Acute Lymphoblastic Leukemia (ALL) Treatment & Management

Acute lymphoblastic leukemia (ALL) is best treated by physicians who have significant experience in the treatment of patients with acute leukemia. In addition, these patients should receive treatment in a setting where appropriate supportive care measures (high-level blood banking and leukapheresis) are available. Patients admitted to hospitals that lack appropriate blood product support facilities, leukapheresis capabilities, or physicians and nurses familiar with the treatment of patients with leukemia should be transferred to an appropriate (generally, tertiary care) hospital.

Traditionally, the four components of ALL treatment are induction, consolidation, maintenance, and central nervous system (CNS) prophylaxis; these are briefly reviewed in the following sections. Other aspects of treatment are also discussed.

Selection of regimens in ALL is based on Philadelphia (Ph) chromosome presence or absence and patient age (adolescent/young adult [AYA] or adult), with consideration of patient comorbidities. See also Acute Lymphoblastic Leukemia Treatment Protocols.

Patients with ALL require hospital admission for induction chemotherapy, and they require readmission for consolidation chemotherapy or for the treatment of toxic effects of chemotherapy. Surgical intervention may be required for the placement of a central venous catheter, such as a triple lumen, Broviac, or Hickman catheter.

Only 20-30% of adults with ALL are cured with standard chemotherapy regimens. Consequently, all patients must be evaluated for entry into well-designed clinical trials. If a clinical trial is not available, the patient can be treated with standard therapy.

Standard induction therapy typically involves either a four-drug regimen of vincristine, prednisone, an anthracycline, and cyclophosphamide or L-asparaginase, or a five-drug regimen of vincristine, prednisone, an anthracycline, cyclophosphamide given over the course of 4-6 weeks, plus an asparaginase product. Using this approach, complete remissions (CRs) are obtained in 65-85% of patients.

An alternative is the hyper-CVAD regimen, which is based on the success achieved with short-term, dose-intensive chemotherapy regimens in children. It incorporates hyperfractionated cyclophosphamide and intensive doses of cytarabine (Ara-C) and methotrexate in combination with dexamethasone and vincristine.

From 1992-2000, 288 patients received hyper-CVAD at MD Anderson Cancer Center; of those, 17% of patients had Philadelphia chromosome–positive (Ph+) ALL, and 13% had T-cell ALL. ^[28] Overall, 92% of patients obtained a complete response (CR). The 5-year survival and percentage of patients in CR at 5 years were both 38%. Patients with Ph+ ALL had a 92% CR rate but only a 12% 5-year survival. Patients with T-cell ALL had a 75% CR rate and a 48% 5-year survival. Patients with Burkitt ALL had a 93% CR rate and a 67% 5-year survival. ^[28]

Newer modifications of the hyper-CVAD regimen include the addition of a tyrosine kinase inhibitor in patients whose leukemia is Ph+, and of rituximab in patients whose leukemia is CD20 positive (see below). Both of these approaches have resulted in improvements in disease-free survival.

The rapidity with which a patient's disease enters CR correlates with treatment outcome. Several studies have shown that patients whose disease is in CR within 4 weeks of therapy have longer disease-free survival and overall survival than those whose disease enters remission after 4 weeks of treatment.

Patients with CD20+ lymphoblasts benefit from the addition of rituximab. Maury et al randomly assigned adults (18 to 59 years of age) with CD20-positive, Philadelphia chromosome (Ph)–negative  (Ph-) ALL to receive chemotherapy with or without rituximab, with event-free survival as the primary end point ^[29] . Rituximab was given during all treatment phases, for a total of 16 to 18 infusions. After a median follow-up of 30 months, event-free survival was longer in the rituximab group than in the control group (hazard ratio, 0.66; 95% confidence interval, 0.45 to 0.98; P=0.04), and the estimated 2-year event-free survival rates were 65% and 52%, respectively.

The use of consolidation chemotherapy in ALL is supported by several studies. Fiere et al compared consolidation therapy with daunorubicin and cytosine arabinoside (Ara-C) versus no consolidation therapy in adults with ALL, demonstrating a 38% 3-year, leukemia-free survival rate for subjects receiving consolidation and maintenance therapy compared with 0% for those receiving maintenance therapy without consolidation. ^[30]

In a study reported by Hoelzer et al, subjects whose disease was in remission after induction received consolidation therapy consisting of dexamethasone, vincristine, and doxorubicin, followed by cyclophosphamide, Ara-C, and 6-thioguanine beginning at week 20. ^[31] Subjects also received maintenance therapy with 6-mercaptopurine and methotrexate during weeks 10-20 and 28-130. The median remission of 20 months was among the longest reported at the time.

In the United Kingdom Acute Lymphoblastic Leukemia XA study, subjects were randomized to receive early intensification with Ara-C, etoposide, thioguanine, daunorubicin, vincristine, and prednisone at 5 weeks; late intensification with the same regimen at 20 weeks; both; or neither. ^[32] The disease-free survival rates at 5 years were 34%, 25%, 37%, and 28%, respectively. These data suggest a benefit to early, rather than late, intensification. ^[32]

Because most studies have showed a benefit to consolidation therapy, regimens using a standard 4- to 5-drug induction usually include consolidation therapy with Ara-C in combination with an anthracycline or epipodophyllotoxin. Patients who receive hyper-CVAD induction receive alternating cycles of high-dose methotrexate/high-dose Ara-c and hyper-CVAD as consolidation therapy.

Use of maintenance therapy significantly improves the outcome in B-cell-precursor ALL, but less so in T-cell ALL, and not in Burkitt lymphoma/leukemia. ^[33] The POMP protocol (prednisone, vincristine [Oncovin], methotrexate, mercaptopurine [Purinethol]; daily mercaptopurine, weekly methotrexate, and monthly pulses of prednisone and vincristine) is a standard regimen for maintenance therapy in ALL. ^[20] The benefit of prednisone/vincristine is uncertain, however, and methotrexate/mercaptopurine alone is used by some groups for childhood ALL and in Europe for adult ALL. ^{[33, 34]}

In Philadelphia chromosome (Ph)–positive ALL, a tyrosine kinase inhibitor (eg, imatinib, dasatinib, nilotinib, ponatinib) is typically added to the maintenance regimen. ^{[20, 35]} Blinatumomab alternating with POMP may be used for maintenance in Ph-negative ALL. ^[20]

Maintenance therapy is typically given for 2 to 3 years. ^{[33, 36]}

The percentage of patients who complete consolidation and maintenance therapy has declined recently as more patients are referred for transplant while they are in first remission. The frequency of transplant has increased with the use of alternative donors (unrelated, cord blood, and haploidentical), which make it unlikely that a patient will not be able to find a donor.

In contrast to patients with acute myeloid leukemia (AML), patients with ALL frequently have meningeal leukemia at the time of relapse. A minority of patients have meningeal disease at the time of initial diagnosis. As a result, central nervous system (CNS) prophylaxis is essential. Options for CNS prophylaxis include the following ^[37] :

• Cranial radiation therapy plus intrathecal methotrexate
• High-dose systemic methotrexate and intrathecal methotrexate without cranial radiation therapy
• Intrathecal chemotherapy alone

Cortes et al analyzed the prevalence of CNS leukemia in four consecutive clinical trials at the MD Anderson Cancer Center and found that high-dose systemic chemotherapy reduces CNS relapse, but early intrathecal chemotherapy is necessary to achieve the lowest risk of CNS relapse. CNS relapse rates were 31% for group 1 (standard chemotherapy, no CNS prophylaxis), 18% for group 2 (high-dose systemic chemotherapy, no CNS prophylaxis), 17% for group 3 (high-dose systemic chemotherapy, intrathecal chemotherapy for high-risk subjects after achieving remission), and 3% for group 4  (hyper-CVAD). ^[38] All subjects received intrathecal chemotherapy starting in induction. High-risk subjects received 16 intrathecal treatments, and low-risk subjects received four intrathecal treatments.

Mature B-cell ALL is a special type, representing only 5% of adult patients with ALL. The hallmark of mature B-cell ALL is the presence of surface immunoglobulin on the lymphoblasts, along with cytogenetic abnormalities such as t(8;14), t(2;8), and t(8;22). With conventional regimens, only 30-40% of patients enter complete remission (CR) and few patients survive long term.

Short-term intensive therapies, similar to those used in aggressive non-Hodgkin lymphoma, show improved results, with 75% CR rates and 40% failure-free survival. ^[39]

Burkitt ALL cells are CD20 positive. This allows for the addition of targeted therapy with rituximab. Many studies are have demonstrated improved efficacy, including prolonged survival, when rituximab is added to chemotherapy in these patients. The combination of hyper-CVAD plus rituximab resulted in an overall 3-year survival of 80% compared with 50% for historical controls treated without rituximab. ^[40]

In patients with relapsed or refractory B-cell ALL, monoclonal antibody–based treatment with blinatumomab and inotuzumab have shown better efficacy than conventional chemotherapy and have become preferred salvage treatment strategies, including as a bridge to allogeneic hematopoietic stem cell transplantation. ^[37] In addition, CD19-directed chimeric antigen receptor (CAR) T-cell therapy has shown promise in  relapsed/refractory B-cell ALL with central nervous system leukemia. ^[41]

 

In the past, Philadelphia chromosome–positive (Ph+) ALL was treated with the same regimens as other types of ALL, with poor results. However, tyrosine kinase inhibitors (TKIs) that inhibit the bcr-abl fusion protein of Ph+ ALL allow targeted therapy of this disease.

Imatinib

The addition of imatinib to chemotherapy has resulted in significantly improved outcomes. The addition of imatinib to hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) resulted in a 3-year disease-free survival rate of 66% and overall survival of 55% compared with a 14% 3-year disease-free survival rate and 15% overall survival for patients treated with hyper-CVAD without imatinib. ^[42] . Longer-term follow-up demonstrated that the 5-year overall survival rate for all patients was 43%. ^[43]

In the German Multicenter ALL (GMALL) trial—a randomized study of imatinib versus standard induction therapy for patients older than 55 years with Ph+ ALL—the overall complete remission (CR) rate was 96.3% in patients assigned to imatinib and 50% in patients allocated to standard chemotherapy. ^[44] Severe adverse events were significantly more frequent during standard induction chemotherapy (90% vs 39%). The estimated overall survival of all patients was 42% at 24 months, with no significant difference between the 2 cohorts. ^[44]

The Ph+ arm of the UKALLXII/ECOG2993 study for adult ALL enrolled 266 patients between 1993 and 2003 (pre-imatinib cohort) ^[45] . In 2003, imatinib was introduced as a single-agent course following induction (N = 86, late imatinib). In 2005, imatinib was added to the second phase of induction (N = 89, early imatinib). The CR rate was 92% in the imatinib cohort vs 82% in the preimatinib cohort (P = .004). At 4 years, the overall survival of all patients in the imatinib cohort was 38% vs 22% in the preimatinib cohort (P = 0.003).

The CALGB 10001 trial studied whether the addition of imatinib to chemotherapy could improve the outcome of autologous transplantation in Ph+ ALL such that the results could be comparable to allogeneic transplantation. ^[46]  In this study of 58 patients, overall survival (median 6.0 years vs not reached) and disease-free survival (median 3.5 vs 4.1 years) were similar between those who underwent autologous and those who underwent allogeneic stem cell transplantation. The authors concluded that autologous stem cell transplantation represented an alternative to allogeneic stem cell transplantation in patients without sibling donors.

Several other studies have demonstrated improved outcomes with the addition of imatinib to chemotherapy. ^{[47, 48, 49]}

Nilotinib

Nilotinib is a TKI that has a higher binding affinity and selectivity for the ABL kinase than imatinib. ^[50] Nilotinib has 20 to 50 times the inhibitory activity against imatinib-sensitive CML cell lines relative to imatinib. In a phase II study in patients with relapsed/refractory Ph+ ALL, complete responses were reported in 24% of patients treated with nilotinib. ^[50]  

Although nilotinib is approved in the relapsed/refractory setting there are few trials of nilotinib in combination with chemotherapy for newly diagnosed Ph+ ALL. Kim et al reported on 90 patients (ages 17 to 71 years) who received induction treatment with vincristine, daunorubicin, prednisolone, and nilotinib. After achieving complete hematologic remission, subjects received either 5 courses of consolidation, followed by 2-year maintenance with nilotinib, or allogeneic stem cell transplantation. The CR rate was 91% and the cumulative MR5 rate was 94%. The 2-year relapse-free survival rate was 72% and the 2-year overall survival rate was 72%. ^[51]  

Dasatinib

Dasatinib is a potent, orally active inhibitor of the BCR-ABL, c-KIT and the SRC family of kinases. ^[52] Dasatinib is a more potent inhibitor of BCR-ABL and c-KIT than imatinib mesylate, and it is effective in patients with CML that is resistant to or intolerant of imatinib.

In the GIMEMA LAL1205 protocol, 53 patients (median age, 53.6 y) with newly diagnosed Ph+ ALL received only dasatinib (for 84 d), steroids (for the first 32 d), and intrathecal chemotherapy as induction therapy. ^[53] All patients achieved a complete hematologic remission; 49 patients (92.5%) achieved this at day 22. Postinduction management was decided by the investigator and included no further treatment (2 patients), TKI alone (19 patients), TKI plus chemotherapy and/or autografting (14 patients), and allografting (18 patients). At 20 months, the overall survival was 69.2% and disease-free survival was 51.1%. Twenty-three patients relapsed after completing induction.

Ravandi et al reported the long-term follow-up results of hyper-CVAD plus dasatinib for the initial treatment of patients with Ph+ ALL. ^[54]  Patients received dasatinib with 8 cycles of alternating hyperCVAD and high-dose cytarabine plus methotrexate. Patients in complete remission (CR) continued maintenance dasatinib, vincristine, and prednisone for 2 years, which was followed by dasatinib indefinitely. Patients eligible for allogeneic stem cell transplantation (SCT) received it during their first CR. Seventy-two patients with a median age of 55 years were treated; 96% achieved CR. Sixty-five patients (94%) were negative for minimal residual disease assessed by flow cytometry at a median of 3 weeks (range, 2-37 weeks). Dasatinib-related grade 3 and 4 adverse events included bleeding, pleural/pericardial effusions, and elevated transaminases. The median disease-free survival and overall survival were 31 (range, 0.3-97 months) and 47 months (range, 0.2-97 months), respectively.

Rousellot et al reported a European Working Group on Adult ALL (EWALL) study of dasatinib and low-intensity chemotherapy in elderly patients with Ph+ ALL ^[55] . Patients older than age 55 years treated with dasatinib 140 mg/day (100 mg/day for those over 70 years) with intrathecal chemotherapy, vincristine, and dexamethasone during induction. Patients in complete remission continued consolidation with dasatinib, sequentially with cytarabine, asparaginase, and methotrexate for 6 months. Maintenance therapy was dasatinib and vincristine/dexamethasone reinductions for 18 months followed by dasatinib until relapse or death. The CR rate was 96% and 65% of patients achieved a 3-log reduction in BCR-ABL1 transcript levels during consolidation. At 5 years, overall survival was 36%.

Treatment of Ph+ ALL without chemotherapy was demonstrated in the GIMEMA LAL2116 D-ALBA trial. In this phase II single-group study, conducted in 63 adults (median age, 54 years; range, 24 – 82 years) with newly diagnosed Ph+ ALL, induction therapy with dasatinib plus dexamethasone was followed by consolidation therapy with two cycles of the bispecific T-cell engager antibody blinatumomab plus dexamethasone. ^[56]

In GIMEMA LAL2116 D-ALBA, at a median follow-up of 18 months, overall survival was 95% and disease-free survival (DFS) was 88%. DFS was lower in patients with IKZF1 deletion plus additional genetic aberrations (CDKN2A or CDKN2B, PAX5, or both [ie, IKZF1plus]). Overall, 21 adverse events of grade 3 or higher were recorded. Twenty-four patients received a stem-cell allograft; two of those died, but only one death was related to transplant. ^[56]

Ponatinib

Ponatinib (Iclusig), which inhibits ABL and T315I mutant ABL as well as other kinases, was approved by the US Food and Drug Administration (FDA) in December 2012 for patients with Ph+ ALL, including those with the T315I mutation, who have shown resistance to or intolerance of TKI therapy. After studies showed that ponatinib poses a high risk for thromboembolic events, its use was restricted to adults with T315I-positive Ph+ ALL, and adults with Ph+ ALL for whom no other TKI therapy is indicated. ^[57]

Ph+ ALL is a much more life-threatening disease than chronic myeloid leukemia. Thus, it is possible that the increased potency of ponatinib could justify the toxicity in patients with ALL.  

Sasaki et al studied hyper-CVAD plus ponatinib (47 patients) versus hyper-CVAD plus dasatinib (63 patients) as frontline therapy for patients with Ph+ ALL. ^[58]  With propensity score matching, the 3-year  event-free survival rates for patients treated with hyper-CVAD plus ponatinib and hyper-CVAD plus dasatinib were 69% and 46%, respectively (P =0.04), and the 3-year OS rates were 83% and 56%, respectively (P =0.03). Patients treated with hyper-CVAD plus ponatinib had significantly higher rates of minimal residual disease negativity by flow cytometry on day 21, complete cytogenetic response at complete response, major molecular response at complete response and at 3 months, and complete molecular response at 3 months.

Older children and younger adults with ALL can be referred to either adult or pediatric hematologists. In the past, patients were treated with either an adult or pediatric regimen based on the referral pattern. However, several studies suggested that younger adult patients were best treated on pediatric protocols. This has resulted in the use of pediatric-style regimens in younger adult patients.

Stock et al performed a retrospective comparison of presenting features, planned treatment, complete remission (CR) rate, and outcome in 321 adolescents and young adults (AYAs) ages 16 to 20 years with newly diagnosed ALL who were treated in consecutive trials in either the Children's Cancer Group (CCG) or the Cancer and Leukemia Group B (CALGB) from 1988 to 2001. CR rates were identical, 90% for both CALGB and CCG AYAs. CCG AYAs had a 63% event-free survival (EFS) and 67% overall survival (OS) at 7 years in contrast to the CALGB AYAs, in which 7-year EFS was only 34% (P < 0.001) and OS was 46% (P < 0.001) ^[59] .

In a retrospective analysis of patients aged 15-20 years treated on either the FRALLE 93 or LALA 94 trials, the CR rate was 94% for patients receiving the pediatric regimen (FRALLE 93) compared with 83% for those receiving the adult regimen (LALA 94). ^[60] The 5-year survival was 67% in the pediatric-regimen group and 41% in the adult-regimen group. Patients treated on the pediatric regimen were younger (15.9 y) than those treated on the adult regimen (17.9 y); however, prognostic factors were otherwise matched. ^[60]

In a study by the Programme for the Study of Therapeutics for Haematological Malignancies (PETHEMA), adolescents and young adults were treated with a pediatric regimen (ALL-96), demonstrating a response to therapy that was similar to previously reported, although a slight increase in hematologic toxicity was observed in the adult patients. ^[61]

Deangelo et al treated adult patients aged 18-50 years with ALL with the DFCI Pediatric ALL Consortium regimen utilizing a 30-week course of pharmacokinetically dose-adjusted E coli L-asparaginase during consolidation. Between 2002 and 2008, 92 eligible patients aged 18-50 years were enrolled. Seventy-eight patients (85%) achieved a CR after 1 month of intensive induction therapy. With a median follow-up of 4.5 years, the 4-year disease-free survival for the patients achieving a CR was 69% and the 4-year overall survival for all eligible patients was 67%. ^[62]

Seftel et al compared 422 HCT recipients aged 18-50 years with Ph-ALL in CR1 reported to the CIBMTR with an age-matched concurrent cohort of 108 Ph- ALL CR1 patients who received a Dana-Farber Consortium pediatric-inspired non-HCT regimen. At 4 years of follow-up, the incidence of relapse after HCT was 24% versus 23% for the non-HCT (chemo) cohort (P=0.97). Treatment-related mortality (TRM) was higher in the HCT cohort (37%) versus chemo (6%), P< 0.0001. DFS in the HCT cohort was 40% versus 71% for chemo, P< 0.0001. Similarly, OS favored chemo (HCT 45%) versus chemo (73%), P< 0.0001. ^[63]

Alabdulwahab et al compared patients < 50 years treated on the Dana Farber consortium protocol (DFCP) versus classic hyper-CVAD for treatment of ALL. The CR rate was 90.7% for DFCP vs. 83.7 for hyper-CVAD (P = 0.7). Three-year leukemia-free survival was 70.9% for DFCP vs. 41.6% for hyper-CVAD (P= 0.1), while 3-year OS was 72.6% for DFCP vs. 48.5% for hyper-CVAD (P= 0.04). ^[64]

Rytting et al compared the results in 106 AYA patients (median age 22 years) who received augmented Berlin-Frankfurt-Münster (BFM) with results in 102 AYA patients (median age 27 years) who received hyper-CVAD. ^[65]  The CR rate was 93% with augmented BFM and 98% with hyper-CVAD. The 5-year CR durations were 53% and 55%, respectively (P = 0.98). The 5-year OS rates were 60% with both regimens. Severe regimen toxicities with augmented BFM included hepatotoxicity in 41%, pancreatitis in 11%, osteonecrosis in 9%, and thrombosis in 19%. Myelosuppression-associated complications were most significant with hyper-CVAD.

Randomized trials are needed to confirm any advantage the pediatric-style regimens may have.

In current practice, most adult patients (except the most elderly and those with significant comorbidities) are offered allogeneic hematopoietic stem cell transplantation (HSCT) in first remission. The use of alternative donors (including matched unrelated donors, cord blood, and haploidentical donors) allows for most patients to have an appropriate donor.

However, as non-transplant therapies have improved, controversy has arisen as to whether transplantation is always needed. Examples include the addition of tyrosine kinase inhibitors in Philadelphia chromosome–positive (Ph+) ALL, and the addition of rituximab in mature B-cell ALL.

Relatively few studies have compared transplantation with chemotherapy in adults with ALL. In a study by the Groupe Ouest-Est des Leucemies Airgues et Maladies du Sang (GOELAMS), subjects younger than 45 years who had a sibling donor and whose disease was in remission were assigned to allogeneic bone marrow transplantation (BMT). ^[66] The remaining subjects received methylprednisolone, Ara-C, mitoxantrone, and etoposide chemotherapy followed by autologous BMT.

For subjects undergoing allogeneic BMT, the rate of freedom from relapse was 70% at 4 years. However, because of transplant-related complications, the event-free survival rate was only 33%. No toxic deaths occurred in the subjects who underwent autologous BMT. However, the event-free survival rate was only 17% at 4 years because of a high rate of relapse. ^[66]

In a prospective, nonrandomized trial, the Bordeaux, Grenoble, Marseille, Toulouse group found that the 3-year probability of disease-free survival was significantly higher with allogeneic BMT (68%) than with autologous BMT (26%). ^[67] No benefit was observed with the addition of recombinant interleukin 2 (IL-2) after autologous BMT.

In the French Group on Therapy for Adult Acute Lymphoblastic Leukemia study, subjects aged 15-40 years whose disease was in CR and who had a human leukocyte antigen (HLA)-compatible sibling donor underwent allogeneic BMT. ^[68] The other subjects were randomized to receive autologous BMT or chemotherapy. Overall, no difference in was observed in 5-year survival between the groups. ^[68]

However, when only high-risk patients were considered (ie, Ph+, null ALL; > 35 y; white blood cell [WBC] count > 30,000/µL; or time to CR > 4 wk), allogeneic BMT proved superior to autologous BMT or chemotherapy with respect to overall survival rates (44% vs 20%) and disease-free survival rates (39% vs 14%). ^[68] Other phase 2 studies have confirmed a benefit for high-risk patients who undergo allogeneic BMT, with as many as 50% achieving long-term remissions.

In the GOELAL02 study, patients with any high-risk feature (age > 35 y, non–T-ALL, WBC > 30,000, adverse cytogenetics: t[9;22], t[4;11], or t[1;19], or no CR after induction) received either allogeneic or autologous stem cell transplantation. For patients younger than 50 years, the 6-year overall survival rate was superior in patients receiving allogeneic transplantation (75%) compared with those receiving autologous transplantation (40%). ^[66]

The United Kingdom Medical Research Council Acute Lymphoblastic Leukemia joint trial with the Eastern Cooperative Oncology Group (MRC UKALL XII/ECOG E2993) demonstrated that matched related allogeneic transplantations for ALL in first complete CR provide the most potent antileukemic therapy and considerable survival benefit for standard-risk patients. A donor versus no-donor analysis showed that Ph-negative patients with a donor had a 5-year improved overall survival, 53% versus 45% (P = 0.01), and that the relapse rate was significantly lower. ^[69]

The survival difference was significant in standard-risk patients but not in high-risk patients with a high nonrelapse mortality rate in the high-risk donor group. Patients randomized to chemotherapy had a higher 5-year overall survival (46%) than those randomized to autologous transplantation (37%). ^[69] However, the transplantation-related mortality for high-risk older patients was unacceptably high and abrogated the reduction in relapse risk.

Allogeneic transplantation can also be effective therapy for patients who have experienced relapse after chemotherapy. Martino et al treated 37 consecutive patients with primary refractory or relapsed ALL with intensive salvage chemotherapy. ^[70] Of the 19 patients assigned to autologous BMT, 10 did not reach transplantation, mostly because of early relapse; 9 received transplants. Of these, 1 died early and 8 experienced relapse 2-30 months after transplantation. Of the 10 patients who received allogeneic BMT, 4 died early and 6 were alive and free from disease 9.7-92.6 months after the transplantation. ^[70]

These results are similar to those in patients in earlier stages, indicating that transplant-related complications are increased in the allogeneic setting. However, a significant number of patients can be cured. Yet, although autologous transplantation is relatively safe, it is associated with a high relapse rate, making this modality of little use in patients with ALL.

For patients without a sibling donor, an alternative is an unrelated-donor (URD) transplant. Weisdorf et al found that autologous BMT was associated with a lower transplant-related mortality rate, but URD transplantations had a lower risk of relapse. ^[71] In patients whose disease was in second CR, URD transplantations resulted in a superior rate of disease-free survival. ^[71]

Although peripheral blood has come to be preferred to bone marrow as the source for stem cells from unrelated donors (about 75% of transplants), a randomized phase III trial by Anasetti et al found that peripheral-blood stem cells did not yield improved survival as compared with bone-marrow cells and were significantly associated with chronic graft-vs-host disease (GVHD) ^[72] ; the authors suggested that peripheral-blood stem cells might be appropriate for patients at higher risk for graft failure and bone-marrow cells for all others.

Patients with relapsed ALL have an extremely poor prognosis. Most patients are referred for investigational therapies. Patients who have not previously undergone transplantation are referred for such therapy, preferably after obtaining a complete response to salvage therapy. Reinduction regimens include standard chemotherapy regimens (similar to the front-line setting), novel chemotherapeutic agents or immunotherapies (blinatumomab, inotuzumab ozogamicin, or tisagenlecleucel). Patients with Ph+ disease generally receive a tyrosine kinase inhibitor either alone or in combination with other therapies. 

The choice of therapy a patient will receive depends on the following:

• The front-line regimen they received
• The duration of prior remission
• Whether the patient relapsed after transplantation
• The comorbidities that the patient has

Standard chemotherapy regimens that are commonly used in the relapsed setting include hyper-CVAD, other high-dose cytarabine-based regimens, and MOAD (methotrexate, vincristine, asparaginase, and dexamethasone).  

Newer agents that are approved in the salvage setting are listed below. These are used either alone or in combination with other agents.

Clofarabine

In 2004, the US Food and Drug Administration (FDA) granted accelerated approval for clofarabine, a novel nucleoside analogue, for the treatment of pediatric patients with refractory or relapsed ALL. Two open-label, multicenter, nonrandomized phase II trials established the efficacy and safety profile of clofarabine in that patient population. In one study of 61 patients (median age, 12 years; range, 1-20 years), the response rate to clofarabine was 30% (seven complete responses [CRs], five CRs without platelet recovery, and six partial remissions), and remissions lasted long enough to allow patients to proceed to hematopoietic stem-cell transplantation (HSCT). ^[73]

In a second study in 42 patients (median age, 13 years; range, 2-22 years), the response rate was 26% and included one CR without platelet recovery and 10 partial responses. The median duration of response was 20 weeks. ^[74]

Nelarabine

In 2005, the FDA granted accelerated approval for nelarabine for the treatment of T-cell ALL (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) in patients whose disease had not responded to or relapsed following treatment with at least two chemotherapy regimens. Approval was based on two phase II trials, one conducted in pediatric patients and the other in adult patients. In the pediatric trial, of the 39 patients who had relapsed or had been refractory to two or more induction regimens, 5 patients (13%) had a CR and 9 patients (23%) had a CR with incomplete hematologic or bone marrow recovery. ^[75]

Vincristine liposomal od

In August 2012, the FDA approved vincristine liposomal (Marqibo) for the treatment of Philadelphia chromosome negative (Ph-) ALL in adults. It is indicated for patients in second or later relapse or those whose disease has progressed following two or more antileukemia therapies. This product is a sphingomyelin/cholesterol liposome-encapsulated formulation of vincristine. In a trial of 65 patients that received at least one dose of vincristine liposomal, 15.4% of the patients had CR lasting a median of 28 days. ^[76]

Blinatumomab

Blinatumomab (Blincyto), a bispecific T-cell engager (BiTE) antibody, was approved by the FDA in 2014 for Ph- relapsed or refractory B-cell precursor ALL. BiTE antibodies enable CD3-positive T cells to recognize and eliminate CD19-positive ALL blasts. Approval of blinatumomab was based on results of a phase 2, multicenter, single-arm open-label study in which 77 (41.6%) of 185 adult patients achieved complete remission or complete remission with partial hematologic recovery within 2 cycles of treatment with blinatumomab. ^{[77, 78]}

A phase III trial in 405 adults with heavily pretreated B-cell precursor ALL found that treatment with blinatumomab (n = 271) resulted in significantly longer overall survival than treatment with chemotherapy (n = 134). Event-free survival estimates at 6 months were 31% with blinatumomab versus 12% with chemotherapy, and median duration of remission was 7.3 vs. 4.6 months, respectively. A total of 24% of the patients in each treatment group underwent allogeneic HSCT. ^[79]

Patients in this study who continued on blinatumomab for consolidation therapy had longer overall and recurrence-free survival than those who stopped blinatumomab after induction, and those whothen continued on blinatumomab for maintenance therapy had improved survival compared with those who stopped blinatumomab after consolidation. Many of the patients who achieved a best hematologic response of CR were able to maintain their responses with additional cycles of blinatumomab. ^[80]

Blinatumomab was also granted accelerated approval for the treatment of CD19-positive B-cell precursor ALL in first or second complete remission with minimal residual disease (MRD) ≥ 0.1% in adults and children. Efficacy was evaluated in the open-label, multicenter, single-arm BLAST study that enrolled 116 adult patients with B-precursor ALL in hematologic complete remission after at least 3 intensive chemotherapy treatments and with MRD ≥10^-3. In BLAST, 78% of patients had a complete MRD response, 98% of which occurred within the first treatment cycle. ^[81]

Inotuzumab

In 2017, inotuzumab was FDA approved for relapsed or refractory B-cell precursor ALL. Approval was based on findings from the phase III INO-VATE trial, which compared inotuzumab  one of the following three standard regimens: FLAG (fludarabine, cytarabine, and granulocyte colony-stimulating factor) for up to four 28-day cycles, cytarabine plus mitoxantrone for up to four 15-20 day cycles, and mitoxantrone as a single agent. ^[82]

The risk of progression or death was reduced by 55% with inotuzumab versus standard therapy. Rates of CR or CR with incomplete hematologic recovery (CR/CRi) were 80.7% in the inotuzumab arm versus 29.4% with chemotherapy. In those who achieved a CR/CRi, 78.4% were minimal residual disease negative with inotuzumab versus 28.1% for chemotherapy. For patients who were receiving their first salvage therapy, the CR/CRi rate was 87.7% with inotuzumab versus 28.8% with chemotherapy. In the second salvage therapy setting, the CR/CRi rate with inotuzumab was 66.7% versus 30.6% with chemotherapy. ^[82]

In chimeric antigen receptor (CAR) T-cell therapy, the patient's own T-cells are collected from peripheral blood and genetically engineered to express a CAR that targets a specific molecule on the cancer cells. The modified T-cells are then expanded and reinfused into the patient, after lymphodepletion with conditioning chemotherapy. ^[83]

Studies of treatment with CAR T-cells targeting CD19 have reported high rates of complete and long-lasting remissions in patients with refractory ALL. Toxicities, which can be fatal, include cytokine release syndrome (CRS), B-cell aplasia, and cerebral edema. ^[83]  

In 2017, the US Food and Drug Administration (FDA) approved the anti-CD19 CAR-T cell therapy agent tisagenlecleucel (Kymriah) for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse. Because of the risk of adverse effects, the FDA approval includes a risk evaluation and mitigation strategy, which requires special certification for hospitals and clinics that administer the treatment and additional training for their physicians and other staff. ^{[84, 85]}

Approval of tisagenlecleucel was based on the results of an open-label, muticenter single-arm trial (Study B2202) that included 88 children and young adults (median age, 12 years) with relapsed or refractory B-cell ALL. Of the treated patients evaluable for efficacy, 52 of 63 responded; of those, 40 patients (63%) had a complete response within the first 3 months after infusion, and 12 (19%) had a complete remission with incomplete blood count recovery. All of those had minimum residual disease–negative status in the bone marrow. ^[86]

In conjunction with the approval of tisagenlecleucel, the FDA also expanded the approval of tocilizumab to include the treatment of severe or life-threatening CRS resulting from CAR T-cell therapy in patients 2 years of age or older. In clinical trials, 69% of patients with CRS related to CAR T-cell therapy had complete resolution of CRS within 2 weeks after receiving one or two doses of tocilizumab. ^[85]

In 2021, the FDA approved approved the anti-CD19 CAR-T cell therapy agent brexucabtagene autoleucel (Tecartus) for the treatment of adult patients with relapsed or refractory B-cell precursor ALL. Approval was based on results of the ZUMA-3 trial, an international, multicenter, single-arm, open-label study in 55 patients. ^[87] Of the 54 patients evaluable for efficacy, 28 achieved a complete response (CR) within 3 months. On median follow-up of 7.1 months in responders, the median duration of CR was not reached; the duration of CR was estimated to exceed 12 months for more than half the patients. ^[88] Like tisagenlecleucel, brexucabtagene autoleucel carries black box warnings for CRS and neurologic toxicities and it is available only through a restricted access program.

Patients with ALL have a deficiency in the ability to produce normal blood cells, and they need replacement therapy. This deficiency is temporarily worsened by the addition of chemotherapy. All blood products must be irradiated to prevent transfusion-related graft versus host disease, which is almost invariably fatal.

Packed red blood cells are given to patients with a hemoglobin level of less than 7-8 g/dL or at a higher level if the patient has significant cardiovascular or respiratory compromise.

Platelets are transfused if the count is less than 10,000-20,000/µL. Patients with pulmonary or gastrointestinal hemorrhage receive platelet transfusions to maintain a value greater than 50,000/µL. Patients with central nervous system CNS hemorrhage are transfused to achieve a platelet count of 100,000/µL.

Fresh frozen plasma is given to patients with a significantly prolonged prothrombin time (PT). Cryoprecipitate is given if the fibrinogen level is less than 100-125 g/dL.

Antibiotics are given to all febrile patients. At a minimum, include a third-generation cephalosporin (or equivalent). In addition to this minimum, other antibiotic agents are added to treat specific documented or possible infections.

Patients with persistent fever after 3-5 days of antibacterial antibiotics should have an antifungal antibiotic (liposomal or lipid complex amphotericin, new generation azole or echinocandin) added to their regimen. Patients with sinopulmonary complaints would receive anti-Aspergillus treatment. Particular care is warranted for patients receiving steroids as part of their treatment, because the signs and symptoms of infection may be subtle or even absent. 

The use of prophylactic antibiotics in neutropenic patients who are not febrile is controversial. However, most clinicians prescribe them for patients undergoing induction therapy. The following is a commonly used regimen:

• Ciprofloxacin (oral [PO] 500 mg twice daily [bid])
• Fluconazole (200 mg PO daily), voriconazole (200 mg PO bid), or posaconazole (200 mg PO three times daily [tid])
• Acyclovir (200 mg PO 5 times/d) or valacyclovir (500 mg PO daily)

If patients taking these antibiotics become febrile, they are switched to intravenous antibiotics.

The use of granulocyte colony-stimulating factor (G-CSF) during induction chemotherapy for ALL is supported by several studies. In a randomized phase 3 trial conducted by Ottman et al, 76 subjects received either G-CSF or no growth factor with the induction chemotherapy (ie, cyclophosphamide, cytosine arabinoside (Ara-C), 6-mercaptopurine, intrathecal methotrexate, and cranial irradiation). The median duration of neutropenia was 8 days in subjects receiving G-CSF versus 12 days in subjects receiving no growth factor, and the prevalence of nonviral infections was decreased by 50% in subjects receiving G-CSF. No difference in disease-free survival was observed between the 2 groups. ^[89]

In a randomized phase III study reported by Geissler et al, subjects who received G-CSF beginning on day 2 of induction chemotherapy (ie, with daunorubicin, vincristine, L -asparaginase, and prednisone) had a marked decrease in the proportion of days with neutropenia of less than 1000/µL (29% for G-CSF vs 84% for controls), a reduction in the prevalence of febrile neutropenia (12% vs 42% in controls), and a decrease in the prevalence of documented infections (40% vs 77%) relative to those who received chemotherapy without G-CSF. No difference was observed in response, remission duration, or survival between the 2 groups. ^[90]

In the Cancer and Leukemia Group B (CALGB) 9111 study, subjects who received G-CSF beginning on day 4 of induction chemotherapy had significantly shorter durations of neutropenia and significantly fewer days of hospitalization compared with those in the group that received placebo. ^[91] In this study, subjects receiving G-CSF also had higher complete remission (CR) rates, because fewer deaths occurred during remission induction. Again, no significant effect on disease-free survival or overall survival was observed. ^[91]

The importance of the early use of G-CSF FOR ALL was demonstrated by the study of Bassan et al, in which subjects who received G-CSF on day 4 of induction therapy recovered significantly faster from neutropenia, had fewer infectious complications, and required less antibiotic and antfungal medication than subjects beginning G-CSF on day 15. ^[92]

Outside of the setting of a clinical trial, few data support the use of granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with ALL. The GOELAMS investigators randomly assigned 67 subjects to receive GM-CSF or placebo during induction chemotherapy with idarubicin, methylprednisolone, and high-dose Ara-C and observed no difference in the CR rate, the duration of neutropenia, or days with fever for the two groups. ^[93] In addition, mucositis of higher than grade 3 was reduced in subjects receiving GM-CSF (two of 35 patients vs six of 29 patients, respectively. ^[93]

In a Groupe d'Etude et de Traitement de la Leucemie Aigue Lymphoblastique de l'Adulte (GET-LALA) study, in patients who received G-CSF, GM-CSF, or no growth factor during induction therapy, the median time for neutrophil recovery was 17 days for G-CSF, 18 days for GM-CSF, and 21 days for no growth factors. ^[94]

Tumor lysis syndrome is a potentially life-threatening complication that may be seen in patients receiving chemotherapy for acute leukemias and high-grade non-Hodgkin lymphomas. This syndrome is characterized by elevated blood levels of uric acid, phosphate, and potassium; decreased levels of calcium; and acute renal failure.

As mentioned earlier, patients with a high tumor burden, particularly those with severe hyperuricemia, can present in kidney failure. Allopurinol at 300 mg 1-3 times per day is recommended during induction therapy until blasts are cleared and hyperuricemia resolves. High-risk patients (those with very high lactate dehydrogenase [LDH] or leukemic infiltration of the kidneys) can benefit from rasburicase.

In a study by Cortes et al, adults with hyperuricemia or those at high risk for tumor lysis syndrome not only had an improved plasma uric acid response rate with rasburicase alone (0.20 mg/kg/d intravenously [IV], days 1-5) (87%) or in combination with allopurinol (IV rasburicase 0.20 mg/kg/d, days 1-3, followed by oral [PO] allopurinol 300 mg/d, days 3-5) (78%) than with allopurinol alone (300 mg/d PO, days 1-5) (66%), but they also had more rapid control of their plasma uric acid level with rasburicase alone (4 h) or rasburicase followed by allopurinol (4 h) than with allopurinol alone (27 h). ^[95]

Patients with ALL are monitored on an outpatient basis for disease status and the effects of chemotherapy. Maintenance therapy for these patients is also administered in an outpatient setting.

In addition, all patients should be on trimethoprim-sulfamethoxazole (TMP-SMZ) to prevent Pneumocystis jiroveci pneumonia, and patients may benefit from receiving oral nystatin or clotrimazole troches to reduce the risk of candidiasis. Patients with a high risk of relapse may also need additional antifungal therapy, such as itraconazole.