The FDA has approved imetelstat (Rytelo – Geron), a first-in-class telomerase inhibitor, for treatment of low- to intermediate-1 risk myelodysplastic syndromes (MDS) in adults with transfusion-dependent anemia requiring 4 or more red blood cell (RBC) units over 8 weeks who have not responded to, are no longer responding to, or are ineligible for erythropoiesis-stimulating agents (ESAs).

The FDA has approved the oral kinase inhibitor quizartinib (Vanflyta – Daiichi Sankyo) for use in combination with standard cytarabine and anthracycline induction and cytarabine consolidation, and as maintenance monotherapy following consolidation chemotherapy in adults with FLT3 internal tandem duplication (ITD)-positive, newly-diagnosed acute myeloid leukemia (AML).

Brexucabtagene autoleucel (Tecartus – Kite) has been approved by the FDA for treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). It was previously approved for treatment of relapsed or refractory mantle cell lymphoma. Tecartus is an individualized cellular product prepared from the patients own T cells, which are genetically modified to express chimeric antigen receptors (CAR) and then infused back into the patient. The CAR T-cell immunotherapy tisagenlecleucel (Kymriah) was approved in 2017 for treatment of relapsed or refractory B-cell precursor ALL in patients ≤25 years old.

Asciminib (Scemblix – Novartis), an oral kinase inhibitor, has been approved by the FDA for treatment of adults with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP) previously treated with ≥2 tyrosine kinase inhibitors and for adults with Ph+ CML in CP with a T315I mutation.

Olutasidenib (Rezlidhia – Rigel), an oral isocitrate dehydrogenase-1 (IDH1) inhibitor, has been approved by the FDA for treatment of relapsed or refractory acute myeloid leukemia (AML) in adults with a susceptible IDH1 mutation. It is the second drug that targets cancer metabolism to be approved for this indication; ivosidenib (Tibsovo) was approved in 2022.

The Bruton's tyrosine kinase (BTK) inhibitor zanubrutinib (Brukinsa), which was previously approved by the FDA for treatment of mantle cell lymphoma, Waldenström's macroglobulinemia, and relapsed or refractory marginal zone lymphoma, has now been approved for treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in adults. The BTK inhibitors ibrutinib (Imbruvica) and acalabrutinib (Calquence) were approved earlier for treatment of CLL and SLL.

The FDA has approved inotuzumab ozogamicin (Besponsa – Pfizer), a humanized anti-CD22 monoclonal antibody conjugated to the cytotoxic antibiotic calicheamicin, for treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) in adults. It is the first CD22-directed antibody-drug conjugate to be approved in the US.

The FDA has approved two new drugs for treatment of specific subtypes of acute myeloid leukemia (AML).

Vyxeos (Jazz Pharmaceuticals) is a liposomal fixed-dose combination of daunorubicin and cytarabine, the standard drugs used for induction treatment of AML. It is approved for induction and consolidation treatment in adults with newly diagnosed chemotherapy- or radiation-related AML or AML with myelodysplasia-related changes. Patients with these subtypes of AML have a poor prognosis. The rationale for development of the combination was that nano-scale liposomal drug delivery vehicles prolong and maintain drug concentrations, resulting in increased efficacy in animal studies.1 In a trial in 309 patients 60-75 years old with these subtypes of AML, median overall survival was significantly longer in those treated with the liposomal combination than in those treated with conventional daunorubicin and cytarabine (9.56 vs 5.95 months). Adverse effects of the liposomal combination were similar to those with the conventional formulations.2

Enasidenib (Idhifa – Celgene) is approved for treatment of adults with relapsed or refractory AML who have mutations in isocitrate dehydrogenase-2 (IDH2); these mutations occur in about 12% of patients with AML. The new drug inhibits mutant-IDH2 enzymes, which block cellular differentiation. In a single-arm trial of enasidenib in 239 such patients, the overall response rate was 40.3%, the median duration of response was 5.8 months, and median overall survival was 9.3 months. A complete remission was achieved in 34 patients (14%). The responses were associated with differentiation of the myeloblasts rather than individual cytotoxicity. Indirect hyperbilirubinemia without apparent liver toxicity (38%) and nausea (23%) were the most common adverse effects of enasidenib in clinical trials. A life-threatening "differentiation syndrome" that affected multiple organs occurred in 23 patients (10%); it generally responded to treatment with corticosteroids, but two patients died from the acute effects of leukocyte proliferation.3

1. EJ Feldman et al. First-in-man study of CPX-351: a liposomal carrier containing cytarabine and daunorubicin in a fixed 5:1 molar ratio for the treatment of relapsed and refractory acute myeloid leukemia. J Clin Oncol 2011; 29:979.
2. JE Lancet et al. Final results of a phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary) AML. J Clin Oncol 2016; 34:15 suppl 7000.
3. EM Stein et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood 2017; 130:722.

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The FDA has approved tisagenlecleucel (Kymriah — Novartis), an individualized, genetically-modified cellular product, for treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) in patients ≤25 years old. The patient's own T cells are genetically modified to express chimeric antigen receptors (CAR) and then reinfused. Kymriah is the first CAR T-cell immunotherapy to become available in the US. A CAR T-cell product for B-cell non-Hodgkin's lymphoma is expected to be approved soon.

The FDA has approved the oral multikinase inhibitor midostaurin (Rydapt – Novartis) for first-line treatment, in addition to standard chemotherapy, of adults with FLT3 (fms-like tyrosine kinase 3) mutation-positive acute myeloid leukemia (AML). About 30% of patients with AML have FLT3 mutations. Midostaurin is also approved as a single agent for treatment of adults with aggressive systemic mastocytosis, systemic mastocytosis with associated hematological neoplasm, or mast-cell leukemia. In mastocytosis, midostaurin targets mutant c-KIT, not FLT3.

In a randomized, double-blind trial, 717 adults 18-59 years old with newly diagnosed FLT3-mutated AML were treated with midostaurin (50 mg twice daily on days 8-21 of each 28-day cycle) or placebo in addition to standard chemotherapy (induction therapy with cytarabine and daunorubicin and consolidation therapy with high-dose cytarabine), followed by up to 12 additional maintenance cycles of midostaurin or placebo. More than half of the patients (57%) stopped treatment and underwent hematopoietic stem-cell transplantation during the trial. Median event-free survival was 8.2 months with midostaurin compared to 3.0 months with placebo, a significant difference. Median overall survival after a median follow-up of 59 months was significantly longer with midostaurin than with placebo (hazard ratio 0.78). The 4-year overall survival rate was 51.4% with midostaurin and 44.3% with placebo.1 Common adverse effects reported in the midostaurin plus chemotherapy group at a rate at least 2% higher than in the placebo plus chemotherapy arm included febrile neutropenia (83% vs 81%), nausea (83% vs 70%), vomiting (61% vs 53%), and mucositis (66% vs 62%). There were no differences between the two groups in the rates of severe (≥grade 3) adverse events.

A single-arm, phase 2 study of midostaurin (100 mg twice daily in 4-week continuous cycles) included 89 adults with advanced systemic mastocytosis (16 had mast-cell leukemia) and evidence of organ damage. The overall response rate was 60%, and 45% of patients had a major response (complete resolution of at least one type of mastocytosis-related organ damage). The median duration of response was 24.1 months. Treatment with midostaurin also decreased splenomegaly and bone marrow mastcell burden. Median progression-free survival was 14.1 months and median overall survival was 28.7 months (9.4 months in patients with mast-cell leukemia). The most common adverse effects of midostaurin were nausea, vomiting, and diarrhea. New or worsening grade 3 or 4 neutropenia, anemia, and thrombocytopenia occurred in >20% of patients.2

Rydapt is available in 25-mg capsules. For patients with AML, a 4-week treatment cycle (50 mg twice daily on days 8-21) costs $7495. For patients with advanced systemic mastocytosis, 4 weeks of treatment at 100 mg twice daily costs $29,980.3

1. RM Stone et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med 2017 Jun 23 (epub).
2. J Gotlib et al. Efficacy and safety of midostaurin in advanced systemic mastocytosis. N Engl J Med 2016; 374:2530.
3. Approximate WAC. WAC = wholesaler acquisition cost or manufacturer's published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price. Source: AnalySource®Monthly. July 5, 2017. Reprinted with permission by First Databank, Inc. All rights reserved. ©2017. www.fdbhealth.com/policies/drug-pricing-policy.

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The FDA has approved omacetaxine mepesuccinate (Synribo – Teva), a cephalotaxine known for many years as homoharringtonine, for treatment of adults with chronic or accelerated phase chronic myeloid leukemia (CML) who are no longer responding to, or who could not tolerate, two or more tyrosine kinase inhibitors.

The FDA has approved blinatumomab (Blincyto – Onyx/Amgen) for treatment of relapsed or refractory Philadelphia chromosome-negative (Ph-) B-cell precursor acute lymphoblastic leukemia (ALL).

The FDA has approved idelalisib (Zydelig – Gilead), an oral kinase inhibitor, for use in combination with rituximab (Rituxan) for treatment of relapsed chronic lymphocytic leukemia (CLL). It is also approved as monotherapy for treatment of relapsed follicular lymphoma and relapsed small lymphocytic lymphoma (both are subtypes of indolent non-Hodgkins lymphoma) in patients who have received at least two prior systemic therapies.

The October 2013 suspension of marketing and sales of ponatinib (Iclusig – Ariad) for treatment of leukemia1 has been lifted by the FDA, and the drug is expected to return to the market this month with narrower indications and heightened safety warnings.2 The reason for its suspension was a high incidence of thrombotic events, some of them fatal. The new indications limit use of the drug to patients with T315I-positive disease and those "for whom no other tyrosine kinase inhibitor is indicated," presumably because of resistance or intolerance.

1. In brief: ponatinib (Iclusig) marketing and sales suspended. Med Lett Drugs Ther 2013; 55:93.

2. FDA. FDA drug safety communication: FDA requires multiple new safety measures for leukemia drug Iclusig; company expected to resume marketing. Available at www.fda.gov. Accessed January 10, 2014.

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The FDA recently issued a Drug Safety Communication saying that it had asked the manufacturer of ponatinib (Iclusig – Ariad) to suspend marketing and sales of the drug because of the risk of life-threatening blood clots and severe narrowing of blood vessels.1 Ponatinib is a tyrosine kinase inhibitor that was granted accelerated approval by the FDA in December 2012 for treatment of chronic-, accelerated, or blast-phase chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) resistant to (or the patients were intolerant to) prior tyrosine kinase inhibitor therapy. It is the first tyrosine kinase inhibitor that is effective against the T315I mutation, which is present in up to 20% of patients with treatment-resistant CML.2

The labeling of Iclusig includes a warning about the risk of arterial thrombosis, but recent clinical trial results showed an unexpectedly high incidence of serious adverse vascular events, some fatal, which occurred in 24% of patients in one clinical trial with a median duration of 1.3 years and 48% in another with a median duration of 2.7 years. These adverse events occurred in some patients as early as 2 weeks after starting ponatinib. Neither trial included a control group. Blindness has occurred in some patients and in one of the trials, 8% of those treated with the drug developed heart failure.

Suspension of marketing and sales does not necessarily mean that Iclusig will be withdrawn permanently; it is the only option available for some treatment-resistant patients.3 The drug could be returned to the market, possibly with new labeling narrowing the selection of patients, lowering the dosage, or recommending use of aspirin concomitantly to decrease the risk of thrombosis.4

1. FDA Drug Safety Communication: FDA asks manufacturer of the leukemia drug Iclusig (ponatinib) to suspend marketing and sales. Available at www.fda.gov. Accessed November 18, 2013.

2. Ponatinib (Iclusig) for CML and Ph+ ALL. Med Lett Drugs Ther 2013; 55:71.

3. JH Doroshow. Overcoming resistance to targeted anticancer drugs. N Engl J Med 2013; 369:1852.

4. Ariad expects narrower label, not withdrawal, for Iclusig following halted study. "The Pink Sheet" 2013; 75:16.

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Ponatinib (Iclusig – Ariad), a tyrosine kinase inhibitor, has been approved by the FDA for treatment of chronic-, accelerated-, or blast-phase chronic myeloid leukemia (CML) or Philadelphia chromosome- positive (Ph+) acute lymphoblastic leukemia (ALL) resistant to prior tyrosine kinase inhibitor therapy. It is the fifth tyrosine kinase inhibitor approved for the treatment of CML or Ph+ ALL.

The FDA has approved asparaginase Erwinia chrysanthemi (Erwinaze – EUSA), an asparagine-specific enzyme derived from the gram-negative bacillus Erwinia chrysanthemi, for use in combination with other chemotherapeutic agents for treatment of acute lymphoblastic leukemia (ALL) in patients who have had allergic reactions to Escherichia coli-derived asparaginase (Elspar or pegaspargase [Oncaspar]).

ALL is the most common malignancy of childhood. Multidrug chemotherapy can cure about 80% of children with ALL.1 Initial treatment ("induction") usually includes vincristine, a glucocorticoid, and an asparaginase and/or an anthracycline. Inclusion of an asparaginase in ALL regimens improves outcomes, especially in pediatric patients, but approximately 15-20% of patients treated with E. coli-derived asparaginase will develop hypersensitivity to the drug.

In one study, 42 E. coli asparaginase-allergic children with ALL were switched to twice-weekly Erwinia asparaginase 25,000 IU/m² to complete 30 weeks of asparaginase treatment; 81% of patients completed ≥26 weeks of therapy. At a median follow-up of 5.4 years, event-free survival in those children was similar to that of children without E. coli asparaginase allergy (86% vs. 81%). Allergy to Erwinia asparaginase developed in 33% of patients.2

1. CH Pui and WE Evans. Treatment of acute lymphoblastic leukemia. N Engl J Med 2006; 354:166.

2. LM Vrooman et al. Erwinia asparaginase after allergy to E. coli asparaginase in children with acute lymphoblastic leukemia. Pediatr Blood Cancer 2010; 54:199.

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The FDA has approved ofatumumab (Arzerra – GlaxoSmithKline), a human anti-CD20 monoclonal antibody, for treatment of patients with chronic lymphocytic leukemia (CLL) refractory to fludarabine (Fludara, and others) and alemtuzumab (Campath). It is the second anti-CD20 antibody approved for treatment of CLL; rituximab (Rituxan), a chimeric murine/human antibody, was the first.

Lenalidomide (Revlimid - Celgene), a thalidomide analog, has been approved by the FDA for treatment of patients with transfusion-dependent anemia due to myelodysplastic syndrome (MDS) associated with a 5q deletion cytogenetic abnormality and a low or low-intermediate risk of mortality and progression to leukemia (based on the International Prognostic Scoring System).

Nelarabine (Arranon - GlaxoSmithKline), a prodrug of the deoxyguanosine analog 9-β-D-arabinofuranosylguanine (ara-G), has been approved by the FDA for treatment of patients with T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) that has not responded to, or has relapsed following, treatment with at least two chemotherapy regimens.

Azacitidine (Vidaza - Pharmion), a pyrimidine nucleoside analog of cytidine, is the first drug approved by the FDA for treatment of myelodysplastic syndrome (MDS). Azacitidine is incorporated into newly synthesized DNA and inhibits DNA methyltransferase. Hypomethylation of DNA can restore the normal expression of genes critical for cell differentiation.

The tables in this article list drugs used for treatment of cancer in the USA and Canada and their major adverse effects. The choice of drugs in Table I is based on the opinions of Medical Letter consultants. Some drugs are listed for indications for which they have not been approved by the US Food and Drug Administration. In some cases, such as elderly patients or those with many co-morbid illnesses, the regimen of choice might not be suitable. For many of the cancers listed, surgery and/or radiation therapy may be the treatment of choice or may also be part of the management. Anticancer drugs and their adverse effects are listed in Table II on page 46. A partial list of brand names appears on page 52.

The tables in this article list drugs used for treatment of cancer in the USA and Canada. The choices of drugs in Table 1 is based on the opinions of Medical Letter consultants. Some drugs are listed for indications for which they have not been approved by the US Food and Drug Administration. For many of the cancers listed, surgery and/or radiation therapy are also part of the management of the disease.

Pegaspargase (peg as par jase; PEG-L-asparaginase; Oncaspar - Rh ne-Poulenc Rorer), a polyethylene glycol (PEG) conjugate of L-asparaginase, has been approved by the US Food and Drug Administration for treatment of acute lymphoblastic leukemia (ALL), the most common malignancy of childhood. The new drug is recommended only for patients who have had allergic reactions to asparaginase. Asparaginase is available commercially as Elspar, which is derived from Escherichia coli. A formulation derived from Erwinia chrysanthemi is available on an investigational basis (Ogden Bioservices, 301-762-0069). Some patients who have had allergic reactions to E. coli asparaginase can tolerate Erwinia asparaginase.

Intravenous formulations of immune globulin (IVIG) have been available for more than ten years for treatment of immune deficiency (Medical Letter, 24:81, 1982). Seven preparations are now licensed in the USA, with additional indications for their use.

Teniposide (ten i poe' side; VM 26; Vumon - Bristol), an anticancer drug that has been under investigation in the USA for 20 years, has now been approved for use in combination induction treatment of refractory acute lymphoblastic leukemia (ALL) in children. A semisynthetic derivative of podophyllotoxin, teniposide is chemically related to etoposide (VePesid - Medical Letter, 26:48, 1984).

Pentostatin (2'-deoxycoformycin; DCF; - Parke-Davis), a purine analog, was recently approved by the US Food and Drug Administration (FDA) for treatment of hairy-cell leukemia resistant to interferon alfa (Intron A; Roferon-A). is a rare (500 cases/year in the USA) form of chronic lymphocytic leukemia. Acutely ill patients may respond rapidly to interferon, but the drug is rarely curative. Another purine analog, 2-chlorodeoxyadenosine (CdA; Leustatin - Ortho Biotech), may also be approved soon for treatment of hairy-cell leukemia (JD Piro, Blood, 79:843, 1992). Fludarabine (Fludara -Medical Letter, 33:89, 1991), a third purine analog, is approved for treatment of refractory chronic lymphocytic leukemia. All three drugs are investigational for use in non-Hodgkin's lymphomas.

Fludarabine phosphate (Fludara - Berlex), an analog of vidarabine (Vira-A), was recently approved by the U.S. Food and Drug Administration for treatment of patients with refractory chronic lymphocytic leukemia (CLL). The drug has not yet been marketed but is still available, as it has been for two years, through the National Cancer Institute.

Idarubicin hydrochloride (Idamycin - Adria), an anthracycline structurally related to daunorubicin (Cerubidine, and others) and doxorubicin (Adriamycin, and others), was recently approved in the USA for treatment of acute myelogenous leukemia (AML) in adults.

Mitoxantrone (Novantrone - Lederle), a synthetic anthracene related to the anthracyclines doxorubicin (Adriamycin) and daunorubicin (Cerubidine), has now been marketed in the USA to be used in combination with other drugs for initial treatment of acute nonlymphocytic leukemia in adults.