenic shift toward AML phenotype could not be completely excluded given the potential for myeloid differentiation in ETP-ALL cells. The patient eventually underwent bone marrow transplant with no evidence of recurrence. Because there is limited literature information regarding monosomy 7 in regards to this entity in adults, its significance in our case is not entirely clear.
Advancements in the management of medically less-fit and older adults with newly diagnosed acute myeloid leukemia
Published in Expert Opinion on Pharmacotherapy, 2018
Laura C. Michaelis, Heidi D. Klepin, Roland B. Walter
Inclusion of purine analogs with induction therapy has long been explored as one strategy to improve treatment outcomes. Data from a randomized trial conducted in younger adults did not support value of fludarabine when added to standard 7 + 3 chemotherapy but indicated addition of cladribine (which, unlike fludarabine, has single agent anti-leukemia activity) to 7 + 3 might be beneficial [82]. Consistent with this, very recent data from a randomized trial in older adults with newly diagnosed AML indicate adding cladribine to standard induction chemotherapy can improve outcomes, at least in some patient subsets [83]. As mentioned above, fludarabine is a component of FLAG-Ida, a high-dose cytarabine-based regimen that resulted in reduced relapses and improved DFS compared to standard induction chemotherapy in a large randomized trial [27]. Less robust data are available with cladribine when used together with high-dose cytarabine, but multiple encouraging single-center experiences have been published with this combination with or without mitoxantrone or idarubicin [84–86]. A third purine analog is clofarabine, which was investigated in the ECOG-ACRIN led intergroup study, E2906. This trial compared clofarabine with 7 + 3 for patients ≥60 years [87]. This study was closed to accrual after 686 patients were randomized because survival was longer in the standard arm, effectively eliminating single-agent clofarabine from the options for newly diagnosed patients.
The combination of clofarabine, etoposide, and cyclophosphamide shows limited efficacy as a bridge to transplant for children with refractory acute leukemia: results of a monitored prospective study
Published in Pediatric Hematology and Oncology, 2020
Jacek Toporski, Ladislav Król, Josefina Dykes, Yvonne Håkansson, Cornelis Pronk, Dominik Turkiewicz
Despite improvement in survival of children with acute leukemia (AL), a significant number of such patients still experience primary or secondary resistance to treatment.1,2 Thus far, cell/immune therapies are applied primarily in B precursor acute lymphoblastic leukemia (ALL), whereas refractory T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloblastic leukemia (AML) still represent an unmet challenge.3 Allogeneic hematopoietic stem cell transplantation (HSCT) seems to improve survival in children with high-risk AL. Better survival can in part be mediated by the graft-versus-leukemia (GvL) effect together with the conditioning regimen. However, the efficacy of HSCT is inversely correlated to the tumor burden. Clofarabine has been shown to induce remissions in refractory cases of pediatric AL. In the Nordic countries, clofarabine has not been incorporated in the primary treatment of AL, thus patients with refractory disease have not been exposed to clofarabine. Responses induced by clofarabine are often transient. Nevertheless, even a temporary decrease in tumor load before HSCT could increase the potency of the GvL, making transplantation a potential consolidation of clofarabine-induced responses. The short duration of clofarabine-elicited responses requires precise timing of HSCT. Transplantation with haploidentical donors offers such precision and may also lead to an enhanced GvL effect due to the HLA disparity between the donor and recipient.4–6 Our aim was to evaluate the safety and toxicity of intensified clofarabine-based multidrug remission induction for heavily pretreated children with r/r AL, and determine the potential of this approach to bridge patients to a promptly timed haploidentical HSCT.