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تعداد آیتم قابل مشاهده باقیمانده : 2 مورد

Treatment of relapsed or refractory acute lymphoblastic leukemia in adults

Treatment of relapsed or refractory acute lymphoblastic leukemia in adults
Author:
Richard A Larson, MD
Section Editor:
Bob Lowenberg, MD, PhD
Deputy Editor:
Alan G Rosmarin, MD
Literature review current through: Apr 2025. | This topic last updated: Mar 03, 2025.

INTRODUCTION — 

More than 80 percent of adults with newly diagnosed acute lymphoblastic leukemia (ALL) achieve a complete remission (CR; ie, <5 percent lymphoblasts in bone marrow and clearance of blasts at all extramedullary sites) with intensive induction chemotherapy. However, up to 20 percent of adults with ALL have primary resistant (refractory) disease. Furthermore, most adults with ALL who achieve CR experience a disease relapse despite consolidation therapy and maintenance chemotherapy.

Management of relapsed or refractory (r/r) ALL is informed by medical fitness, the immunophenotype of the lymphoblasts (ie, B cell versus T cell), cytogenetic findings, duration of remission, and prior therapies.

This topic reviews the treatment of r/r ALL in adults.

Related topics include:

(See "Clinical manifestations, pathologic features, and diagnosis of B cell acute lymphoblastic leukemia/lymphoma" and "Clinical manifestations, pathologic features, and diagnosis of precursor T cell acute lymphoblastic leukemia/lymphoma".)

(See "Induction therapy for Philadelphia chromosome-negative acute lymphoblastic leukemia in adults".)

(See "Philadelphia chromosome-negative acute lymphoblastic leukemia in adults: Post-remission management".)

(See "Induction therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults".)

(See "Philadelphia chromosome-positive acute lymphoblastic leukemia in adults: Post-remission management".)

Treatment of ALL in children and adolescents is discussed separately:

(See "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents".)

EVALUATION — 

Patients suspected of r/r ALL are evaluated to confirm the diagnosis and assess fitness to receive intensive treatments.

Diagnosis

Relapse – Relapse refers to the reappearance of leukemia cells in bone marrow, blood, or extramedullary sites after attaining complete remission (CR).

Evaluation includes:

Bone marrow – Bone marrow aspirate and biopsy are analyzed for morphology, immunophenotyping, and cytogenetics.

The marrow aspirate or peripheral blood blasts should also be evaluated by next-generation sequencing (NGS) for mutations and for BCR::ABL1 (by reverse transcriptase polymerase chain reaction [RT-PCR]). Blasts should be tested by fluorescence in situ hybridization (FISH) for rearrangements involving MLL on chromosome 11q23.

Extramedullary sites – The central nervous system (CNS) and testes must be evaluated even in asymptomatic patients.

Details of the clinical presentation, evaluation, and diagnosis of ALL are presented separately. (See "Clinical manifestations, pathologic features, and diagnosis of B cell acute lymphoblastic leukemia/lymphoma" and "Clinical manifestations, pathologic features, and diagnosis of precursor T cell acute lymphoblastic leukemia/lymphoma".)

Refractory disease – Refractory (resistant) ALL is defined as failure to achieve a CR (ie, <5 percent blasts in bone marrow and blood and no extramedullary involvement after two rounds of induction therapy).

Induction therapy for ALL varies according to the blast immunophenotype and cytogenetic findings (eg, presence of BCR::ABL1). (See "Induction therapy for Philadelphia chromosome-negative acute lymphoblastic leukemia in adults" and "Induction therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults".)

Clinical and laboratory evaluation — Further pretreatment evaluation should include:

History – Assess symptoms related to cytopenias (eg, fatigue, dyspnea, bleeding/bruising, infections), organomegaly (eg, early satiety), bony pain (from expansion of blasts in bone marrow), CNS (eg, meningeal symptoms, cranial neuropathy), and systemic symptoms (eg, fever, drenching sweats, unintended weight loss).

Assess comorbid conditions and document details of the prior diagnosis of ALL and treatments.

Physical examination – Evaluate for evidence of cytopenia-related findings, organomegaly, and comorbidities.

Dental evaluation for possible infectious foci; testicular examination for patients with testes.

Laboratory and clinical evaluation

Hematology

-Complete blood count with differential

-Prothrombin time (PT), partial thromboplastin time (PTT), d-dimer, fibrinogen

Chemistries – Electrolytes and glucose; kidney function; liver function tests, including lactate dehydrogenase (LDH); calcium, phosphorus, uric acid, albumin, and total protein.

Infectious – Serology for hepatitis B and C, herpes simplex virus (HSV), cytomegalovirus (CMV) infection, and human immunodeficiency virus (HIV).

Serotyping – Human leukocyte antigen (HLA) typing of potential candidates for hematopoietic cell transplantation (HCT).

HLA-A and HLA-B typing should be considered in the event that HLA-matched platelet transfusions are needed for patients who become refractory to platelet transfusions.

Imaging

-Chest radiograph.

-Echocardiogram or radionuclide ventriculogram to evaluate cardiac function, especially in patients with cardiac comorbidities, cardiovascular findings, or prior anthracycline exposure.

-Brain magnetic resonance imaging (MRI) or computed tomography (CT), if needed, to evaluate neurologic findings.

-CT of neck/chest/abdomen/pelvis with intravenous contrast, as indicated for symptoms.

-Scrotal ultrasound, if indicated.

CNS

-Lumbar puncture – Lumbar puncture (LP) should be performed in all patients. The first LP can be performed at the time of the initial scheduled intrathecal therapy unless it is needed earlier to evaluate neurologic symptoms.

Care must be taken to avoid contaminating the cerebrospinal fluid (CSF) specimen with peripheral blood if circulating blasts are present. CSF should be evaluated by cytology and flow cytometry for the detection of ALL blasts.

Platelets and cryoprecipitate should be given, if clinically indicated, to ensure adequate hemostasis.

Other

-Placement of a central venous access device

-Pregnancy testing, if relevant

Medical fitness — Determination of medical fitness is based on clinical evaluation and assessment of performance status (PS) and comorbidities.

Fit patients should be referred for transplant evaluation and an initiation of a donor search. Eligibility for allogeneic HCT is discussed separately. (See "Allogeneic hematopoietic cell transplantation: Indications, eligibility, and prognosis".)

Assessment instruments – Assessment of medical fitness includes an evaluation of:

Performance status – Eastern Cooperative Oncology Group (ECOG) performance scale (table 1).

Physiologic fitness – We assess physiologic fitness, including comorbid conditions, activities of daily living, physical performance tests, and cognition.

Various instruments can be useful for assessing physiologic fitness, such as the HCT-Comorbidity Index (table 2), the Charlson comorbidity index (CCI) (table 3), or the Short Physical Performance Battery (SPPB) [1].

Fitness categories – There are no clear distinctions between fitness categories, and some measures of PS or physiologic fitness can apply to different categories. Importantly, fitness may improve or decline during the illness and its treatment.

Age, per se, does not determine medical fitness. However, because comorbidities increase with age, caution should be used when considering intensive therapy for patients ≥75 years old.

We categorize fitness as:

Medically fit – The patient can tolerate intensive treatments.

Less fit but not frail – The patient is unlikely to tolerate intensive therapy, but this category includes a broad range of physical functions. Some patients have only modest, recent, or transient impairment of functional status, while others have substantial comorbid illnesses, cognitive impairment, or other conditions that may affect their ability to tolerate treatment.

Frail – Debility or comorbidities do not permit treatment aimed at modifying the disease course.

OVERVIEW — 

Management of r/r ALL begins with remission induction therapy, but most remissions are brief. Patients generally require post-remission therapy to sustain the response.

Remission induction – Remission induction therapy can alleviate symptoms, decrease transfusion needs, prolong survival, and enable further treatment to achieve longer-term disease control.

The choice of remission induction therapy is guided by immunophenotype (ie, B cell versus T cell), cytogenetic and molecular findings, patient fitness, duration of the prior remission, institutional approach, and patient preference:

B cell – Most cases of r/r B cell ALL express CD19 and/or CD22. Treatment with immunotherapy for CD19-positive or CD22-positive r/r ALL is discussed below. (See 'CD19-positive or CD22-positive' below.)

For cases of r/r B cell ALL that express neither CD19 nor CD22, treatment is informed by the presence of chromosome 11q23/KMT2A-rearrangement and patient fitness for chemotherapy. (See 'CD19- and CD22-negative' below.)

Philadelphia chromosome (Ph)-positive – Patients with t(9;22) and/or BCR::ABL1 require treatment that includes a tyrosine kinase inhibitor, as discussed below. (See 'Ph-positive ALL' below.)

T cell – Induction therapy for T cell ALL is discussed below. (See 'T cell ALL' below.)

Post-remission management – Remissions of r/r ALL are generally brief, and most patients relapse without further treatment.

The choice of allogeneic hematopoietic cell transplantation or other treatments is guided by the patient's medical fitness. (See 'Post-remission management' below.)

Extramedullary disease – All patients with r/r ALL are evaluated for involvement of the central nervous system (CNS). Evaluation of the CNS, testes, and other extramedullary sites is described above. (See 'Clinical and laboratory evaluation' above.)

Management of the CNS and other extramedullary sites is discussed below. (See 'Extramedullary disease' below.)

B CELL ALL — 

Management of r/r B cell ALL begins with remission induction therapy, which is guided by immunophenotype, cytogenetic findings, and clinical features.

Response assessment and post-remission management are described below. (See 'Response assessment' below and 'Post-remission management' below.)

CD19-positive or CD22-positive — For CD19-positive or CD22-positive r/r B cell ALL, we suggest immunotherapy-based remission induction therapy, based on the balance of efficacy and toxicity.

In most cases of r/r B cell ALL, leukemic blasts express CD19 and/or CD22 on the cell surface. Immunotherapy options for these patients include blinatumomab, inotuzumab ozogamicin, and chimeric antigen receptor (CAR)-T cell products. Each is effective for r/r ALL and associated with substantial toxicity, but the various approaches have not been directly compared in randomized trials. The choice of approach is individualized according to availability, toxicity, comorbidities, clinician/institutional approach, and patient preference.

Treatment options for other cases of r/r B cell ALL are discussed below. (See 'CD19- and CD22-negative' below.)

For patients with a prolonged remission prior to the relapse (eg, ≥3 years from diagnosis), retreatment with the prior induction regimen is also acceptable. (See "Induction therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults", section on 'Remission induction therapy'.)

Patients who are not fit to receive treatments directed at the underlying leukemia can receive supportive/palliative care alone, as discussed separately. (See "Induction therapy for Philadelphia chromosome-negative acute lymphoblastic leukemia in adults", section on 'Older or medically unfit adults'.)

Immunotherapy for remission induction in patients with r/r B cell ALL requires treatment in a center with the expertise and resources needed to recognize and manage potentially life-threatening complications, including cytokine release syndrome (CRS) and neurologic toxicities. Immunotherapy options for r/r B cell ALL include:

BlinatumomabBlinatumomab is a bispecific (CD19 x CD3) monoclonal antibody that achieved superior outcomes compared with chemotherapy in a phase 3 trial for r/r B cell ALL in adults [2]. (See 'Blinatumomab' below.)

Inotuzumab ozogamicinInotuzumab ozogamicin is a CD22-directed immunoconjugate that achieved superior outcomes compared with chemotherapy in a phase 3 trial for r/r CD22-positive ALL in adults [3].

Inotuzumab ozogamicin can be administered in the outpatient setting and is better tolerated than blinatumomab, but it is only effective when the leukemic blasts express cell surface CD22 (approximately 90 percent of adult patients). Inotuzumab ozogamicin is associated with an increased risk for liver adverse effects (AEs), especially in patients who will later undergo allogeneic hematopoietic cell transplantation (HCT). (See 'Inotuzumab ozogamicin' below.)

CAR-T cell therapy – CAR-T cell therapy is an autologous immunotherapy generated by transducing the patient's T lymphocytes with a gene that encodes a CD19-directed CAR. The T cells are genetically modified ex vivo, expanded in a production facility, and then infused back into the patient as therapy.

Various CD19-directed CAR-T cell products that can achieve robust remissions are available, but availability is restricted, and treatment is associated with substantial, potentially life-threatening, complications. CAR-T cell products can only be dispensed in qualified centers, and indications for some CAR-T cell products are restricted by age or the number of prior treatments. (See 'CAR-T cell therapy' below.)

Transplant-eligible patients who achieve a response should generally proceed to allogeneic HCT because most remissions last only for months, although it is presently uncertain if this is needed for patients with deep molecular remissions. (See 'Transplant-eligible' below.)

Blinatumomab — Blinatumomab is a bispecific T cell engager antibody directed at both CD19 on B cell blasts and CD3 on cytotoxic T cells.

AdministrationBlinatumomab is administered by continuous intravenous infusion (CIVI) over four weeks, followed by a two-week treatment-free interval. The antibody has a very short half-life in the bloodstream. If the infusion is well-tolerated, the initial dose is escalated after the first eight days.

For patients with a substantial leukemic burden (eg, >50 percent marrow blasts or high levels of circulating blasts), we generally treat with a glucocorticoid and lower-intensity cyclophosphamide (or other chemotherapy) for one week prior to beginning blinatumomab, to lower the risk for CRS.

For patients who do not plan to undergo HCT, maintenance treatment may continue as a four-week CIVI every 12 weeks.

Blinatumomab is approved by the European Medicines Agency (EMA) for the treatment of r/r Philadelphia chromosome (Ph)-negative B cell ALL and by the US Food and Drug Administration (FDA) for r/r Ph-negative and Ph-positive precursor B cell ALL.

Toxicity – Boxed warnings include CRS and neurologic toxicities, which can be life-threatening or fatal. Patients are hospitalized around the time of infusion to monitor for CRS and immune effector cell-associated neurotoxicity syndrome (ICANS; which can manifest as encephalopathy, convulsions, speech disorders, disturbed consciousness, delirium, coordination and balance issues). CRS and ICANS are discussed separately. (See "Cytokine release syndrome (CRS)" and "Immune effector cell-associated neurotoxicity syndrome (ICANS)".)

Other common AEs include fever, fatigue, headache, tremor, and leukopenia.

OutcomesBlinatumomab achieved superior overall survival (OS) compared with chemotherapy for remission induction in a phase 3 trial of 405 heavily pretreated adults with r/r Ph-negative ALL [2]. Compared with cytarabine-based chemotherapy, blinatumomab achieved superior median OS (7.7 versus 4.0 months; hazard ratio [HR] 0.71 [95% CI 0.55-0.93]), event-free survival (EFS) at six months (31 versus 12 percent; HR 0.55 [95% CI 0.43-0.71]), and response rate (ie, complete remission [CR] plus CR with incomplete hematologic recovery [CRi]; 76 versus 48 percent). Health-related quality of life was also superior with blinatumomab [4]. One-quarter of patients in each arm underwent allogeneic HCT. Chemotherapy was associated with more grade ≥3 neutropenia (58 versus 38 percent) and infections (52 versus 34 percent). Blinatumomab was associated with grade ≥3 CRS in 5 percent, and grade ≥3 neurologic events were similar in both groups (8 to 9 percent) [2].

Similar outcomes were demonstrated in other trials of blinatumomab in r/r Ph-negative ALL and Ph-positive ALL [5-9]. More than three-quarters of patients treated with blinatumomab became measurable residual disease (MRD)-negative in some studies [9-11].

Inotuzumab ozogamicin — Inotuzumab ozogamicin is a humanized anti-CD22 monoclonal antibody conjugated to calicheamicin (a cytotoxic antibiotic). CD22 is a B cell-restricted molecule of the immunoglobulin superfamily that is expressed on leukemic blasts in >90 percent of B cell ALL.

AdministrationInotuzumab ozogamicin is given by intravenous infusion. Patients should be premedicated with a corticosteroid, antipyretic, and antihistamine, and observed for ≥1 hour after the end of the infusion for infusion-related reactions.

Liver function tests (LFTs) must be monitored; elevated LFTs may require treatment interruption, dose reduction, or discontinuation.

Cycle 1 – Cycle 1 comprises inotuzumab ozogamicin 0.8 mg/m2 on day 1, 0.5 mg/m2 on day 8, and 0.5 mg/m2 on day 15.

Cycle 1 is three weeks in duration, but it may be extended to four weeks if the patient achieves CR or CRi and/or to allow recovery from toxicity.

Cycle 2 – Guided by treatment response to cycle 1:

-CR or CRi – Inotuzumab ozogamicin 0.5 mg/m2 on days 1, 8, and 15.

-Less than CR/CRi – As described for cycle 1: 0.8 mg/m2 on day 1 and 0.5 mg/m2 on day 8 and day 15.

Inotuzumab ozogamicin is approved for the treatment of r/r CD22-positive B cell ALL by the EMA and FDA.

Toxicity – The label for inotuzumab ozogamicin has a boxed warning for hepatotoxicity, including potentially life-threatening hepatic sinusoidal obstruction syndrome (SOS; also called veno-occlusive liver disease) and a boxed warning for increased risk for post-HCT nontransplant mortality.

OutcomesInotuzumab ozogamicin was associated with better outcomes than intensive chemotherapy in a phase 3 trial of 218 adults with r/r ALL [3]. Inotuzumab achieved superior median progression-free survival (PFS; five versus two months; HR 0.45 [97.5% CI 0.34-0.61]) and better two-year OS that approached statistical significance (23 versus 10 percent; HR 0.77 [97.5 CI 0.58-1.03]). Inotuzumab also achieved more CRs (81 versus 29 percent), a longer median duration of CR (five versus three months), and a higher rate of MRD negativity (78 versus 28 percent). Compared with chemotherapy, inotuzumab was associated with less grade ≥3 febrile neutropenia (24 versus 49 percent) and less thrombocytopenia (37 versus 59 percent), and fewer patients received platelet transfusions (64 versus 95 percent). However, inotuzumab was associated with more grade ≥3 hepatic SOS (9 versus 1 percent), which occurred up to two years after randomization. Of the 48 patients treated with inotuzumab who underwent HCT after the trial, 10 had hepatic SOS after transplantation (including 3 who had undergone prior HCT).

CAR-T cell therapy — CAR-T cell therapy is a form of genetically modified autologous immunotherapy that can be directed at B cell ALL that expresses CD19.

No randomized trials have directly compared CD19-directed CAR-T cell agents, and none has proved superior for achieving long-term remission/cure of r/r B cell ALL. Obecabtagene autoleucel, which uses a lower-affinity CD19-directed antibody, is associated with less CRS and neurologic AEs than other CAR-T cell preparations. (See 'Obecabtagene autoleucel' below.)

Preparation of CAR-T cells – The patient's T lymphocytes are transduced with a gene that encodes a CAR directed against CD19 on leukemic cells. The T cells are genetically modified ex vivo, expanded in a production facility, and then infused back into the patient as therapy.

Facilities that dispense CAR-T cell products require special certification, staff must be trained to recognize and manage CRS and ICANS, and tocilizumab (anti-interleukin-6 receptor [IL-6R]) must be available for immediate administration.

Toxicity – All CAR-T cell products can cause CRS, which is manifest as high fever, flu-like symptoms, hypotension, and/or other findings related to the activation and proliferation of CAR-T cells. CRS is seen in most patients treated with CAR-T cells. Severe cases may be life-threatening, but CRS typically responds to treatment with corticosteroids, tocilizumab, and other management. ICANS and other neurologic toxicities can also be severe or life-threatening. (See "Cytokine release syndrome (CRS)".)

Obecabtagene autoleucel, which uses a lower-affinity CD19-directed antibody, is associated with less CRS and neurologic AEs than other CAR-T cell preparations. (See 'Obecabtagene autoleucel' below.)

Other AEs include hypersensitivity reactions, serious infections, prolonged cytopenias, prolonged hypogammaglobulinemia, and second malignancies.

Tisagenlecleucel — Tisagenlecleucel is a CD19-directed CAR-T cell product.

Tisagenlecleucel is approved by the FDA for the treatment of patients ≤25 years with refractory B cell ALL or ALL after ≥2 relapses [12]. It is available in the United States through a risk evaluation and mitigation strategy (REMS) and the FDA label carries a boxed warning for neurologic events and CRS.

The treatment of 75 patients (≤25 years) with tisagenlecleucel for r/r B cell ALL was associated with 76 percent OS and 50 percent EFS at 12 months [13]. Response by three months was seen in 81 percent of patients, and all responding patients were MRD-negative by flow cytometry. Tisagenlecleucel persisted in the blood for as long as 20 months. CRS occurred in 77 percent of patients (46 percent grade ≥3) and began a median of three days after infusion; neurologic events occurred in 40 percent (13 percent grade 3, none grade 4). Other grade ≥3 AEs included infections (24 percent), febrile neutropenia (35 percent), and prolonged cytopenias (32 percent).

Brexucabtagene autoleucel — Brexucabtagene autoleucel is a CD19-directed CAR-T cell therapy.

Brexucabtagene autoleucel is approved by the FDA and EMA for r/r B cell ALL in adults. The FDA label includes a boxed warning about CRS and neurologic toxicities, and it is available through a REMS program in the United States.

Brexucabtagene autoleucel was associated with 56 percent CR plus 15 percent CRi in a study of 71 adults (median 40 years) with r/r B cell ALL [14]. Median OS was >18 months. Grade ≥3 CRS occurred in 24 percent of patients and grade ≥3 neurologic syndrome in 25 percent; other grade ≥3 AEs included anemia in one-half of patients and fever in one-third.

A phase 1 study that administered higher doses reported more CRS and ICANs [15].

Obecabtagene autoleucel — Obecabtagene autoleucel is a CD19-directed CAR-T cell therapy that uses an intermediate-affinity CAR to reduce toxicity and improve persistence.

Obecabtagene autoleucel is approved by the FDA and EMA for r/r B cell ALL.

Treatment of 127 evaluable patients with r/r B cell ALL using obecabtagene autoleucel reported 55 percent CR and 21 percent CRi [16]. The median OS was 16 months, and the estimated 12-month OS was 61 percent. Grade ≥3 CRS developed in 2.4 percent of patients and grade ≥3 ICANS in 7.1 percent.

CD19- and CD22-negative — Management of CD19-negative, CD22-negative r/r B cell ALL is guided by the molecular findings and patient fitness.

CD19-negative and/or CD22-negative relapses are increasing because many patients received immunotherapy against these antigens during initial therapy [17].

KMT2A (chromosome 11q23) rearranged — For r/r ALL with KMT2A (lysine methyltransferase 2A)/chromosome 11q23 translocation, we suggest the KMT2A inhibitor, revumenib.

Revumenib is an oral small-molecule inhibitor of the menin-KMT2A interaction (which results from chromosome 11q23 translocations) that is effective and well-tolerated for r/r ALL.

Administration – Dosing varies by weight and concomitant use of strong CYP3A4 inhibitors.

Patients ≥40 kg - Revumenib 270 mg is taken orally twice daily. Patients taking a strong CYP3A4 inhibitor should take revumenib 160 mg twice daily. A list of strong CYP3A4 inhibitors is provided in the table (table 4).

Patients <40 kg – Dosing is by body surface area (BSA). Patients should take 160 mg/m2 twice daily (95 mg/m2 twice daily if taking a strong CYP3A4 inhibitor); the revumenib Lexidrug monograph describes how to deliver the BSA-based dose using whole tablets.

Revumenib is approved by the FDA for adult and pediatric patients ≥1 year with KMT2A rearrangement.

ToxicityRevumenib is associated with differentiation syndrome (DS), prolongation of the QT interval, febrile neutropenia, and embryo-fetal toxicity.

The most common grade ≥3 AEs in heavily pretreated patients were DS (16 percent), QT prolongation (14 percent; all resolved with dose adjustment and without treatment discontinuation), and febrile neutropenia (37 percent) [18]. Fatal AEs were reported in 15 percent of patients while receiving or within 30 days of the last dose of revumenib. Dose modification (interruption or reduction) was required in 44 percent of patients.

The evaluation, diagnosis, and management of DS are discussed separately. (See "Differentiation syndrome associated with treatment of acute leukemia".)

Outcomes – Treatment with revumenib in 57 patients (median age 37 years; range 1 to 75 years) with KMT2A-rearranged r/r ALL was associated with 63 percent overall response rate (including 23 percent CR) and eight-month median OS [18]. Responses were rapid, with two-month median time to CR and six-month median duration of CR. MRD was negative in 7 of 10 patients who were tested in CR. Allogeneic HCT was performed in 40 percent of patients, and one-half of them resumed revumenib after transplantation. Responses were observed across subgroups, including age, blast lineage, prior treatment with venetoclax, and KMT2A translocation partner.

Others — For CD19-negative/CD22-negative r/r B cell ALL without a KMT2A-rearrangement, we treat with chemotherapy selected according to medical fitness.

We encourage participation in a clinical trial, when possible.

Patients who relapse after a prolonged remission (eg, ≥3 years since the start of treatment) can be treated with the same induction regimen that was used for the initial treatment of the disease. (See "Induction therapy for Philadelphia chromosome-negative acute lymphoblastic leukemia in adults".)

Chemotherapy regimens vary in intensity, and the choice must be individualized, with consideration of medical fitness, comorbidities, and patient preference. Assessment of medical fitness is discussed above. (See 'Medical fitness' above.)

Salvage chemotherapy regimens have not been directly compared in randomized trials. The preferred regimen varies among institutions, and none provides a clearly superior balance of efficacy and toxicity. Rituximab is generally included for CD20-positive blasts in patients <60 years, based on extrapolation from results from induction therapy. (See "Induction therapy for Philadelphia chromosome-negative acute lymphoblastic leukemia in adults", section on 'Chemotherapy'.)

Following are examples of acceptable chemotherapy regimens for r/r B cell ALL according to the intensity of treatment:

High intensity – The following regimens may be appropriate for fit, younger patients without significant comorbidities, but they are associated with substantial toxicity:

CALGB (Cancer and Leukemia Group B) 9111 [19]

Dose-adjusted hyper-CVAD (hyperfractionated cyclophosphamide, mesna, doxorubicin, vincristine, dexamethasone; alternating with methotrexate, cytarabine, leucovorin) [20]

High-dose cytarabine plus idarubicin [21]

Moderate intensity – The following regimens may be appropriate for older patients or those with moderate comorbidities:

PETHEMA (Programa Español de Tratamiento en Hematología) ALLOLD07 [22]

GMALL (German Multicenter Study Group for Adult ALL) regimen [23]

GRAALL (Group for Research on Adult ALL)-SA1 [24]

Modified DFCI (Dana-Farber Cancer Institute) 91-01 [25]

FLAG-Ida (fludarabine, cytarabine, G-CSF [filgrastim], idarubicin) [26]

Clofarabine plus cytarabine [27,28]

FLAM (fludarabine, cytarabine, mitoxantrone) [29]

Etoposide, ifosfamide, mitoxantrone [30]

Idarubicin plus cytarabine [21]

MEC (mitoxantrone, etoposide, cytarabine) [31]

Low intensity – These treatments can be tolerated by older or frail patients:

Vincristine plus prednisone [32]

POMP (mercaptopurine, vincristine, methotrexate, prednisone) [33]

MOpAD (methotrexate, vincristine, pegylated asparaginase, dexamethasone) [34]

Ph-POSITIVE ALL — 

For patients with Philadelphia chromosome (Ph)-positive r/r ALL, we suggest a suitable BCR::ABL1 tyrosine kinase inhibitor (TKI) plus induction immunotherapy or chemotherapy, rather than induction therapy alone.

Inclusion of a TKI in the induction regimen for r/r Ph-positive ALL is extrapolated from studies of induction therapy for de novo Ph-positive ALL, as described separately. (See "Induction therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults", section on 'Remission induction therapy'.)

The selection of a second-generation (2G) TKI (ie, bosutinib, dasatinib, nilotinib), asciminib, or ponatinib is based on results of kinase domain mutation testing, toxicity, and comorbid conditions, as discussed separately. (See "Treatment of chronic phase chronic myeloid leukemia after failure of the initial tyrosine kinase inhibitor".)

We encourage participation in a clinical study when possible.

The selection of an induction regimen is guided by the immunophenotype of the lymphoid blasts:

For blasts that express CD19 or CD22, the patient is treated with a TKI plus induction therapy like that described for r/r B cell ALL. (See 'CD19-positive or CD22-positive' above.)

For blasts that express neither CD19 nor CD22, the patient is treated with a TKI plus remission induction therapy guided by medical fitness and patient preference.

There is no consensus treatment for r/r CD19-negative/CD22-negative ALL, but options include a TKI plus a corticosteroid or a TKI plus multiagent chemotherapy like the treatment for Ph-positive ALL. (See "Induction therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults", section on 'Remission induction therapy'.)

Induction therapy should be followed by allogeneic hematopoietic cell transplantation (HCT) for transplant-eligible patients. (See 'Transplant-eligible' below.)

Small studies have reported outcomes with r/r Ph-positive ALL.

Treatment of 45 patients with r/r Ph-positive ALL who previously received ≥1 TKI reported that blinatumomab was associated with 36 percent complete remission (CR); 88 percent of the responding patients became MRD-negative, and 44 percent of responding patients proceeded to allogeneic HCT [7]. Responses to blinatumomab were independent of BCR::ABL1 status, as more than one-third had ≥1 BCR::ABL1 mutation, and among the 10 patients with BCR::ABL1 T315I, 4 achieved CR.

In a study that included 22 patients with r/r Ph-positive ALL or advanced-stage chronic myeloid leukemia (CML), ponatinib was associated with 36 percent major hematologic response and 32 percent major cytogenetic response [35].

A study of dasatinib plus hyper-CVAD (hyperfractionated cyclophosphamide, mesna, doxorubicin, vincristine, dexamethasone alternating with methotrexate, cytarabine, and leucovorin rescue) in 19 patients with relapsed Ph-positive ALL and 15 patients with CML lymphoid blast crisis reported 91 percent response rate (including 71 percent CR) and complete molecular response in 42 percent [36]. Among the patients with relapsed ALL, 26 percent were alive and remained in CR after three years. Other small studies reported that dasatinib was effective for r/r Ph-positive ALL [37,38].

T CELL ALL — 

For patients with r/r T cell ALL, we suggest nelarabine-based induction chemotherapy, rather than other regimens.

Induction therapy should be followed by allogeneic hematopoietic cell transplantation (HCT) for transplant-eligible patients. (See 'Transplant-eligible' below.)

For relapses occurring ≥3 years from initial diagnosis, retreatment with the same induction regimen is an acceptable option.

Administration – For patients ≥16 years old, nelarabine 1500 mg/m2 is administered intravenously over two hours on days 1, 3, and 5 of 21-day cycles.

Nelarabine has been given in combination with etoposide and cyclophosphamide [39-41], but it is not clear if such regimens are more beneficial than single-agent nelarabine [39-41].

Nelarabine is approved by the European Medicines Agency (EMA) for refractory T cell ALL or after ≥2 prior regimens; it is approved for those indications by the US Food and Drug Administration (FDA) for patients ≥1 year old.

Toxicity – Grade ≥3 cytopenias occur in >10 percent of patients.

Grade ≥3 neurologic adverse effects (AEs) were reported in one-fifth of patients (although only 8 percent in the study reported below) and neurologic AEs of any grade in three-quarters of patients in clinical studies; the median time to onset was five days from the start of the first infusion, and the median duration is six days. Neurologic toxicity may be worsened with concomitant intrathecal or radiation therapy, active central nervous system (CNS) disease, or a history of neuropathy; full recovery has not always occurred with cessation of nelarabine therapy.

Outcomes – Treatment of 118 adults ≥25 years old with nelarabine for r/r T cell ALL was associated with 36 percent complete remission (CR) and 14 percent partial response (PR) [42]. One-year overall survival (OS) was 37 percent for the entire study population; patients who underwent allogeneic HCT had 38 percent five-year OS. Toxicity was modest, with grade ≥3 neurologic AEs in 8 percent and grade ≥3 thrombocytopenia and neutropenia in 41 and 43 percent, respectively. Other studies of nelarabine for r/r T cell ALL reported comparable outcomes and toxicity [43-46].

Clofarabine appears to be less effective and more toxic in adults than in children [47-50]. Clofarabine-containing regimens require close monitoring and intensive supportive care measures; patients should only be treated in centers with expertise in managing ALL, preferably in a clinical trial.

Other regimens used to treat r/r T cell ALL include high-dose cytarabine or regimens containing daratumumab [51,52]; mitoxantrone, etoposide, cytarabine [31]; venetoclax [53,54]; or bortezomib [55].

RESPONSE ASSESSMENT — 

Treatment response in patients with r/r ALL is guided by the goals of therapy.

For patients who simply seek symptom relief, we monitor the response with blood counts to adjust treatments and provide supportive care; it is not necessary to perform a bone marrow examination for these patients.

When the goal is prolonged remission/cure, treatment response is assessed by bone marrow aspirate/biopsy soon after completing remission induction therapy. The bone marrow specimens are evaluated by morphology and for measurable residual disease (MRD).

Treatment responses include [56,57]:

Complete remission (CR)

No circulating lymphoblasts or extramedullary disease (ie, no lymphadenopathy, splenomegaly, skin/gum infiltration, testicular mass, central nervous system [CNS] involvement, or other extramedullary involvement).

Bone marrow reveals trilineage hematopoiesis and <5 percent blasts.

Absolute neutrophil count (ANC) ≥1000/microL and platelets ≥100,000/microL.

CR with partial hematologic recovery – Meets all criteria for CR but with only partial recovery of blood counts (ie, ANC ≥500/microL and/or platelets ≥50,000/microL).

CR with incomplete hematologic recovery – Meets all criteria for CR but without recovery of both neutrophils and platelets.

Refractory disease – CR was not achieved at the end of induction therapy.

Relapse – Reappearance of blasts in blood or marrow (>5 percent) or in any extramedullary site after achieving CR.

Progressive disease – Detection of circulating blasts or an increase ≥25 percent in the number of circulating or marrow blasts, or development of extramedullary disease.

POST-REMISSION MANAGEMENT — 

Post-remission management is guided by eligibility for allogeneic hematopoietic cell transplantation (HCT).

Transplant-eligible — For transplant-eligible patients who achieved a complete remission (CR) or a partial response with induction therapy, we suggest allogeneic HCT rather than immunotherapy or chemotherapy consolidation, based on a superior balance of efficacy and toxicity with transplantation.

A decision to proceed to allogeneic HCT should be made jointly by the patient, clinician, and transplant specialists. The decision is individualized, with consideration of the level of measurable residual disease (MRD), availability of a suitable graft donor, comorbidities, prior treatments, social supports, and patient preference. Deferring transplantation until there is evidence of relapse (ie, loss of CR) and/or increasing MRD reduces the likelihood of long-term disease control/cure and may entail greater transplant-related toxicity from comorbidities.

Allogeneic HCT is the only approach that is proven to cure r/r ALL, but it is associated with substantial short-term and long-term toxicity. No studies have randomly assigned adults with r/r ALL to allogeneic HCT compared with immunotherapy or chemotherapy consolidation. There is no evidence of benefit from autologous HCT in adults with ALL.

Long-term outcomes with consolidation chemotherapy are poor, and there are scant data regarding long-term outcomes with immunotherapy. Prolonged CR and/or persistent MRD negativity have been observed in a subset of patients treated with chimeric antigen receptor (CAR)-T cell therapy or blinatumomab, but long-term outcomes are not well-defined at present. In some patients, CAR-T cells have been detected in blood >1 year after treatment, and durable clinical responses without subsequent allogeneic HCT have been seen [58]. Some patients with Philadelphia chromosome (Ph)-positive r/r ALL have had prolonged remissions with tyrosine kinase inhibitor-containing therapies.

Outcomes with allogeneic HCT are best in patients with negative MRD. Allogeneic HCT performed when patients have only partial remission or detectable MRD is not optimal due to early relapses. Eligibility for allogeneic HCT is discussed separately. (See "Allogeneic hematopoietic cell transplantation: Indications, eligibility, and prognosis".)

In primary refractory or advanced relapsed ALL, allogeneic HCT is associated with three-year leukemia-free survival rates of 12 to 23 percent [59-63].

Survival was superior with allogeneic HCT compared with consolidation chemotherapy among 609 patients (15 to 60 years old) with r/r ALL in the UKALLXII/ECOG2993 study [64]. Five-year overall survival (OS) was better with allogeneic HCT using either a matched sibling donor graft (23 percent) or a matched unrelated donor graft (16 percent) compared with chemotherapy alone (4 percent). The survival advantage with allogeneic HCT was independent of age, sex, duration of prior remission, and site(s) of relapse in multivariate analysis.

Among 582 patients (median age 29 years old) who underwent allogeneic HCT for r/r ALL in the CIBMTR (Center for International Bone Marrow Transplantation) database, three-year OS was 16 percent [62]. Acute graft-versus-host disease (GVHD) was seen in 52 percent of patients (27 percent with grade ≥3), and chronic GVHD was seen in approximately one-quarter of patients.

Among patients with second or later MRD-negative CR, OS at three years was 69 percent, and event-free survival was 62 percent [65]. These outcomes were comparable with those of patients who underwent allogeneic HCT in first CR at the same institution.

Less fit — There is no consensus on treatment for patients who are ineligible for HCT. Management is individualized according to prior treatment, institutional approach, and patient preference.

Maintenance therapy can be given for patients who respond to blinatumomab. This is given as a four-week continuous intravenous infusion of blinatumomab every 12 weeks, as discussed above. (See 'Blinatumomab' above.)

Others may choose consolidation chemoimmunotherapy followed by prolonged maintenance therapy like that used for de novo ALL. Consolidation and maintenance therapy for ALL is discussed separately. (See "Philadelphia chromosome-negative acute lymphoblastic leukemia in adults: Post-remission management", section on 'High-risk ALL'.)

EXTRAMEDULLARY DISEASE

Central nervous system management

Evaluation of the central nervous system – All patients should have a diagnostic lumbar puncture (LP) when diagnosed with r/r ALL. This should be performed with the initial scheduled intrathecal (IT) therapy.

Brain MRI or CT, if needed to evaluate neurologic findings.

Initial evaluation of the central nervous system (CNS) in patients with r/r ALL is described above. (See 'Clinical and laboratory evaluation' above.)

Prophylaxis – We suggest CNS prophylaxis for all patients with r/r ALL.

The preferred regimen for prophylaxis varies among institutions. Patients should receive prophylaxis using systemic therapy (eg, methotrexate, cytarabine) and/or IT therapy (eg, IT methotrexate; IT cytarabine; triple IT therapy with methotrexate, cytarabine, corticosteroid), as discussed separately.

IT prophylaxis should continue through induction and consolidation phases, but we generally give a truncated course of IT therapy for patients who do not achieve systemic complete remission (CR). (See "Induction therapy for Philadelphia chromosome-negative acute lymphoblastic leukemia in adults", section on 'Central nervous system involvement'.)

CNS involvement – We suggest cranial radiation therapy (RT) plus IT chemotherapy for documented CNS involvement.

Typically, RT 24 gray (Gy; in 12 divided doses of 2 Gy) is given to the entire cranium, along with ≥6 treatments with preservative-free IT methotrexate or cytarabine [66].

Outcomes of treatment of CNS involvement by ALL are presented separately. (See "Induction therapy for Philadelphia chromosome-negative acute lymphoblastic leukemia in adults", section on 'Central nervous system involvement'.)

Testicular involvement — A testicular examination should be performed for all patients with testes at diagnostic workup. (See 'Clinical and laboratory evaluation' above.)

Testicular involvement is especially common in patients with T cell ALL. Patients with clinical evidence of testicular disease at diagnosis that did not fully resolve by the end of induction therapy should be considered for RT to both testes in the scrotal sac. RT testicular total dose 24 Gy (in 2 Gy/fraction)

is typically performed concurrently with the first cycle of maintenance chemotherapy. [67-69]

MULTIPLY RELAPSED ALL — 

For patients with multiple relapses or progressive disease after salvage therapy, we encourage participation in a clinical trial when available.

Treatment choice for others is guided by medical fitness and prior therapy:

CD19- or CD22-directed immunotherapy can be used if it was not previously given. (See 'CD19-positive or CD22-positive' above.)

Patients with a KMT2A (lysine methyltransferase 2A) rearrangement that was not previously treated with revumenib should be treated with revumenib, as discussed above. (See 'KMT2A (chromosome 11q23) rearranged' above.)

For medically fit patients who did not previously undergo allogeneic hematopoietic cell transplantation (HCT), allogeneic HCT is an option.

For patients who relapse after an allogeneic transplant, donor lymphocyte infusion should be performed. (See "Immunotherapy for the prevention and treatment of relapse following allogeneic hematopoietic cell transplantation", section on 'Donor lymphocyte infusion (DLI)'.)

CLINICAL TRIALS — 

Often there is no better therapy to offer a patient than enrollment onto a well-designed, scientifically valid, peer-reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health (www.clinicaltrials.gov).

Many agents are under active investigation, including combinations of agents already used in ALL, agents used for other diseases, new antibodies (eg, anti-CD22 antibodies), and other novel agents (eg, entospletinib and other SYK [spleen tyrosine kinase] inhibitors).

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute lymphoblastic leukemia".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

Beyond the Basics topics (see "Patient education: Acute lymphoblastic leukemia (ALL) treatment in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Description – Many adults with acute lymphoblastic leukemia (ALL) who achieve complete remission (CR) later relapse, while some patients have disease that is refractory to initial therapy.

Evaluation

Diagnosis of relapsed ALL is based on morphology and immunophenotype of bone marrow and/or other involved sites. (See 'Diagnosis' above.)

Clinical evaluation and testing should define sites of involvement, including a lumbar puncture to evaluate central nervous system (CNS) involvement. (See 'Clinical and laboratory evaluation' above.)

Medical fitness is assessed by clinical evaluation, performance status, and comorbidities. Fit patients should be evaluated for transplant eligibility. (See 'Medical fitness' above.)

Overview – Remission induction therapy is guided by blast immunophenotype (ie, B cell versus T cell), cytogenetic findings, mutation analysis, patient fitness, and other clinical features. (See 'Overview' above.)

Treatment response is assessed, with post-remission management guided by fitness, measurable residual disease (MRD), and prior therapy. Participation in a clinical trial is encouraged.

B cell – Induction therapy for r/r B cell ALL is guided by immunophenotype and cytogenetic and clinical features:

CD19-positive or CD22-positive – We suggest immunotherapy-based remission induction, rather than chemotherapy (Grade 2C). (See 'CD19-positive or CD22-positive' above.)

The choice of immunotherapy is individualized, with consideration of antigen expression, availability, toxicity, and comorbidities. Each of the following can achieve remission but is associated with significant toxicity:

-Blinatumomab – CD19 x CD3 T cell engager antibody, for CD19-positive disease

-Inotuzumab ozogamicin – CD22-directed immunoconjugate, for CD22-positive disease

-CAR (chimeric antigen receptor)-T cell products – CAR-T cell therapy can be used for cancers that are CD19-positive and/or CD22-positive, but is available only at qualified sites; choices include:

(See 'Tisagenlecleucel' above.)

(See 'Brexucabtagene autoleucel' above.)

(See 'Obecabtagene autoleucel' above.)

CD19-negative and CD22-negative – Guided by cytogenetics and medical fitness:

-KMT2A-rearranged – We suggest revumenib (Grade 2C). (See 'KMT2A (chromosome 11q23) rearranged' above.)

-Others – We treat with chemotherapy, and the choice of regimen is informed by medical fitness. (See 'Others' above.)

Patients with prolonged remission (eg, ≥3 years) can be treated with the prior induction regimen. We suggest including rituximab for CD20-positive disease in younger patients (eg, <60 years) (Grade 2C).

Philadelphia chromosome-positive ALL – We suggest a BCR::ABL1 tyrosine kinase inhibitor (guided by BCR::ABL1 mutation status) plus induction immunotherapy or chemotherapy, rather than induction therapy alone (Grade 2C). (See 'Ph-positive ALL' above.)

T cell – We suggest nelarabine-based chemotherapy, rather than other chemotherapy (Grade 2C). (See 'T cell ALL' above.)

Response assessment – Response criteria are presented above. (See 'Response assessment' above.)

Post-remission management – Guided by medical fitness:

Transplant-eligible – We suggest allogeneic hematopoietic cell transplantation for transplant-eligible patients (Grade 2C). (See 'Transplant-eligible' above.)

Some patients may choose maintenance therapy alone, especially if they are MRD-negative after remission induction therapy.

Less fit – There is no consensus for patients who are transplant-ineligible. Consolidation and/or maintenance therapy is individualized according to prior treatment, institutional approach, and patient preference. (See 'Less fit' above.)

CNS management – We suggest CNS prophylaxis for all patients with r/r ALL (Grade 2C). (See 'Central nervous system management' above.)

Multiply relapsed – We encourage participation in a clinical trial. For others, management is guided by fitness, prior treatments, and patient preference, as discussed above. (See 'Multiply relapsed ALL' above.)

  1. http://geriatrictoolkit.missouri.edu/SPPB-Score-Tool.pdf (Accessed on October 24, 2017).
  2. Kantarjian H, Stein A, Gökbuget N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med 2017; 376:836.
  3. Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab Ozogamicin versus Standard Therapy for Acute Lymphoblastic Leukemia. N Engl J Med 2016; 375:740.
  4. Topp MS, Zimmerman Z, Cannell P, et al. Health-related quality of life in adults with relapsed/refractory acute lymphoblastic leukemia treated with blinatumomab. Blood 2018; 131:2906.
  5. Topp MS, Gökbuget N, Zugmaier G, et al. Phase II trial of the anti-CD19 bispecific T cell-engager blinatumomab shows hematologic and molecular remissions in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia. J Clin Oncol 2014; 32:4134.
  6. Zugmaier G, Gökbuget N, Klinger M, et al. Long-term survival and T-cell kinetics in relapsed/refractory ALL patients who achieved MRD response after blinatumomab treatment. Blood 2015; 126:2578.
  7. Martinelli G, Boissel N, Chevallier P, et al. Complete Hematologic and Molecular Response in Adult Patients With Relapsed/Refractory Philadelphia Chromosome-Positive B-Precursor Acute Lymphoblastic Leukemia Following Treatment With Blinatumomab: Results From a Phase II, Single-Arm, Multicenter Study. J Clin Oncol 2017; 35:1795.
  8. Topp MS, Gökbuget N, Zugmaier G, et al. Long-term survival of patients with relapsed/refractory acute lymphoblastic leukemia treated with blinatumomab. Cancer 2021; 127:554.
  9. Martinelli G, Boissel N, Chevallier P, et al. Long-term follow-up of blinatumomab in patients with relapsed/refractory Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukaemia: Final analysis of ALCANTARA study. Eur J Cancer 2021; 146:107.
  10. Topp MS, Kufer P, Gökbuget N, et al. Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol 2011; 29:2493.
  11. Goekbuget N, Bargou RC, Richle A, et al. BLAST: A confirmatory, single-arm, phase 2 study of blinatumomab, a bispecific T-cell engager (BiTE) antibody construct, in patients with minimal residual disease B-precursor acute lymphoblastic leukemia (abstract 0379). Blood 2014.
  12. https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM573941.pdf (Accessed on August 31, 2017).
  13. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N Engl J Med 2018; 378:439.
  14. Shah BD, Ghobadi A, Oluwole OO, et al. KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study. Lancet 2021; 398:491.
  15. Shah BD, Bishop MR, Oluwole OO, et al. KTE-X19 anti-CD19 CAR T-cell therapy in adult relapsed/refractory acute lymphoblastic leukemia: ZUMA-3 phase 1 results. Blood 2021; 138:11.
  16. Roddie C, Sandhu KS, Tholouli E, et al. Obecabtagene Autoleucel in Adults with B-Cell Acute Lymphoblastic Leukemia. N Engl J Med 2024; 391:2219.
  17. Lamble AJ, Kovach AE, Shah NN. How I treat postimmunotherapy relapsed B-ALL. Blood 2025; 145:64.
  18. Issa GC, Aldoss I, Thirman MJ, et al. Menin Inhibition With Revumenib for KMT2A-Rearranged Relapsed or Refractory Acute Leukemia (AUGMENT-101). J Clin Oncol 2025; 43:75.
  19. Larson RA, Dodge RK, Linker CA, et al. A randomized controlled trial of filgrastim during remission induction and consolidation chemotherapy for adults with acute lymphoblastic leukemia: CALGB study 9111. Blood 1998; 92:1556.
  20. O'Brien S, Thomas DA, Ravandi F, et al. Results of the hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone regimen in elderly patients with acute lymphocytic leukemia. Cancer 2008; 113:2097.
  21. Weiss MA, Aliff TB, Tallman MS, et al. A single, high dose of idarubicin combined with cytarabine as induction therapy for adult patients with recurrent or refractory acute lymphoblastic leukemia. Cancer 2002; 95:581.
  22. Ribera JM, García O, Oriol A, et al. Feasibility and results of subtype-oriented protocols in older adults and fit elderly patients with acute lymphoblastic leukemia: Results of three prospective parallel trials from the PETHEMA group. Leuk Res 2016; 41:12.
  23. Goekbuget N, Beck J, Brueggemann M, et al. Moderate Intensive Chemotherapy Including CNS-Prophylaxis with Liposomal Cytarabine Is Feasible and effective in Older Patients with Ph-Negative Acute Lymphoblastic Leukemia (ALL): Results of a Prospective Trial From the German Multicenter Study Group for Adult ALL (GMALL). Blood 2012; 120:1493.
  24. Hunault-Berger M, Leguay T, Thomas X, et al. A randomized study of pegylated liposomal doxorubicin versus continuous-infusion doxorubicin in elderly patients with acute lymphoblastic leukemia: the GRAALL-SA1 study. Haematologica 2011; 96:245.
  25. Martell MP, Atenafu EG, Minden MD, et al. Treatment of elderly patients with acute lymphoblastic leukaemia using a paediatric-based protocol. Br J Haematol 2013; 163:458.
  26. Specchia G, Pastore D, Carluccio P, et al. FLAG-IDA in the treatment of refractory/relapsed adult acute lymphoblastic leukemia. Ann Hematol 2005; 84:792.
  27. Advani AS, Gundacker HM, Sala-Torra O, et al. Southwest Oncology Group Study S0530: a phase 2 trial of clofarabine and cytarabine for relapsed or refractory acute lymphocytic leukaemia. Br J Haematol 2010; 151:430.
  28. Zeidan AM, Ricklis RM, Carraway HE, et al. Phase 1 dose-escalation trial of clofarabine followed by escalating dose of fractionated cyclophosphamide in adults with relapsed or refractory acute leukaemias. Br J Haematol 2012; 158:198.
  29. Giebel S, Krawczyk-Kulis M, Adamczyk-Cioch M, et al. Fludarabine, cytarabine, and mitoxantrone (FLAM) for the treatment of relapsed and refractory adult acute lymphoblastic leukemia. A phase study by the Polish Adult Leukemia Group (PALG). Ann Hematol 2006; 85:717.
  30. Schiller G, Lee M, Territo M, et al. Phase II study of etoposide, ifosfamide, and mitoxantrone for the treatment of resistant adult acute lymphoblastic leukemia. Am J Hematol 1993; 43:195.
  31. Liedtke M, Dunn T, Dinner S, et al. Salvage therapy with mitoxantrone, etoposide and cytarabine in relapsed or refractory acute lymphoblastic leukemia. Leuk Res 2014; 38:1441.
  32. Hardisty RM, McElwain TJ, Darby CW. Vincristine and prednisone for the induction of remissions in acute childhood leukaemia. Br Med J 1969; 2:662.
  33. Berry DH, Pullen J, George S, et al. Comparison of prednisolone, vincristine, methotrexate, and 6-mercaptopurine vs. vincristine and prednisone induction therapy in childhood acute leukemia. Cancer 1975; 36:98.
  34. Kadia TM, Kantarjian HM, Thomas DA, et al. Phase II study of methotrexate, vincristine, pegylated-asparaginase, and dexamethasone (MOpAD) in patients with relapsed/refractory acute lymphoblastic leukemia. Am J Hematol 2015; 90:120.
  35. Cortes JE, Kantarjian H, Shah NP, et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med 2012; 367:2075.
  36. Benjamini O, Dumlao TL, Kantarjian H, et al. Phase II trial of hyper CVAD and dasatinib in patients with relapsed Philadelphia chromosome positive acute lymphoblastic leukemia or blast phase chronic myeloid leukemia. Am J Hematol 2014; 89:282.
  37. Ottmann O, Dombret H, Martinelli G, et al. Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study. Blood 2007; 110:2309.
  38. Lilly MB, Ottmann OG, Shah NP, et al. Dasatinib 140 mg once daily versus 70 mg twice daily in patients with Ph-positive acute lymphoblastic leukemia who failed imatinib: Results from a phase 3 study. Am J Hematol 2010; 85:164.
  39. Luskin MR, Ganetsky A, Landsburg DJ, et al. Nelarabine, cyclosphosphamide and etoposide for adults with relapsed T-cell acute lymphoblastic leukaemia and lymphoma. Br J Haematol 2016; 174:332.
  40. Commander LA, Seif AE, Insogna IG, Rheingold SR. Salvage therapy with nelarabine, etoposide, and cyclophosphamide in relapsed/refractory paediatric T-cell lymphoblastic leukaemia and lymphoma. Br J Haematol 2010; 150:345.
  41. Whitlock JA, Malvar J, Dalla-Pozza L, et al. Nelarabine, etoposide, and cyclophosphamide in relapsed pediatric T-acute lymphoblastic leukemia and T-lymphoblastic lymphoma (study T2008-002 NECTAR). Pediatr Blood Cancer 2022; 69:e29901.
  42. Candoni A, Lazzarotto D, Ferrara F, et al. Nelarabine as salvage therapy and bridge to allogeneic stem cell transplant in 118 adult patients with relapsed/refractory T-cell acute lymphoblastic leukemia/lymphoma. A CAMPUS ALL study. Am J Hematol 2020; 95:1466.
  43. DeAngelo DJ, Yu D, Johnson JL, et al. Nelarabine induces complete remissions in adults with relapsed or refractory T-lineage acute lymphoblastic leukemia or lymphoblastic lymphoma: Cancer and Leukemia Group B study 19801. Blood 2007; 109:5136.
  44. Gökbuget N, Basara N, Baurmann H, et al. High single-drug activity of nelarabine in relapsed T-lymphoblastic leukemia/lymphoma offers curative option with subsequent stem cell transplantation. Blood 2011; 118:3504.
  45. Zwaan CM, Kowalczyk J, Schmitt C, et al. Safety and efficacy of nelarabine in children and young adults with relapsed or refractory T-lineage acute lymphoblastic leukaemia or T-lineage lymphoblastic lymphoma: results of a phase 4 study. Br J Haematol 2017; 179:284.
  46. Kurtzberg J, Ernst TJ, Keating MJ, et al. Phase I study of 506U78 administered on a consecutive 5-day schedule in children and adults with refractory hematologic malignancies. J Clin Oncol 2005; 23:3396.
  47. Jeha S, Gaynon PS, Razzouk BI, et al. Phase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. J Clin Oncol 2006; 24:1917.
  48. Hijiya N, Thomson B, Isakoff MS, et al. Phase 2 trial of clofarabine in combination with etoposide and cyclophosphamide in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. Blood 2011; 118:6043.
  49. Locatelli F, Testi AM, Bernardo ME, et al. Clofarabine, cyclophosphamide and etoposide as single-course re-induction therapy for children with refractory/multiple relapsed acute lymphoblastic leukaemia. Br J Haematol 2009; 147:371.
  50. Miano M, Pistorio A, Putti MC, et al. Clofarabine, cyclophosphamide and etoposide for the treatment of relapsed or resistant acute leukemia in pediatric patients. Leuk Lymphoma 2012; 53:1693.
  51. Ofran Y, Ringelstein-Harlev S, Slouzkey I, et al. Daratumumab for eradication of minimal residual disease in high-risk advanced relapse of T-cell/CD19/CD22-negative acute lymphoblastic leukemia. Leukemia 2020; 34:293.
  52. Voruz S, Blum S, de Leval L, et al. Daratumumab and venetoclax in combination with chemotherapy provide sustained molecular remission in relapsed/refractory CD19, CD20, and CD22 negative acute B lymphoblastic leukemia with KMT2A-AFF1 transcript. Biomark Res 2021; 9:92.
  53. Luskin MR, Shimony S, Keating J, et al. Venetoclax plus low-intensity chemotherapy for adults with acute lymphoblastic leukemia. Blood Adv 2025; 9:617.
  54. Richard-Carpentier G, Jabbour E, Short NJ, et al. Clinical Experience With Venetoclax Combined With Chemotherapy for Relapsed or Refractory T-Cell Acute Lymphoblastic Leukemia. Clin Lymphoma Myeloma Leuk 2020; 20:212.
  55. Horton TM, Whitlock JA, Lu X, et al. Bortezomib reinduction chemotherapy in high-risk ALL in first relapse: a report from the Children's Oncology Group. Br J Haematol 2019; 186:274.
  56. Bloomfield CD, Estey E, Pleyer L, et al. Time to repeal and replace response criteria for acute myeloid leukemia? Blood Rev 2018; 32:416.
  57. Buchmann S, Schrappe M, Baruchel A, et al. Remission, treatment failure, and relapse in pediatric ALL: an international consensus of the Ponte-di-Legno Consortium. Blood 2022; 139:1785.
  58. Laetsch TW, Maude SL, Rives S, et al. Three-Year Update of Tisagenlecleucel in Pediatric and Young Adult Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia in the ELIANA Trial. J Clin Oncol 2023; 41:1664.
  59. Doney K, Fisher LD, Appelbaum FR, et al. Treatment of adult acute lymphoblastic leukemia with allogeneic bone marrow transplantation. Multivariate analysis of factors affecting acute graft-versus-host disease, relapse, and relapse-free survival. Bone Marrow Transplant 1991; 7:453.
  60. Forman SJ, Schmidt GM, Nademanee AP, et al. Allogeneic bone marrow transplantation as therapy for primary induction failure for patients with acute leukemia. J Clin Oncol 1991; 9:1570.
  61. Biggs JC, Horowitz MM, Gale RP, et al. Bone marrow transplants may cure patients with acute leukemia never achieving remission with chemotherapy. Blood 1992; 80:1090.
  62. Duval M, Klein JP, He W, et al. Hematopoietic stem-cell transplantation for acute leukemia in relapse or primary induction failure. J Clin Oncol 2010; 28:3730.
  63. Oliansky DM, Larson RA, Weisdorf D, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the treatment of adult acute lymphoblastic leukemia: update of the 2006 evidence-based review. Biol Blood Marrow Transplant 2012; 18:18.
  64. Fielding AK, Richards SM, Chopra R, et al. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood 2007; 109:944.
  65. Cassaday RD, Alan Potts D Jr, Stevenson PA, et al. Evaluation of allogeneic transplantation in first or later minimal residual disease - negative remission following adult-inspired therapy for acute lymphoblastic leukemia. Leuk Lymphoma 2016; 57:2109.
  66. Larson RA. Managing CNS disease in adults with acute lymphoblastic leukemia. Leuk Lymphoma 2018; 59:3.
  67. Weisdorf DJ, Billett AL, Hannan P, et al. Autologous versus unrelated donor allogeneic marrow transplantation for acute lymphoblastic leukemia. Blood 1997; 90:2962.
  68. Soiffer RJ, Roy DC, Gonin R, et al. Monoclonal antibody-purged autologous bone marrow transplantation in adults with acute lymphoblastic leukemia at high risk of relapse. Bone Marrow Transplant 1993; 12:243.
  69. Abdallah A, Egerer G, Goldschmidt H, et al. Continuous complete remission in adult patients with acute lymphocytic leukaemia at a median observation of 12 years after autologous bone marrow transplantation. Br J Haematol 2001; 112:1012.
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