In this issue

Director's Corner by David Poplack, M.D.

Molecular Genetics of Acute Lymphoblastic Leukemia
by Karen Rabin, M.D., and Judith Margolin, M.D.

Novel Agents in Pediatric Leukemia
by Terzah M. Horton, M.D., Ph.D., and Stacey L. Berg, M.D.

Acute Lymphoid Leukemia in Infants: Advances in Recent Years
by ZoAnn Dreyer, M.D.

Stem Cell Transplant in Childhood Acute Lymphoblastic Leukemia by Kathryn Leung, MD, and Robert Krance, M.D.

Acute Lymphoid Leukemia in Infants:
Advances in Recent Years
by ZoAnn Dreyer, M.D.

Dr. ZoAnn Dreyer

Malignancy in the first year of life is a biologically intriguing event. Infantile acute lymphoid leukemia (ALL) represents only 4 percent of childhood ALL with an annual incidence of 20 per 1 million infants at risk and a slight predominance of girls.^{(1-4, 5)} The incidence of ALL is nearly double that of acute non-lymphoid leukemia during the first year of life.^(6,7). ALL in infancy differs significantly from ALL in older children not only in presentation but also in prognostic factors, response to therapy and outcome.

ALL in infants presents a therapeutic challenge and represents a form of ALL which has been far more difficult to treat and cure than that in any other age group. The event free survival (EFS) for older children with ALL approaches 70 percent to 75 percent while in infant ALL published five year EFS ranges from 17 percent to 43 percent. In the early 1980s, most infants were treated on the high risk, more intensive arms of pediatric ALL protocols with dismal outcomes characterized by short-term disease control, early relapse and five year EFS in the range of 20 percent (8-10). Subsequently, many groups have developed intensified, infant specific therapy with some improvement increasing average EFS to 30 percent to 45 percent.^{(1, 11-15)}

In infant ALL, first remission is easily attained with complete remission rates of 94 percent to 95 percent, mirroring those of older children. The most common cause of failure is marrow relapse followed much less frequently by central nervous system (CNS) and testicular failure. In a review of the literature by Pieters, 318 of 593 patients failed for a 54 percent relapse rate.⁽¹⁶⁾ Eighty percent of failures were marrow, 30 percent CNS and 8 percent  testicular. Combined relapse represented 19 percent of the total relapses observed with 14 percent combined marrow and CNS relapses. Time to relapse was early in all studies with two-thirds of relapses occurring within six to 12 months post-initial diagnosis.^{(1, 9, 11)}

Infantile ALL is characterized by hyperleukocytosis and extreme organomegaly. Evidence of tumor lysis syndrome with hyperuricemia and renal compromise are much more common complications at presentation in infants compared with older children with ALL. Presenting white blood cell (WBC) counts are greater than 50,000 x109 /l in two-thirds of infants and greater than 100,000 x 109/1 in more than half.⁽¹⁶⁾ In the very young infant, WBC counts greater than 1,000,000x 109/1 may be seen.

Historically, risk factors associated with a poorer prognosis in infant ALL appear interrelated and include absence of CD10 ^{(1, 10, 11, 16, 17)}, evidence of the MLL gene rearrangement associated with a variety of translocations involving 11q23 ^{(1, 11, 15, 18-23)}, co-expression of myeloid antigens ^(18,24), higher WBC counts (greater than 50-100,000 x109 /l) ^{(1, 10-12, 25, 26)}, organomegaly ⁽¹¹⁾ and younger age (less than three to six months) at presentation.^{(1, 10-12, 18)} In general, 90 percent of infants with CD 10 negative ALL have the MLL gene rearrangement; 80% percent of infants with germline MLL are CD10 positive and at least two-thirds of infants who have MLL rearrangements are less than six months of age.^{(19, 20)} Unlike older children, gender is not prognostic in infant ALL.^{(1, 10, 12, 16, 20)}

In a review of the major infant ALL studies published to date ^{(1, 9-16)}, event free survival ranges as follows by risk factor:

In the European Infant Leukemia Trial, Interfant 99, preliminary analysis demonstrated that the two year EFS in a small group of prednisone good responders who did not have the MLL rearrangement exceeded 80 percent (personal communication, R. Pieters).

It remains difficult to compare outcome protocol to protocol and thus selecting the optimal treatment strategy for infants remains challenging. The reproducibility of outcomes observed in a population with a small sample can be quite difficult using similar therapy in a large patient population. Several larger trials of single arm therapy (Children’s Cancer Group study CCG-1953; Pediatric Oncology Group study POG 9407; Interfant –99) recently have been completed with results forthcoming.

In the largest group reported to date of similarly treated infants, the Children’s Cancer Group studies CCG 107 and 1883 registered 99 and 135 infants respectively with four year EFS of 33 percent and 39 percent.⁽¹¹⁾ These CCG studies confirmed that cranial irradiation for CNS treatment or prophylaxis was not necessary in the face of intensified systemic therapy including HDAC, CTX, intensified L-asparaginase, HDM and intrathecal therapy with methotrexate and araC.

In a most recent publication of outcomes on a collaborative group protocol, the Japanese have reported the EFS for 55 infants registered on two different trials between 1995-1998.⁽¹⁵⁾ Three year EFS was 34 percent overall though only 20 percent in those less than 6 months of age at diagnosis. For those with CNS disease at diagnosis, the EFS was particularly dismal at 10 percent.

Two recently completed concurrent North American pilots, CCG-1953 and POG 9407, shared an identical three-week induction followed immediately by induction intensification with two weeks of HDM (4 gm/m2/dose) and a five-day cycle of cyclophosphamide and etoposide. This intensification was designed to address the pattern of early relapse typical of infant ALL. Re-induction followed induction intensification. After completion of re-induction, infants on the CCG pilot with MLL rearrangements were to undergo stem cell transplant (SCT) with either matched related donors (MRD) or matched unrelated donors (MUD) while SCT was optional for the POG pilot. Therapy following re-induction diverged with the CCG infants receiving four courses of VHMTX at 33.6 gm/m2/dose and approximately two years of maintenance therapy. On POG 9407, consolidation similar to induction intensification with an additional cycle of HDAC followed re-induction. Maintenance therapy was short lasting only from weeks 18 to 46.

On CCG-1953, in rank order of significance, CD 10 negativity, age less than six months and MLL rearrangement all had a negative impact on prognosis.⁽²⁷⁾ On POG 9407, the prognostic factor of greatest relevance to outcome was age less than 90 days at presentation in which EFS was 17 percent — typical of that in most previous infant studies. In children greater than 90 days at diagnosis, presenting WBC (greater or less than 300,000 x10 9 /l) and the presence or absence of an MLL rearrangement within the blasts had far less impact on EFS than in previous studies: 52 percent vs. 56 percent for WBC and 52 percent vs. 65 percent for MLL status respectively. Early relapse at less than six to nine  months post diagnosis was nearly eliminated on this therapy incorporating early intensification. Extended maintenance on the CCG trial did not offer an EFS advantage for either the MLL rearranged or MLL germline infants when compared with the shorter therapy on POG 9407 (Dreyer, manuscript in progress).

Both studies, however, were associated with high toxic death rates related to bacterial, viral and fungal infections particularly during the dexamethasone based induction. Nearly two-thirds of events in both studies were toxic deaths. In the recently closed Children’s Oncology Group Infant ALL study (COG - P9407), a change in induction steroid from dexamethasone to prednisone as the only change in therapy from the original POG pilot, has resulted in a dramatic reduction in toxic deaths offering a better opportunity to assess the impact of this shortened, intensified therapy on outcome.

The role of SCT in first remission (CR-1) in infants is controversial.^{(14, 28-34)} Critically evaluating outcomes with SCT vs. aggressive systemic chemotherapy in first remission (CR-1) is dependent on comparing characteristics of the infant population including age, WBC, the presence of the MLL gene rearrangement, presence of extramedullary disease, donor source, preparative regimen and disease status at time of transplant.

The efficacy of transplant for MLL rearranged infants (CCG 1953 / POG 9407) and prednisone poor responders (Interfant 99) is under evaluation internationally. After completing identical prior therapy on the concurrent CCG/POG pilots, 48 infants underwent SCT in CR1 - the largest SCT study in infants in CR1. Preliminary results of this collaborative CCG – POG study demonstrated that compared with the control, MLL rearranged infants who received chemotherapy only, there was no advantage for SCT over the intensified chemotherapy delivered on protocol (personal communication, manuscript in preparation, P. Dinndorf).

It is anticipated that infants cured of their malignancies will experience a normal life span. For that reason, this population presents unique challenges to the pediatric oncologist. To maintain a normal, physically healthy and psychologically sound life, it is critical that infants survivors are followed closely for delayed effects of their therapy. Inherent in that challenge is the need to work to design therapies that are successful yet which avoid exposure to toxic therapies we know present the greatest risks such as excessive anthracyclines and radiation therapy.

While all organs in the rapidly growing and developing infant are potentially at risk from high dose therapy which includes potential cardiotoxins (anthracyclines), renal and hepatotoxins (methotrexate, cyclophosphamide, ifosfamide), pulmonary toxins (total body irradiation) and neurotoxins (vincristine, high dose methotrexate, high dose AraC, intrathecal chemotherapy and cranial irradiation / TBI), the most striking and severe late effects are those associated with radiation therapy delivered to the developing brain. Based on these debilitating late effects, POG and CCG lead the way in the elimination of cranial radiation for infant ALL despite high incidence rates of CNS disease at diagnosis averaging 25 percent.

Continued improvement in EFS in infant ALL is dependent on better using existing therapies as well as developing targeted therapies directed at the unique features present in the blasts of infants with ALL. Maximizing conventional agents through pharmacologically-based dosing will avoid under treatment and untoward toxicity.

Aggressive efforts to pilot novel agents targeted at infant blasts perhaps will play one of the most significant roles in successfully treating infant ALL. Identifying prognostic features of greatest impact on outcome will allow the development of risk-based therapy. The Children’s Oncology Group infant ALL successor study will build on the P9407 backbone using risk based therapy including a novel FLT-3 inhibitor in a randomized setting.

As in older children with ALL, the ability to complete randomized trials in a reasonable period of time with adequate statistical power is key. Though limited by available patient numbers in the past, international collaborative trials may permit large, randomized studies in the future.

About the author
ZoAnn Dreyer, M.D., is an associate professor of pediatrics at Baylor College of Medicine and medical director of the Long term Survivor Program at Texas Children’s Cancer Center. Dr. Dreyer is also renowned for her expertise in the treatment of acute lymphoid leukemia in infants. She was the principal investigator (PI) for the Pediatric Oncology Group (POG) protocol 9407 for infants with ALL and is currently the PI for the Children’s Oncology Group protocol P9407 used nationally for treating infant ALL.

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