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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: Aug 2022. | This topic last updated: Jun 03, 2022.

INTRODUCTION — Over 80 percent of adult patients with newly diagnosed acute lymphoblastic leukemia (ALL) will attain a complete remission with intensive induction chemotherapy. After further consolidation therapy and maintenance chemotherapy, less than half will have long-term leukemia-free survival; the majority of adults with ALL will ultimately relapse. In addition, up to 20 percent will have primary resistant disease.

This topic review will review the treatment of relapsed or refractory ALL in adults. The following related subjects are discussed separately:

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

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

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

Detection of measurable residual disease (MRD; also referred to as minimal residual disease) following treatment of ALL. (See "Detection of measurable residual disease in acute lymphoblastic leukemia/lymphoblastic lymphoma" and "Clinical use of measurable residual disease detection in acute lymphoblastic leukemia".)

The clinical and pathologic features and diagnosis of ALL in adults. (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".)

EVALUATION FOR RELAPSE OR RESISTANCE

Monitoring for relapse — After initial therapy of ALL, patients are followed at routine intervals to monitor for treatment-related complications and relapsed disease. At these visits, patients are evaluated with a history, physical examination, and blood work. Bone marrow aspiration and biopsy is performed every three to six months for at least the next two years.

The expectation is that a patient with ALL in continuous complete remission (CR) for seven to eight years is "cured" and no longer requires routine bone marrow examination. However, relapses of adult ALL as long as 21 years after diagnosis have been reported [1].

In a study of unselected adult patients with ALL who survived more than three years, the relapse rate was 74 percent, with the latest relapse occurring eight years after diagnosis [2].

In patients with ALL who received hematopoietic cell transplantation and were in CR at two years, the overall chance of being alive in CR at nine years was 82 percent [3]. The latest relapses in this group occurred at four to seven years.

Additional information on the subject of measurable residual disease (MRD; also referred to as minimal residual disease) in ALL is presented separately. (See "Detection of measurable residual disease in acute lymphoblastic leukemia/lymphoblastic lymphoma" and "Clinical use of measurable residual disease detection in acute lymphoblastic leukemia".)

Evaluation of suspected relapse — Essentially all patients with relapse after CR have ALL present in their bone marrow, although it may be patchy and remain occult. Up to one-third can have concurrent involvement of extramedullary sites such as the central nervous system, testes, skin, or pleura [4].

Patients suspected of having relapsed disease should be evaluated with a bone marrow aspiration and biopsy. This sample should be sent for pathologic review, immunophenotyping, cytochemistry, and cytogenetics. Marrow aspirate or peripheral blood blasts should also be sent for reverse transcriptase polymerase chain reaction (RT-PCR) analysis for BCR-ABL1 in order to rapidly identify Philadelphia chromosome positive ALL because more specific therapy is available for these patients. (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".)

Areas suspected of harboring extramedullary disease, such as the central nervous system and testes, must also be evaluated even in asymptomatic patients.

Definitions of relapse and refractory disease — The majority of adults diagnosed with ALL will relapse after initial CR, one-quarter will have primary resistant disease, and most will ultimately die of their disease [5].

Refractory (resistant) disease is defined as those patients who fail to obtain a CR with induction therapy, ie, failure to eradicate all detectable leukemia cells (less than 5 percent blasts) from the bone marrow and blood with subsequent restoration of normal hematopoiesis (greater than 25 percent marrow cellularity and normal peripheral blood counts).

Relapsed disease describes the reappearance of leukemia cells in the bone marrow or peripheral blood after the attainment of a complete remission. As yet, the significance of the reappearance of ALL detected only by PCR analysis is uncertain.

Pretreatment evaluation — Once relapsed disease is identified, further pretreatment evaluation should include:

Human leukocyte antigen (HLA) typing should be performed for patients who are candidates for hematopoietic cell transplantation (HCT). This is extremely important since HCT is the most likely method for curing patients with relapsed ALL.

Other laboratory studies include a complete blood count with differential; chemistries with liver and renal function, electrolytes, glucose, lactate dehydrogenase (LDH), calcium, phosphorus, uric acid, albumin and total protein; and serology for hepatitis B, herpes simplex virus (HSV), and cytomegalovirus (CMV) infection. Women of childbearing age should undergo a pregnancy test.

A chest x-ray, an electrocardiogram (EKG), and a study of cardiac function (eg, ejection fraction measured by echocardiogram or MUGA) should be performed at baseline, especially for patients with a cardiac history, prior anthracycline exposure, or cardiovascular symptoms.

Dental evaluation for possible infectious foci is warranted.

Patients with neurologic signs or symptoms should undergo imaging studies to evaluate for meningeal disease or central nervous system bleeding. Lumbar puncture is indicated in all patients to examine the cerebrospinal fluid (CSF) for leukemic involvement. Care must be taken to avoid contaminating the CSF specimen with peripheral blood, if circulating blasts are present. CSF should be sent for both cytology (examination of stained cytospin slides) and flow cytometry for detection of ALL blasts.

REMISSION INDUCTION — The primary goal of remission induction therapy in relapsed or refractory ALL is achievement of complete remission (CR) or sufficient cytoreduction to enable allogeneic hematopoietic cell transplantation (HCT). HCT offers a chance of cure in a small, highly selected group of patients. Even for patients who are not candidates for HCT, remission induction may prolong survival.

Some individuals may choose not to undergo remission induction due to frailty, comorbidities, or patient preference; in such settings, symptom-directed therapy (palliative care) is appropriate.

The general treatment principles for relapsed or refractory ALL apply to most disease presentations and patient populations. However, certain clinical presentations and disease subtypes require distinctive approaches. (See 'Special scenarios' below.)

Salvage (rescue) therapy

Selection of therapy — Induction of a CR is the first step in the treatment of relapsed or refractory ALL. Remissions with most regimens typically last only a few months, so patients should proceed as soon as possible to allogeneic HCT [6]. (See 'Transplantation' below.)

Options for remission induction therapy include:

Immunotherapeutic approaches (eg, blinatumomab, inotuzumab ozogamicin, chimeric antigen receptor T cell therapy) (see 'Blinatumomab' below and 'Inotuzumab ozogamicin' below and 'CAR-T' below)

Cytarabine-based or other chemotherapy regimens (see "Induction therapy for Philadelphia chromosome negative acute lymphoblastic leukemia in adults")

Participation in a therapeutic trial (see 'Clinical trials' below)

For most patients, we suggest remission induction with an immunotherapeutic approach when available, rather than chemotherapy-based approaches. These approaches require treatment in a center with access to these agents and the expertise and resources needed to manage potentially life-threatening complications (eg, cytokine release syndrome, neurologic toxicities). The immunotherapeutic approaches have not been directly compared in randomized trials.

Our preference for immunotherapeutic approaches is based on the following:

Blinatumomab demonstrated superior rates of CR, overall survival (OS), and event-free survival (EFS) when compared with state-of-the-art chemotherapy regimens in a randomized, multicenter, international trial [7]. These findings are consistent with results from other trials of blinatumomab in relapsed or refractory ALL [8,9]. For some patients, access to blinatumomab, its expense, or the logistics of administration may be a barrier to its use. Some patients may benefit from chemotherapy to minimize disease burden prior to blinatumomab treatment. (See 'Blinatumomab' below.)

Inotuzumab ozogamicin (InO) achieved superior CR, OS, progression-free survival (PFS), and molecular responses compared with conventional chemotherapy for relapsed/refractory ALL [10]. InO can be administered in the outpatient setting, and is better tolerated than blinatumomab. InO is only effective when the ALL blast cells express cell surface CD22 (approximately 90 percent of adult patients). (See 'Inotuzumab ozogamicin' below.)

Chimeric antigen receptor T cell therapy achieved robust responses in early phase trials [11-13]. The US Food and Drug Administration has approved tisagenlecleucel for patients ≤25 years old with relapsed ALL who are treated at approved centers, but availability is restricted and treatment is associated with substantial, potentially life-threatening complications. (See 'CAR-T' below.)

Leukemic blasts can escape from cytolytic attack by blinatumomab or InO by downregulating cell surface expression of CD19 or CD22, respectively, and this mechanism has led to relapses and/or phenotypic change in leukemic blasts under selective pressure from the immunotherapy.

If relapse occurs more than two years after completion of initial treatment of ALL, a second remission may be attained using an induction chemotherapy regimen similar to that used in newly diagnosed ALL. (See "Induction therapy for Philadelphia chromosome negative acute lymphoblastic leukemia in adults" and "Induction therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults", section on 'Remission induction therapy'.)

Blinatumomab — Blinatumomab is a bispecific T cell engager (BiTE) monoclonal antibody directed at both CD19 on precursor B cell ALL tumor cells and CD3 on cytotoxic T cells [14]. Blinatumomab is approved by the European Medicines Agency for treatment of relapsed or refractory Philadelphia chromosome (Ph)-negative precursor B cell ALL, and by the US Food and Drug Administration for relapsed or refractory Ph-negative and Ph-positive precursor B cell ALL.

In an international, multicenter trial, 405 heavily pretreated adults with relapsed or refractory Ph-negative ALL were randomly assigned to either blinatumomab or cytarabine-based therapy [7]. A total of 24 percent of patients in each treatment group later underwent allogeneic HCT. When compared with chemotherapy, blinatumomab resulted in superior rates of:

OS (7.7 versus 4.0 months; hazard ratio [HR] 0.71; 95% CI 0.55-0.93)

CR with full hematologic recovery (34 versus 16 percent) plus CR with incomplete hematologic recovery (44 versus 25 percent)

EFS at six months (31 versus 12 percent; HR for relapse or death after achieving CR 0.55; 95% CI 0.43-0.71)

Blinatumomab was associated with comparable levels of severe (grade 3/4) toxicity (neutropenia, infection, neurologic events), but uniquely associated with cytokine release syndrome in <5 percent of patients

Health-related quality of life (HRQL) was superior for patients who received blinatumomab compared with those who received chemotherapy [15]. HRQL was improved in all 30 domains (eg, physical, cognitive, emotional functioning; fatigue, pain, nausea/vomiting, appetite, diarrhea) except financial difficulties, in repeated measures analysis of 342 patients available for testing.

Similar outcomes were demonstrated in other trials of blinatumomab in patients with relapsed/refractory Ph-negative ALL and Ph-positive ALL [8,9,16-18]. In some trials, blinatumomab eradicated measurable residual disease (MRD; also referred to as minimal residual disease) in more than three-quarters of patients [18-20].

Blinatumomab is administered by continuous intravenous infusion (CIVI) over four weeks, followed by a two-week treatment-free interval; maintenance treatment may continue as four-week CIVI every 12 weeks [21].

Boxed warnings include a cytokine release syndrome and neurological toxicities, each of which may be life-threatening or fatal. Patients are hospitalized around the time of infusion initiation to monitor for cytokine release syndrome and neurologic toxicity. Potential neurologic events include encephalopathy, convulsions, speech disorders, disturbances in consciousness, delirium, and coordination and balance issues. Other common toxicities include pyrexia, fatigue, headache, tremor, and leukopenia.

Inotuzumab ozogamicin — Inotuzumab ozogamicin (InO) is a humanized anti-CD22 monoclonal antibody conjugated to calicheamicin, a cytotoxic antibiotic [22]. CD22 is a B cell restricted molecule of the immunoglobulin superfamily that is expressed on leukemic blasts in >90 percent of B cell ALL [23,24]. InO is approved for treatment of relapsed/refractory CD22 positive B cell ALL by the European Medicines Agency and by the US Food and Drug Administration.

A multicenter trial randomly assigned 218 adults with relapsed or refractory ALL to treatment with InO or standard intensive chemotherapy [10]. Compared with standard therapy, InO achieved superior:

CR rate (81 versus 29 percent), and median duration of CR (5 versus 3 months)

OS at two years (23 versus 10 percent) and median PFS (5 versus 2 months)

Undetectable MRD (<0.01 percent marrow blasts) among patients who achieved CR (78 versus 28 percent)

The most frequent grade ≥3 adverse events associated with InO were liver-related; sinusoidal obstruction syndrome (also called veno-occlusive liver disease) of any grade occurred in 11 percent of patients who received InO and 1 percent of those who received standard therapy.

A phase 1/2 trial of InO in 72 patients with relapsed or refractory ALL reported comparable response and toxicity data [25].

CAR-T — CAR-T (chimeric antigen receptor T) cells are a form of genetically modified autologous immunotherapy that can be directed at B cell precursor ALL [26-33]. This customized treatment uses the individual's own T lymphocytes, which are transduced with a gene that encodes a chimeric antigen receptor to direct the patient's T cells against the leukemic cells. The T cells are genetically modified ex vivo, expanded in a production facility, and then infused back into the patient as therapy.

Tisagenlecleucel is a CD19-directed genetically modified autologous T cell immunotherapy that is approved by the US Food and Drug Administration (FDA) for treatment of patients ≤25 years of age with B cell precursor ALL that is refractory or in second or later relapse [11]. It is only available in the US through a risk evaluation and mitigation strategy (REMS) and the FDA label carries a boxed warning for neurological events and for cytokine release syndrome (CRS), which is a severe systemic response (eg, high fever, flu-like symptoms, hypotension, mental status changes) to the activation and proliferation of CAR-T cells. Facilities that dispense tisagenlecleucel require special certification, staff must be trained to recognize and manage its adverse events, and tocilizumab (a humanized monoclonal antibody against the interleukin-6 receptor [IL-6R]) must be available for immediate administration.

Brexucabtagene is a CD19-directed CAR-T cell therapy that is FDA-approved for treatment of relapsed or refractory B-ALL in adults [34]. Brexucabtagene is available in the US through a REMS program and the FDA label includes a boxed warning about CRS and neurologic toxicities.

Safety and efficacy of CAR-T cells against B-precursor ALL were demonstrated in the following studies:

A single institution study reported outcomes with 19-28z CAR T cells (directed against CD19) in 53 heavily pretreated adults (median age, 44 years; range 23 to 74 years) with relapsed or refractory B cell ALL [13]. Outcomes included CR in 83 percent and, with median follow-up of 29 months, median EFS and OS were six and 13 months, respectively. Patients with a low disease burden (<5 percent bone marrow blasts) before treatment had more favorable outcomes (median EFS 11 months, median OS >20 months) than those with higher disease burden or extramedullary disease (median OS 12 months).

Toxicity included CRS of any grade in 85 percent of patients, and was severe (grade ≥3) in 26 percent; one patient died with severe CRS and multi-organ failure. Severe neurologic toxicity (grade ≥3) occurred in 42 percent of patients. Those patients with higher disease burden had a higher incidence of CRS and neurotoxic events.

A multicenter study of tisagenlecleucel in 63 pediatric and young adult patients with relapsed or refractory B cell precursor ALL reported an 83 percent overall remission rate, all responding patients were negative for MRD by flow cytometry; 63 percent achieved CR and 19 percent achieved CR with incomplete hematologic recovery (CRi) [11]. With median follow-up of five months from response, the median duration of CR/CRi was not reached.

Another study evaluated CD19-directed CAR-T cells (generated with CTL019 lentiviral vector) in 30 children and adults with relapsed or refractory ALL, including patients with primary refractory disease (10 percent) and those who had relapsed after allogeneic transplantation (60 percent) [35]. CR was attained in 90 percent, with an estimated six-month EFS of 67 percent and overall survival of 78 percent.

Brexucabtagene autoleucel (KTE-X19) was associated with 56 percent CR (plus 15 percent CR with incomplete hematologic recovery) in a phase 2 study of 71 adults (median age 40 years) with relapsed or refractory B cell ALL [36]. With median follow-up >16 months, median OS was >18 months. Grade ≥3 CRS occurred in 24 percent and grade ≥3 neurologic syndrome in 25 percent; other grade ≥3 AES included anemia in half and fever in one-third. There were two treatment-related deaths: brain herniation and sepsis. A phase 1 study reported higher rates of CRS and ICANs with larger doses [37].

Cytokine release syndrome is observed in nearly all treated patients and may be life-threatening, but it typically responds to treatment with tocilizumab. Neurologic toxicities may also be severe or life-threatening. Other adverse events include hypersensitivity reactions, serious infections, prolonged cytopenias, prolonged hypogammaglobulinemia, and second malignancies.

Cytarabine-based regimens — First-line salvage chemotherapy is often based on the use of cytarabine in combination with other agents [38-42]. As an example, 29 adults with recurrent or refractory ALL were treated with cytarabine (3 g/m2 by three-hour intravenous infusion daily for five days) and idarubicin (40 mg/m2 intravenously on day 3) [41]. CR was attained in 11 (38 percent), with moderate but acceptable toxicity. There was one treatment-related death. Median duration of CR and OS of those attaining CR were short (three and eight months, respectively). In contrast, the combination of high dose mitoxantrone (80 mg/m2) with an identical dose and schedule of high dose cytarabine was found to be insufficiently active (23 percent CR among 31 evaluable patients) by the Southwest Oncology Group to merit further study [38]. The differences between these two small series are likely related to the extent of prior exposure to cytarabine and anthracyclines and/or biological characteristics of the disease.

Other regimens

Alkylating agents — There is anecdotal evidence for the use of an alkylating agent such as ifosfamide plus etoposide and dexamethasone for the treatment of relapsed ALL in adults. This regimen is based on experience in pediatric patients.

Clofarabine — Clofarabine is a deoxyadenosine (nucleoside purine) analog approved by the US Food and Drug Administration for the treatment of pediatric patients (ages 1 to 21 years) with relapsed or refractory ALL who have experienced treatment failure with two prior regimens [43]. The response rate in this setting is approximately 30 percent.

There are limited data regarding the use of clofarabine in adults with relapsed ALL:

The phase I/II trials of clofarabine in ALL included 25 adult patients with ALL treated at a dose of 40 mg/m2 daily for five days [44,45]. Overall response rates in this population were approximately 17 percent.

A similar combined rate of CR plus CR with insufficient hematological recovery of 17 percent was observed among 37 patients treated with the same dose and schedule of clofarabine combined with cytarabine (1 gm/sq m given daily for five days) [46]. Almost half of the patients were at least in second relapse or refractory. Whether cytarabine may contribute to the efficacy of clofarabine in a more uniform population of relapsed and/or refractory patients is not clear.

A single center report of clofarabine (52 mg/m2 daily for five days) in three adults (age 19 to 49) with relapsed disease refractory to salvage therapy reported responses in all three patients [47]. One remains in CR one year after a second HCT. Another achieved a second CR, proceeded to HCT, but relapsed three months after HCT. The third had a partial response that was lost after a temporary discontinuation of clofarabine due to elevated transaminases.

Nelarabine — Nelarabine, a prodrug converted in vivo to ara-GTP especially in T cells, has shown efficacy as a single agent for the treatment of relapsed or resistant T cell ALL in children and adults [48-51]. CR rates of 20 to 35 percent have permitted some patients to go on to HCT. Neurotoxicity, which can be severe, is dose-limiting. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Nelarabine'.)

Nelarabine has been approved by the US Food and Drug Administration for the treatment of patients with T cell ALL (T cell lymphoblastic lymphoma) that has not responded to, or has relapsed following treatment with at least two chemotherapy regimens [52]. Different doses and schedules are recommended for children and for adults. It has considerably less activity in B-lineage ALL.

Liposomal vincristine — A liposomal formulation of vincristine sulfate that was only available in the United States, was withdrawn from the market in May 2022.

Special scenarios

Philadelphia chromosome positive ALL — Patients with Philadelphia chromosome positive (Ph-positive) ALL are a distinct population whose standard induction therapy includes the use of a BCR-ABL1 tyrosine kinase inhibitor (TKI) with or without chemotherapy, typically followed by allogeneic HCT. (See "Induction therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults", section on 'TKI plus chemotherapy'.)

Patients with resistance or intolerance to one TKI may respond to another TKI, typically administered with combination chemotherapy. A second response is likely to be short-lived, so attempts should be made to proceed with allogeneic HCT as soon as remission is achieved. Treatment with blinatumomab is an acceptable alternative therapy as a bridge to HCT.

The ideal TKI to use in this setting is not known and practice varies. All patients should undergo mutation analysis of BCR-ABL1 to help direct further therapy. A choice among the available agents is usually made based upon prior exposure, the presence and nature of BCR-ABL1 mutations, comorbid illnesses, and toxicity profile (table 1).

Second generation TKIs (eg, dasatinib, nilotinib, bosutinib) may be used for the treatment of patients with Ph-positive ALL with intolerance to prior therapy and for many cases of resistant disease; importantly, only the third generation TKI, ponatinib, has substantial activity in the setting of the BCR-ABL1 T315I mutation.

Small prospective trials have evaluated the use of TKIs with or without chemotherapy in patients with relapsed or refractory Ph-positive ALL.

The efficacy and safety of dasatinib (70 mg orally twice daily) was tested in an open-label phase II trial in 36 patients with Ph-positive (or BCR/ABL1 positive), imatinib-resistant or imatinib-intolerant patients with ALL who were previously treated with standard induction or consolidation chemotherapy, as well as in imatinib-resistant or imatinib-intolerant patients with chronic myeloid leukemia (CML) in lymphoid blast crisis [53]. Complete cytogenetic responses were attained in 58 percent, and the overall median duration of PFS was 3.3 months, although 10 of 15 responders had not progressed at the eight-month follow-up.

A randomized trial of dasatinib 140 mg once daily versus 70 mg twice a day in 84 patients with Ph-positive or BCR/ABL1+ ALL with resistance or intolerance to imatinib reported that the two dosing schedules had similar efficacy and safety [54].

In a phase I study of ponatinib, a major cytogenetic response was seen in 32 percent of the 22 heavily pretreated patients with Ph-positive ALL, accelerated phase CML, or blast crisis [55].

An open-label phase II trial evaluated the combination of dasatinib plus chemotherapy (hyper-CVAD) in patients with relapsed Ph-positive ALL (19 patients) or CML in lymphoid blast crisis (15 patients) [56]. The overall response rate was 91 percent (71 percent complete) and 13 patients (42 percent) achieved a complete molecular response. Of the patients with ALL, 26 percent were alive and in CR at three years.

Blinatumomab, a bispecific T cell engager (BiTE) monoclonal antibody directed at both CD19 on precursor B cell ALL tumor cells and CD3 on cytotoxic T cells, may be an effective bridge to HCT for patients with relapsed or refractory Ph-positive B-ALL. (See 'Blinatumomab' above.)

A phase 2 study reported that 16 of 45 (36 percent) patients who received single agent blinatumomab achieved CR or CR with partial hematologic recovery (CRh) during the first two treatment cycles [16]. Patients had been refractory or intolerant of at least one second generation (or later) TKI. Among patients who achieved CR/CRh (which included 4 of 10 patients who had BCR-ABL1 T315I mutations) 88 percent achieved a complete MRD response. Seven responding patients (44 percent) proceeded to allogeneic HCT, including 6 of 11 (55 percent) who had not previously undergone transplantation.

The most frequent adverse events associated with blinatumomab treatment were pyrexia (58 percent), febrile neutropenia (40 percent), and headache (31 percent). Three patients had grade 1/2 cytokine release syndrome, and three patients had grade 3 neurologic events (one of whom had aphasia that required temporary treatment interruption).

Central nervous system involvement — Twenty to thirty percent of patients with relapsed ALL will also have involvement of the central nervous system (CNS), defined by the presence of leukemic blasts in a centrifuged preparation of cerebrospinal fluid (CSF) that does not have evidence of blood contamination. Cranial irradiation plus intrathecal chemotherapy is the mainstay of treatment of CNS involvement [57]. Typically, 2400 cGy of radiation is given to the entire cranium over 12 doses. In addition, at least six doses of intrathecal methotrexate should be administered. There are very preliminary data available on the use of intrathecal rituximab in sequence with conventional therapy for the treatment of refractory CNS ALL [58]. A liposomal formulation of cytarabine has also been approved for intrathecal therapy [57]. (See "Treatment of leptomeningeal disease from solid tumors" and "Induction therapy for Philadelphia chromosome negative acute lymphoblastic leukemia in adults", section on 'Central nervous system involvement'.)

T cell ALL — For patients with relapsed or refractory T cell ALL, treatment may incorporate cytotoxic chemotherapy and/or novel agents such as nelarabine or liposomal vincristine. (See 'Nelarabine' above and 'Liposomal vincristine' above.)

Multiply relapsed disease — For patients with multiply relapsed disease, including those who relapse following allogeneic HCT, treatment options include participation in a clinical trial, immunotherapeutic approaches, a cytotoxic chemotherapy regimen that was not previously used, or palliative treatment. (See 'Clinical trials' below.)

TRANSPLANTATION — Approximately one-half of adults who suffer a relapse of ALL will attain a second complete remission (CR), although most will eventually die from leukemia. This dismal prognosis justifies the use of high dose alternative treatments after relapse. In primary refractory or advanced relapsed ALL, allogeneic hematopoietic cell transplantation (HCT) is associated with three-year leukemia-free survival (LFS) rates of 12 to 23 percent [59-63]. This is clearly superior to chemotherapy alone, which achieves no cures at this stage of the disease.

Disease-related factors — Data from the International Bone Marrow Transplant Registry (IBMTR) indicate that the status of the disease is one of the most significant predictors for LFS following HLA-identical sibling transplants for ALL. The three-year actuarial probabilities of LFS for children and adults undergoing transplantation in first CR, second CR or higher, and for advanced (relapsed or refractory) ALL are 54 percent, 40 percent, and 20 percent, respectively [64]. Treatment-related mortality ranges from 25 to 35 percent and appears comparable for patients transplanted at all stages of the disease. Thus, the increased risk of failure with each subsequent remission is due to the parallel increase in the rate of relapse.

The impression that allogeneic HCT is less effective during overt relapse than subsequent remission may not be valid, since this issue has never been analyzed on an intention-to-treat basis in clinical trials designed to address this question specifically. The potential benefit of tumor cytoreduction prior to HCT may be balanced or exceeded by increased morbidity from the reinduction chemotherapy. In one study of 37 consecutive adults with primary refractory ALL or in first relapse, only 65 percent of patients who reached CR, and only 51 percent of the total group, underwent the intended HCT because of complications from reinduction chemotherapy and early relapse [65]. In addition, only about one-half of patients will achieve a second CR whereas all will experience the toxicity of treatment.

The greatest experience with myeloablative HCT for relapsed or refractory disease is provided by a retrospective analysis of 2255 patients with relapsed or refractory leukemia reported to the Center for International Blood and Marrow Transplant Research between 1995 and 2004 [62]. This analysis included 583 patients with primary refractory ALL (25 percent), first untreated relapse (12 percent), first refractory relapse (43 percent), first relapse with unknown treatment status (2 percent), or second or additional relapse (19 percent). Overall, the survival rate at three years was 16 percent. Acute graft-versus-host disease (GVHD) was seen in 52 percent of patients with 27 percent experiencing severe (grade 3/4) acute GVHD. Chronic GVHD was seen in approximately one-quarter of patients.

A pretransplant scoring system was devised to predict the survival of patients not in CR who undergo myeloablative HCT based upon the assessment of four criteria (maximum score 6 points) [62]:

Timing of transplant: First refractory relapse = 1 point, Second or additional relapse = 2 points

Donor cytomegalovirus (CMV) status: Positive = 1 point

Percent bone marrow blasts: >25 percent = 1 point

Age: 10 to 39 years = 1 point; ≥40 years = 2 points

Total score predicted long-term survival when applied to 582 patients with relapsed or refractory ALL not in CR at the time of myeloablative HCT. Rates of three-year overall survival were 46, 22, and 10 percent for patients with 0 or 1, 2, and 3 points, respectively.

Allogeneic HCT — Allogeneic HCT, when carried out in adults in second complete remission, results in long-term LFS rates of 18 to 45 percent (table 2) [59,60,63,66-71]. The primary cause of failure is relapse. The IBMTR found that adults with high-risk or standard-risk ALL transplanted in second CR had similar relapse rates (56 versus 49 percent, respectively), but the LFS rates at four years were significantly lower for high-risk patients (22 versus 36 percent) [69]. This observation suggests that nonrelapse causes for death account for the poorer prognosis in the high-risk patients.

The profile of prognostic factors for patients undergoing HCT in second CR is even more elusive than for patients in first CR. Almost all analyses addressing this issue have been performed on populations consisting of both adults and children, and the conclusions may not be directly applicable to the adults separately. Nevertheless, based upon indirect comparisons, HLA-identical allogeneic HCT appears superior to rescue with chemotherapy alone.

Autologous HCT — Results of autologous HCT have been disappointing for adults with more advanced ALL. In one study, for example, there were no survivors among adults (greater than 18 years of age) transplanted in CR2 [72]. In two other series, relapse rates were unacceptably high in older patients and none of the patients over 28 years of age who were autografted in advanced disease survived [73,74].

As such, there appears to be little benefit from autologous HCT in adults with ALL in general. This is most likely due to the inability to collect leukemia-free stem cells from patients despite morphological CR. There is no advantage of autologous HCT over chemotherapy for consolidation of either high-risk or standard-risk patients in first CR. For patients beyond first CR, the relapse rate is unacceptably high following autologous HCT, with or without purging, and the overall results are very poor.

However, special situations may exist for those with Ph-positive ALL and those with no detectable residual disease by highly sensitive, multicolor, flow cytometry. The role of autologous HCT in patients with Ph-positive ALL who are rendered molecularly negative prior to stem cell collection and then maintained on a BCR-ABL1 inhibitor after transplantation remains under investigation. Long-term disease-free survival has been observed in some of these patients.

PROGNOSIS — The prognosis of adults with relapsed or refractory ALL is generally poor. Median survival is less than one year, and less than one-quarter of patients survive three years. Long-term overall survival (OS) is dependent on attaining a complete remission (CR) with subsequent allogeneic hematopoietic cell transplantation (HCT). Approximately 31 to 44 percent of patients will attain a CR with second-line therapy, while 18 to 23 percent will attain a CR following third-line therapy [4,5,43,49,50,75-78]. Less than half of patients will be candidates for HCT.

Retrospective studies and observational series have identified certain patient and disease-related characteristics that appear to impact outcome. As examples:

Of 609 adults with ALL who were treated on the MRC/ECOG UKALL12/ECOG2993 study, the rates of five-year OS were 38 and 7 percent in those with newly diagnosed or relapsed ALL, respectively [5]. Factors predicting a good outcome after second-line therapy included:

Young age – Five-year OS rates were 12 versus 3 percent for those younger than 20 or older than 50 years, respectively.

Long duration of first CR – Five-year OS rates were 11 versus 5 percent for those whose duration of first remission was more than or less than two years, respectively.

In a highly selected group of patients with recurrent ALL who were able to receive HCT while in relapse, the estimated survival rate was 23 percent at five years.

Another retrospective analysis of 547 consecutive patients in first relapse following initial therapy within GMALL studies reported a median OS after relapse of 8.6 months with 24 percent survival at three years [71]. Factors associated with outcome following second-line therapy included:

Age – Patients 25 years or younger were more likely to attain a CR (53 versus 37 percent). Survival at three years decreased with increasing age with estimated rates of 38, 28, and 12 percent in patients ≤25 years, 26 to 45 years, and >45 years, respectively.

Site of relapse – Estimated OS at three years was 23 percent following relapse in the bone marrow with or without involvement of additional sites (428 patients); 27 percent with isolated central nervous system involvement (18 patients); and 47 percent with other isolated extramedullary relapse (32 patients).

Prior therapy – 378 patients relapsed during or after first-line chemotherapy with a median survival of 10 months and an estimated survival rate at three years of 28 percent. In comparison, 169 patients relapsed following HCT performed during first CR with a median survival of 5.8 months and an estimated survival rate at three years of 15 percent.

Time to relapse – When compared with patients with a longer duration of first CR, patients whose disease relapsed <18 months from initial therapy were less likely to attain a CR (36 versus 58 percent).

Status of disease at HCT – 149 patients underwent HCT with an estimated three-year survival of 38 percent. In comparison, none of the patients who did not undergo HCT survived longer than one year. Survival rates were higher for those who underwent HCT in CR after first salvage (56 percent) than for those in CR after later salvage (39 percent) or for those not in CR at the time of HCT (20 percent).

A single institution retrospective analysis of 288 patients administered a second rescue therapy reported achievement of a complete response in 18 percent [75]. Median durations of remission and OS were seven and three months, respectively. Inferior survival rates were noted in patients with the following characteristics:

First complete response less than 36 months

Bone marrow blasts >50 percent

Platelet count <50,000/microL

Serum albumin level <3 g/dL (30 g/liter)

For patients with zero or 1, 2, 3, or 4 of these factors, survival rates at one year were 33, 14, 8, and zero percent, respectively.

SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The coronavirus disease 2019 (COVID-19) pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. Additionally, immunocompromised patients are candidates for a modified vaccination schedule (figure 1), other preventive strategies (including pre-exposure prophylaxis), and the early initiation of COVID-directed therapy. These issues and recommendations for cancer care during the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)

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

The majority of adults diagnosed with acute lymphoblastic leukemia (ALL) will ultimately relapse and die from their disease. In general, the only curative therapy for relapsed or refractory ALL is allogeneic hematopoietic cell transplantation (HCT).

The diagnosis of relapsed or refractory ALL must be confirmed with a bone marrow aspirate and biopsy that is examined for morphology, cytogenetics, and molecular studies. (See 'Evaluation of suspected relapse' above.)

Pretreatment evaluation should include a lumbar puncture to determine if there is involvement of the central nervous system, and HLA typing in anticipation of allogeneic HCT. (See 'Pretreatment evaluation' above.)

The primary goal of remission induction therapy is achievement of complete remission or sufficient cytoreduction to enable allogeneic HCT. For most patients, we recommend remission induction therapy followed by allogeneic HCT rather than remission induction therapy alone (Grade 1B). (See 'Transplantation' above.)

Options for remission induction include (see 'Salvage (rescue) therapy' above):

Immunotherapeutic approaches (eg, blinatumomab, inotuzumab ozogamicin, chimeric antigen receptor T cell therapy) (see 'Blinatumomab' above and 'Inotuzumab ozogamicin' above and 'CAR-T' above)

Cytarabine-based or other chemotherapy regimens (see 'Cytarabine-based regimens' above)

Participation in a clinical trial (see 'Clinical trials' above)

The choice of remission induction therapy depends on the disease subtype and clinical characteristics:

For most patients with Philadelphia chromosome negative precursor B ALL, we suggest remission induction therapy with blinatumomab or inotuzumab ozogamicin (InO) rather than chemotherapy-based induction (Grade 2B). The choice may be informed by availability, expected toxicities, and immunophenotypic characteristics (ie, blinatumomab should be given only if the leukemic blasts express CD19 and InO should be given only if the leukemic blasts express CD22). (See 'Blinatumomab' above and 'Inotuzumab ozogamicin' above and 'Cytarabine-based regimens' above.)

Chimeric antigen receptor T cell (CAR-T) therapy (eg, tisagenlecleucel) is an acceptable alternative for patients ≤25 years old with B cell precursor ALL that is refractory or in second or later relapse, in facilities with the proper resources and expertise. (See 'CAR-T' above.)

Cytotoxic chemotherapy is an acceptable alternative, especially among patients whose relapse occurs more than two years following initial treatment.

For patients with Philadelphia chromosome positive precursor B ALL, treatment should incorporate a tyrosine kinase inhibitor selected based upon prior exposure and the presence and nature of BCR-ABL1 mutations. Treatment with blinatumomab is an acceptable alternative in this setting. (See 'Philadelphia chromosome positive ALL' above.)

For patients with T ALL, treatment may incorporate cytotoxic chemotherapy and/or novel agents such as nelarabine or liposomal vincristine. (See 'T cell ALL' above.)

For patients with second or later relapse, including those who relapse following allogeneic HCT, treatment options include participation in a clinical trial, immunotherapeutic approaches, cytotoxic chemotherapy that was not previously used, or palliative treatment. (See 'Clinical trials' above.)

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